Endo Flashcards

Question

Secondary/Tertiary Adrenal Insufficiency - general

Answer 1

Lots of causes - congenital vs acquired 1. Clinical manifestations a. ONLY manifestations of glucocorticoid deficiency (mineralocorticoids not affected) 2. Investigations a. Low-dose ACTH stimulation test 3. Treatment a. Iatrogenic i. Best avoided by using the smallest effective dose for the shortest period of time ii. Require adequate tapering dose to allow the body time to start producing its own hormone b. Anatomic lesions of pituitary i. Treatment indefinitely with glucocorticosteroids

Answer 2

• Family of autosomal recessive disorders of cortisol biosynthesis • Cortisol deficiency  increases secretion of ACTH  adrenocortical hyperplasia and overproduction of metabolites • Consequences depend on enzymatic step which is missing • Combination: 1. Mineralocorticoid deficiency or excess 2. Incomplete virilisation or precocious puberty in affected males 3. Virilisation or sexual infantilism in affected females

Answer 3

``` • CYP21A2 (21 hydroxylase) deficiency (17OHP up) o 95% of adrenal steroid defects o Autosomal recessive o 1/14,000 live births o CYP21A2 chromosome 6p o Impairs 17OP to 11 deoxycortisol o Most common cause CAH ``` • CYP11B1 (11-beta-hydroxylase) deficiency (11deoxycortisol up) o 5% of CAH o Cortisol synthesis is reduced o Excess deoxycortisone (which acts like aldosterone), adrenal androgen overproduction o Hypertension and virilisation of affected females • 3 Beta hydroxysteroid dehydrogenase deficiency o Rare o All steroid hormone synthesis impaired o Thus deficiencies in GC, MC and active androgens o Most present as neonates – feeding difficulties, vomiting, hypotension, hyponatremia, hyperkalemia o Affected females may have mild virilisation – males have varying degree of failure of gonad developments from hypospadias to severe ambiguity • CYP17 (17 alpha hydroxylase deficiency) o Rare o Although sufficient cortisol is not produced, large quantities of corticosterone (a steroid with both GC and MC activities) are synthesized, reducing symptoms of cortisol deficiency o HTN o Androgen and oestrogen synthesis are impaired – male patients have female external genitalia and a blind vagina, and affected females have primary amenorrhea and absent secondary sexual characteristics • Congenital lipoid adrenal hyperplasia – StAR deficiency – cholesterol unable to enter metabolic pathway o Most rare and most severe form o All major adrenal steroids inhibited o Adrenal glands are filled with lipid granules o Present as neonates with adrenocortical insufficiency – poor feeding, vomiting, lethargy, hypotension, resp distress, hyponatremia, hyperkalemia, hypoglycaemia and metabolic acidosis o Affected males have female genitalia, and affected females have normal

Answer 4

1. Key points a. >90% of CAH cases caused by 21-hydroxylase deficiency b. Autosomal recessive c. 3 main clinical phenotypes d. Classic CAH i. Severe salt wasting form (75%) = deficiency in both hormones ii. Simple virilising form (25%) = less-severely affected patients are able to synthesize adequate amounts of aldosterone but have elevated levels of androgens of adrenal origin e. Non-classic (late onset) i. Presents later in life with signs of androgen excess WITHOUT neonatal genital ambiguity 2. Genetics a. P450 enzyme hydroxylates i. Progesterone  11-deoxycoritocsterone  aldosterone ii. 17-hydroxyprogesterone  11-deoxycortisol  cortisol b. 21-hydroxylase mediates conversion of 17-hydroxyprogesterone to 11-deoxycortisol c. 2 steroid 21-hydroxylase genes – CYP21P and CYP21 i. CYP21 is the active gene ii. CYP21P is 98% identical to CYP21 but is a pseudogene because of 9 different mutations d. >90% of mutations causing 21-hydroxylase deficiency are recombinations between CY21 and CYP21P i. 20% are deletions generated by unequal meiotic crossing over ii. Gene conversion – caused by non-reciprocal transfer of deleterious mutations e. Deleterious mutations in CYP21P can have different effects on enzymatic activity of CYP21 i. Completely prevent synthesis ii. Missense mutations that yield enzymes with 1-50% of activity f. Disease severity correlates with mutations – ie. salt wasting disease results from mutations on both alleles that completely destroy enzymatic activity g. Closely adjacent to CYP21 is the TNX gene (encodes CT protein); patients with deletions of both have contiguous gene syndrome consisting of CAH and EDS

Answer 5

a. Aldosterone and cortisol deficiency i. Both cortisol and aldosterone require 21-hydroxylation for synthesis  both deficient in most severe form of disease ii. Signs and symptoms as per adrenal crisis notes  weight loss, anorexia, vomiting, dehydration, weakness, hypotension, hypoglycaemia, hyponatreamia, hyperkalaemia iii. Typically develop in affected infants at 10-14 days of life iv. Ineffective cortisol production  compensatory elevation in ACTH  adrenal cortex hyperplasia v. Accumulation of enzyme precursors  elevated levels of 17-hydroxyprogesterone + progesterone b. Prenatal androgen excess i. Accumulation of 17-hydroxyprogesterone  shunted into pathway for androgen biosynthesis  elevated levels of androstenedione  converted outside the adrenal gland to testosterone ii. FEMALES 1. Genitalia development b. Characterised by enlargement of clitoris (may resemble a penis) and by partial or complete labial fusion (common opening with urethra – urogenital sinus) c. Severity of virilisation is usually greatest in females with salt-losing form of 21-hydroxylase deficiency d. The internal organs are normal, because affected females have normal ovaries and no testes and therefore do not secrete anti-mullerian hormone 2. Sexually dysmorphic behaviors a. Elevated androgens may affect brain development b. Girls may demonstrate aggressive play behavior, play with masculine toys c. Women have decreased interest in maternal roles etc iii. MALES 1. Appear normal at birth 2. Therefore diagnosis may not be made until adrenal insufficiency develops c. Postnatal androgen excess i. Untreated or inadequately treated children of both sexes develop additional signs of androgen excess after birth ii. Boys with the simple virilising form often have delayed diagnosis as they appear normal iii. Signs of androgen excess 1. Rapid somatic growth 2. Accelerated skeletal maturation – tall in childhood but premature closure of epiphyses causes growth to stop relatively early, and adult stature is stunted 3. Muscular development may be excessive 4. Pubic and axillary hair may appear 5. Acne 6. Males – penis scrotum and prostate may become enlarged, testes are usually pre-pubertal size 7. Females – clitoris further enlarged, breast and menstruation may not occur unless production of androgens is suppressed iv. Similar but milder signs of androgen excess occur in non-classic 21-hydroxylase deficiency 1. Males and females may present with precocious pubarche and early development of pubic and axillary hair 2. Hirsutism, acne, menstrual disorders, and infertility occur d. Adrenomedullary dysfunction i. Development of the adrenal medulla requires exposure to the extremely high cortisol levels normally present within the adrenal gland ii. Thus patients with classic CAH have abnormal adrenomedullary function 1. Blunted adrenaline responses 2. Decreased blood glucose 3. Lower HR with exercise

Answer 6

Salt wasting - hyponatraemia - hyperkalaemia - dehydration

Answer 7

Adrenal crisis - shock - hypoglycaemia

Answer 8

Pigmentation Further stimulation of adrenal gland Adrenal hyperplasia

Answer 9

4. Clinical presentation a. Classic CAH i. Females with classic form (salt losing AND non-salt losing) = present with genital ambiguity 1. Rarely present with salt wasting if ambiguous genitalia not recognized 2. Note that there are NO palpable testes ii. Males 1. Salt losing = FTT, dehydration, hyponatraemia, and hyperkalaemia at 7-14 days of life (can present up to 21 days) 2. Non-salt losing = present at 2-4 year of age with early virilisation (pubic hair, growth spurt, adult body odour), often very advanced bone age at presentation b. Non-classical CAH females i. Milder defect of glucocorticoid pathway – non-salt wasting ii. Early pubic hair (pubarche), hirsutism, PCOS/secondary amenorrhoea iii. May be no symptoms 5. Investigations a. Electrolyte disturbance – can take 10-14 days after birth to develop i. Hyponatreamia ii. Hyperkalaemia iii. Metabolic acidosis iv. Hypoglycaemia b. Markedly elevated 17-hydroxyprogesterone – highest in morning, lowest at night i. Most reliably measured by taking sample 30-60 minutes after IV bolus of Cosyntropin (ACTH1-24) c. Cortisol levels – low (normal in patients with simple virilising disease, but inappropriately low in relation to ACTH and 17-hydroxyprogesterone levels) d. Androstenedione and testosterone – elevated in females e. Testosterone – not elevated in males, as normal infant males have higher testosterone levels f. Urinary 17-ketosteroids and pregnanetreiol – elevated g. ACTH – elevated (but not often tested over 17-hydroxprogesterone) h. Renin – elevated i. Aldosterone – inappropriately low for level of renin

Answer 10

a. Goals of treatment i. Replace adrenal hormones = life saving ii. Restore normal salt balance iii. Optimise growth b. Salt replacement i. Particularly important for infants c. Glucocorticoid replacement - also suppresses excess androgen production - often requires larger doses than other forms of adrenal insufficiency (15-20mg/m^2/d in 3 divided doses) - double/triple dose for stress dosing - monitor growth, puberty, bones, hormones (17OHprogesterone+adrostenedione) - overtreatment = iatrogenic Cushings - undertreatment = adrenal crisis and androgen excess (precocious puberty, rapid growth, advanced epiphyseal maturation, hair) - currently growth is compromised 8-10cm overall - can result in iatrogenic HTN d. Fludrocortisone replacement - normalise electrolytes, fluid balance, plasma renin - also require higher doses (0.1-0.3mg/d in 2 divided doses) - can often be tapered at 4-6mo of age, risk of HTN as kidneys become more sensitive - monitor HR, BP, renin e. Surgery i. Highly controversial f. Antenatal treatment (ONLY in a research setting) i. Use of antenatal dexamethasone treatment has been increasingly used – attempting to suppress excess androgen production early in weeks of gestation ii. Concerns regarding cognitive and developmental outcomes in those treated unnecessarily

Answer 11

1. Key points - still due to 21-hydroxylase deficiency a. Most severely affected individuals with classic CAH due to CYP21A2 deficiency present during neonatal period and early infancy with adrenal insufficiency with or without salt wasting b. "Nonclassic," or late-onset CYP21A2 deficiency, does not manifest with neonatal genital ambiguity; rather, it presents later in life with signs of androgen excess 2. Pathogenesis a. The severity of disease relates to the degree to which the mutations compromise enzyme activity b. In patients with the nonclassic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production, at the expense of excessive androgen production 3. Clinical presentation a. Present AFTER the neonatal period with signs of hyperandrogenism and WITHOUT adrenal insufficiency b. Premature pubarche – body odour, hirsutism, pubic hair i. Children with non-classic CYP21A2 deficiency differ from children with ordinary premature adrenarche in having advanced bone age c. Medication-resistant cystic acne d. Accelerated growth with tall stature i. These children may enter puberty early, with early epiphyseal closure resulting in short stature as an adult ii. Advanced bone age e. Female adolescents i. Clinical features 1. Acne 2. Hirsutism 3. Menstrual irregularity 4. Low fertility rates ii. DDx from PCOS 1. Non-classic CAH is uncommon in African-American individuals 2. Insulin resistance may be more severe, but probably not more common in PCOS 3. Polycystic ovaries on ultrasound 4. Obesity more common in PCOS

Answer 12

1. Key points a. Accounts for up to 5% of CAH b. 2nd most common type of CAH c. Results from mutation in CYP11B1 gene d. Also results in blockage of glucocorticoid + mineralocorticoid pathways (one step further than 21-hydroxylase) i. Adjacent CYP11B2 gene encoding aldosterone synthase is generally unaffected – able to synthesize aldosterone (Aldosterone synthase mediates the 3 final steps in the synthesis of aldosterone from deoxycorticosterone (11β-hydroxylation, 18-hydroxylation, and 18- oxidation)) - it is the absence of cortisol that drives inc ACTH and therefore inc androgens/DOC 2. Pathogenesis a. Blocks conversion of: i. DOC (deoxycorticosterone)  corticosterone (which then  aldosterone) ii. 11-DOC (deoxycortisol)  cortisol b. Consequences i. ↑ ACTH secretion ii. ↑ levels of DOC and 11-DOC 1. Shunted into androgen biosynthesis in similar manner to classical CAH 2. DOC has mineralocorticoid function iii. Some corticosterone is synthesized from progesterone by the intact aldosterone synthase enzyme and has weak glucocorticoid potency – therefore unusual for patients to manifest signs of adrenal insufficiency c. Summary i. Excess androgens – milder than 21-hydroxyalse ii. Excess mineralocorticoid activity (via DOC) iii. Cortisol insufficiency (NOT adrenal insufficiency) 3. Clinical manifestations a. Hypertension + hypokalaemia – characteristic b. Female newborns – ambiguous genitalia c. Boys – may have increased penile size d. Children not diagnosed at birth i. Premature adrenarche with advanced bone age 1. Somatic growth and bone age advance faster than idiopathic premature adrenarche e. If untreated i. Isosexual or contrasexual precocious puberty ii. Hirsutism and menstrual irregularities in adolescent girls 4. Investigations a. ↑ 11-Deoxycortisol and Deoxycorticosterone b. ↓ cortisol and corticosterone c. ↓ Renin 5. Differential diagnoses a. Hypertension and hyperkalaemia – distinguishes 11OHD from 21OHD and HSD3B2 deficiency b. Androgen excess – distinguishes 11OHD from 17OHD 6. Treatment a. Hydrocortisone b. Fludrocortisone not necessary – may even require spironolactone to antagonize the androgens and mineralocorticoids

Answer 13

AKA Conn syndrome Key features a. Excessive aldosterone secretion INDEPENDENT of RAAS b. Rare in children but account for 5-10% of HTN in adults c. Although usually sporadic, some familial forms 2. Etiology a. Aldosterone-secreting adenomas i. Reported in children as young as 3.5 years ii. More common in girls b. Bilateral micronodular adrenocortical hyperplasia i. Tends to occur in older children ii. More common in males c. Unilateral hyperplasia 3. Clinical manifestations a. Often asymptomatic – hypertension detected incidentally b. Others have severe hypertension with headache, dizziness, visual disturbance c. Chronic hypokalaemia can lead to polyuria, nocturia, enuresis and polydipsia d. Muscle weakness and discomfort, tetany, intermittent paralysis + growth failure affects children with severe hypokalaemia 4. Investigations a. Hypokalaemia b. Serum pH, CO2, Na+ = may be ↑ c. Serum chloride and Mg = may be ↓ d. Plasma levels of aldosterone = ↑ e. Plasma renin = ↓(suppressed) f. Urine i. Urine = neutral or alkaline ii. Urinary potassium excretion = high iii. 24 Urine aldosterone = high g. Diagnostic test i. Controversial diagnostic test of choice ii. Renin and aldosterone vary based on time of day, posture, sodium intake iii. Affected by diuretics, beta blockers, ACI, ARB, clonidine, NSAIDs iv. Plasma aldosterone: renin = high v. Aldosterone does NOT decrease with administration of saline solution or fludrocortisone vi. Renin does not respond to salt and fluid restriction 5. DDx a. Primary aldosteronism should be distinguished from glucocorticoid suppressible hyperaldosteronism – which can be treated with glucorticoids b. Glucocorticoid suppressible hyperaldosteronism is diagnosed by dexamethasone suppression test 6. Treatment a. Aldosterone-secreting adenoma = surgical excision b. Bilateral adrenal hyperplasia = spironolactone or eplerenone i. Normalise BP and potassium

Answer 14

1. Key points a. Rare in childhood b. Occur in all age groups – more commonly in children <6 years c. 2-10% of cases – bilateral d. Almost half of childhood adrenocortical tumours are carcinomas e. Symptoms of endocrine hyperfunction are present in 80-90% of children f. Tumours may be associated with hemihypertrophy g. Also associated with other congenital defects, particularly genitourinary tract and CNS abnormalities and hamartomatous defects h. Aldosterone secreting adenomas are a separate category from other adrenocortical tumours – very rarely malignant 2. Etiology a. Familial cancer syndromes i. Li Fraumeni = p53 tumour suppressor (TP53) ii. Multiple endocrine neoplasia = menin (MEN1) iii. Familial adenomatous polyposis = APC iv. PRKAR1A gene b. Other i. Over-expression of IGFF2 in 80% of sporadic childhood adrenocortical tumours (also in Beckwith-Wideman syndrome – loss of imprinting of genes on this chromosome) 3. Clinical manifestations a. Virilisation = most common presenting symptom in children with adrenocortical tumours  50-80% i. Males = accelerate growth velocity and muscle development, acne, penile enlargement, precocious development of pubic and axillary air (similar to CAH) ii. Females = masculinization of previously normal female (clitoral enlargement, growth acceleration, acne, deepening of voice, premature pubic and axillary air) b. High oestrogens (10%) – due to over-expression of CYP19 aromatase i. Males = gynecomastia ii. Female = premature thelarche c. Cushing’s syndrome = 15-40% i. Isolated virilisation frequently occurs alone, children with adrenal tumours do not have Cushing syndrome alone 4. Investigations a. Androgens elevated, often markedly (Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), androstenedione) b. Testosterone = increased (due to peripheral conversion) c. Oestrone and oestradiol = elevated in patients with feminizing signs d. Urinary 17-ketoteroids (sex steroid metabolites) = elevated e. Imaging (USS, CT, MRI) 6. DDx of virilisation i. Virilising forms of adrenal hyperplasia ii. Exposure to androgens such as topical testosterone 7. Treatment a. Surgical removal

Answer 15

Term used to describe signs of prolonged glucocorticoid excess

Answer 16

Cushing syndrome due to pituitary adenoma secreting ACTH

Answer 17

1. Key points a. Cushing’s syndrome – term used to describe prolonged glucocorticoid excess b. Cushing’s disease – Cushing’s syndrome caused by a pituitary adenoma secreting ACTH c. Caused by abnormally high blood levels of cortisol or other glucocorticoids d. Most commonly caused by exogenous administration of glucocorticoid hormone

Answer 18

Cushing disease - pituitary adenoma secreting ACTH | 68%

Answer 19

a. ACTH-dependent i. Cushing disease (68%) 1. Excess ACTH secreted by pituitary adenoma  bilateral adrenal hyperplasia 2. Rare in infants, most common aetiology in children >7 years 3. Usually micro-adenoma 4. Mostly sporadic 5. Syndromes associated with pituitary adenomas a. Familial isolated pituitary adenoma syndrome i. Mutation in the aryl hydrocarbon receptor interactive protein (AIP) gene ii. Accounts for 2% pituitary adenomas b. Multiple endocrine neoplasia (MEN1) – however typically prolactinomas ii. Ectopic ACTH production (12%) 1. Uncommon in children 2. Cause = Islet cell carcinoma of the pancreas, neuroblastoma or ganglioneuroblastoma, hemangiopericytoma, Wilm’s tumour, thymic carcinoid 3. Hypertension more common in ectopic ACTH syndrome than other forms of Cushing syndrome as very high cortisol levels overwhelm 11-beta-hydroxysteroid dehydrogenase in the kidney, therefore enhanced mineralocorticoid effect b. ACTH-independent i. Iatrogenic ii. Adrenal adenoma (10%)/carcinoma (10%) – primary excess cortisol production iii. Several syndromes associated with autonomously hyperfunctioning nodules of adrenocortical tumour (rather than single adenomas or carcinomas) 1. Primary pigmented nodular adrenocortical disease (PPNAD) a. Isolated or occurs as familial disorder with other manifestations b. Adrenal glands are small 2. McCune-Albright syndrome = precocious puberty + fibrous dysplasia + café au lait a. Nodular hyperplasia and adenoma formation b. Begins in infancy Pseudo Cushings - alcoholism (1%) - major depressive disorder (<<1%)

Answer 20

3. Clinical manifestations a. Moon facies b. Generalised obesity in younger children, severe obesity of face + trunk compared with extremities in children c. Adrenal tumours – signs of abnormal masculinization (hirsutism on the face or trunk, pubic hair, acne, deepening voice, enlargement of clitoris) d. Impaired growth – results in short stature e. Hypertension f. Increased susceptibility to infection g. Purplish striae on hips, abdomen and thighs h. Pubertal development may be delayed – amenorrhoea may occur past menarche i. Weakness, headache, emotional lability j. Hypertension and hyperglycaemia, can result k. Osteoporosis and pathological fractures ``` Fat • Central weight gain • Moon facies • Dorsal fat pad (hump) Protein • Proximal muscle wasting • Thin skin • Bruising • Striae (decrease collagen in SC tissue) CHO • Hyperglycaemia (diabetogenic) Haematological • Immune suppression • Recurrent infection • Poor wound healing Endocrine • Osteoporosis • Poor growth • Acne, hirsutism, frontal alopecia • Amenorrhoea, delayed puberty CVS • Hypertension (mineralocorticoid effect) CNS • Depression • Psychosis ``` +/- hyperpigmentation in ACTH excess (MSH (melanocyte stimulating hormone) from ATCH proteolysis from POMC (pro-opiomelanocortin)) +/- bitemporal hemianopia in Cushing’s disease

Answer 21

Establish hypercortisolaemia Look for cause a. Confirm elevated cortisol levels (serum/saliva/urine) i. Midnight cortisol level = elevated 1. Highest at 0800 and decrease to less than 50% by midnight (except in infants and young children when diurnal pattern not always established) 2. Midnight cortisol levels >4.4ug/dL 3. Serum or saliva ii. Urinary excretion of free cortisol = elevated 1. Best measured in 24 hour urine sample and expressed as micrograms of cortisol per creatinine iii. Low dose dexamethasone suppression test – dose of dexamethasone at 2300 > cortisol at 0800 1. Normal = <5 ug/dL (you should have suppressed cortisol production if given a big dose) 2. Elevated in Cushing’s disease (autonomous cortisol production) b. Determining cause of elevated cortisol (dex suppression test, imaging) i. 2 step dexamethasone suppression test – determine if ACTH dependent on independent 1. Low dose then high dose dexamethasone in 4 doses over 2 days 2. At 24 hours – low dose result a. No suppression of cortisol confirms diagnosis Cushing’s 3. At 48hours – high dose result - cortisol will be suppressed in ACTH dependent Cushings, as high dose dex suppresses ACTH ii. Paired ACTH level 1. ↓ in patients with cortisol producing tumour, exogenous steroids 2. ↑ with ACTH secreting tumour (but may be normal in ACTH-secreting pituitary adenoma) iii. CRH 1. IV bolus of CRH 2. ACTH-dependent Cushing’s = exaggerated ACTH and cortisol response 3. ACTH-independent (eg. adrenal tumour) = no increase to ACTH c. Other i. Glucose tolerance test – often abnormal but not diagnostic ii. Electrolytes – usually normal 1. Potassium may be decreased in patients who have ectopic ACTH production d. Imaging i. CT = adrenal tumours 1. Unilateral = tumour 2. Bilateral hyperplasia = usually due to ACTH production ii. MRI = pituitary tumours

Answer 22

a. Dependent on cause b. Pituitary adenoma (Cushing’s disease) = resection c. Cyproheptadine (serotonin antagonist) = used in adults but rarely used in children d. Inhibitors of adrenal steroidogenesis (metyrapone, ketoconazole, aminoglutethimide, etomidate) have been used pre-operatively e. Mifepristone = glucocorticoid receptor antagonist, sometimes used f. Somatostatin analogue = can inhibit ACTH secretion g. Adrenalectomy = very rarely done i. Results in increased ACTH and marked pigmentation if there is a pituitary adenoma – Nelson syndrome

Answer 23

1. Key points a. Catecholamine secreting tumours arising from chromaffin cells i. Produce adrenaline, noradrenaline and dopamine  symptoms b. 10% occur in children – present between 6-14 years of age c. 80% associated with familial disorder d. 50% malignant – require lifelong surveillance e. Features i. Vary in size from 1-10cm ii. More often on the R) side than the L) iii. In >20% adrenal tumours are bilateral – more likely if familial iv. 30-40% tumours found in both adrenal and extra-adrenal areas or only in extra-adrenal areas f. Location i. Adrenal medulla (90%) ii. Can develop anywhere along the abdominal sympathetic chain iii. Extra-adrenal = paraganglioma 2. Etiology a. Von Hippel Lindau disease i. Retinal and CNS haemangioblastomas, renal cell carcinoma, phaeochromocytoma ii. Germline mutation in VHL tumour suppressor gene b. Multiple endocrine neoplasm MEN2A and MEN2B i. Medullary thyroid cancer and parathyroid tumour, 50% develop phaeochromocytoma ii. Mutations in RET proto-oncogene c. Neurofibromatosis type 1 (NF1) or TS d. Sturge-Weber syndrome e. Ataxia-telangiectasia

Answer 24

3. Clinical manifestations a. Detected by surveillance in children with known genetic syndromes b. Symptoms present in 50% of patients c. Classic triad = headache, sweating, tachycardia d. Key features i. Hypertension – results from excessive secretion of adrenaline and noradrenaline 1. Paroxysmal hypertension particularly suggestive of phaeochromocytoma 2. More often sustained in children ii. Attacks of symptoms – headache, palpitations, abdominal pain, dizziness, pallor, vomiting, sweating iii. Convulsions and other manifestations of hypertensive encephalopathy e. Other points i. Symptoms may be exacerbated by exercise ii. Good appetite due to hypermetabolic state but may not gain weight iii. Polyuria and polydipsia can occur iv. Growth failure v. Opthal examination – papilloedema, haemorrhages, exudate, arterial constriction vi. Cardiomyopathy 4. Investigations a. Urinary noradrenaline + metanephrines (particularly normetanephrine) + total catecholamine excretion i. All elevated in phaeochromocytoma ii. Children with phaeochromocytoma secrete noradrenaline in the urine (cf adults who secrete noradrenaline and adrenaline) iii. If normal but suspicious – re-check during paroxysm b. Plasma free catecholamines and metanephrines = elevated c. Imaging = abdominal CT/MRI  MIBG/PET if negative d. Genetic panel = SDH panel, VHL, RET (MEN2), NF1 5. DDx a. DDx of hypertension in children b. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma – frequently produce catecholamines i. Urinary levels of most catecholamines are higher in patients with phaeochromocytoma ii. Levels of dopamine and homovanillic acid higher in neuroblastoma

Answer 25

Surgery 6. Treatment a. Surgical excision i. MEN2 – bilateral adrenalectomy due to the recurrence risk ii. VHL – cortical-sparing bilateral adrenalectomy b. Careful peri-operative management i. Goals 1. Control hypertension – to avoid hypertensive crisis during surgery 2. Control tachycardia 3. Volume expansion ii. Treatment 1. Alpha blocker (phenoxybenzamine) for 7-14 days, followed by beta blocker (propranolol) to control tachycardia 3-4 days prior to surgical resection a. NEVER start beta blocker first – risk of worsening hypertension 2. High sodium diet – catecholamine-induce volume contraction and orthostasis associated with alpha adrenergic blockade 7. Malignant pheochromocytoma a. 10% malignant – paragangliomas more likely malignant b. Histology identical for benign vs malignant c. Diagnosis of malignant phaeochromocytoma is based on documentation of metastatic disease i. Only accurate indicator of malignancy are the presence of metastatic disease or local invasion that precludes complete resection d. No curative treatments for metastatic phaeochromocytoma unless the sites of disease are surgically resectable

Answer 26

i. Insulin independent 1. Brain = GLUT1 2. B islet cells, liver, kidney + small intestine (basolateral) = GLUT2 3. Neurons = GLUT3 4. GI tract (apical – fructose transport) + spermatocytes = GLUT5 ii. Insulin dependent 1. Skeletal muscle + adipocytes = GLUT4

Answer 27

a. Peptide hormone b. Half-life = ~ 6 minutes, usually cleared from circulation by 10-15 minutes c. Insulin synthesis i. Pre-pro-insulin = produced in the ribosome of the RER ii. Pro-insulin = cleavage product, packaged into vesicles iii. Insulin = cleavage product inside vesicles, results in C-peptide + insulin d. Normal secretin of insulin i. Pulsatile (periodicity of 9-14 minutes) ii. Loss of pulsatility = one of the earliest signs of beta cell dysfunction f. Insulin secretion i. Glucose enters B cell of pancreas via GLUT-2 transporter ii. Glucose is phosphorylated to glucose-6-phosphate by glucokinase iii. Glucose-6-phosphate can then be metabolised to generate ATP iv. ↑ ATP leads to closure of ATP-sensitive K channel (K-ATP) v. Closure of channel = intracellular accumulation of potassium = depolarisation of membrane vi. Calcium channels open vii. Influx of calcium leads to secretion of insulin g. Insulin receptor i. Insulin interacts with other cells via an insulin receptor ii. Receptor has two alpha subunits (lie OUTSIDE the cell) and two beta subunits (lie INSIDE the cell) iii. Insulin binds to alpha subunits  activates tyrosine kinase  phosphorylation of insulin receptor substrates iv. Activates a pathway that causes the cell to increase uptake of glucose via GLUT-4 transporters h. Actions of insulin i. Glucose transport in skeletal muscle + adipose tissue ii. Glycogen synthesis and storage iii. Triglyceride synthesis iv. Na+ retention at kidneys v. Protein synthesis vi. Cellular uptake of K+ and amino acids vii. ↓ glucagon release

Answer 28

a. Peptide hormone produced by alpha cell – has extracellular receptors b. Opposite to insulin (counter-regulatory hormones) c. Glucagon works with other counter-regulatory hormones – adrenaline, cortisol, growth hormone i. All these hormones are required to counteract insulin d. The only site of action of glucagon (clinically) is the liver e. Stimulates the use of non-carbohydrate sources in gluconeogenesis

Answer 29

a. Glycolysis – glucose series of steps to form 2 x pyruvic acid i. Anaerobic fermentation – occurs without oxygen – pyruvic acid to lactic acid 1. Lactic acid metabolized in liver in presence of oxygen 2. Only in some tissues, predominantly skeletal muscle, not brain ii. Aerobic respiratory – in presence of oxygen – pyruvic acid via Kreb cycle and electron transport chain to produce carbon dioxide + water + 38ATP 1. Occurs in mitochondria b. Glycogenolysis i. Glycogen stored in liver (1/4), skeletal muscle (3/4), other tissues ii. Broken down to feed glycolysis iii. Triggered by glucagon and adrenaline iv. Glycogen synthesized in times of CHO excess – triggered by insulin c. Gluconeogenesis i. Formation of glucose from FFA and AA ii. Triggered by glucagon and adrenaline

Answer 30

a. Lipolysis i. Triggered by: adrenaline, noradrenaline, corticosteroids, thyroid hormone, growth hormone ii. Triglycerides broken down into FFA + glycerol iii. Glycerol broken down via glycolysis + anaerobic/aerobic metabolism iv. FFA broken down via beta oxidation into acetyl CoA to feed into TCA cycle v. Excess acetyl CoA taken to liver and undergoes ketogenesis: 1. Ketone bodies - B-hydroxybutyrate, acetoacetic acid, acetone b. Gluconeogenesis i. Glucose can be made from glycerol from lipolysis c. Lipogenesis i. Triggered by: insulin + intestinal hormones ii. Glycolysis from excess glucose and AA/FFA via gluconeogenesis forms glycerol iii. FFA produced from TCA cycle iv. Form TG

Answer 31

a. Breakdown i. Protein breakdown 1. Source of AA from breakdown cells/enzymes/food 2. Broken down into ketoacids + NH2 via deamination 3. Ketoacids enter glycolysis or TCA cycle for energy 4. NH2 transferred to liver, forms ammonia 5. Ammonia enters ornithine cycle to form urea (excreted in urine) ii. Gluconeogenesis 1. Ketoacids produced from AA break down can enter glycolysis – reversed to form glucose b. Synthesis i. Triggered by insulin ii. Non-essential AA can be synthesized from TCA cycle intermediates iii. Essential AA from diet only

Answer 32

1. Type I diabetes (beta cell destruction leading to deficiency) 2. Type 2 diabetes (variable combinations of insulin resistance and deficiency) 3. Genetic defects of beta cell function a. Maturity onset diabetes of the young (MODY 1-6, different mutations associated with each) b. Mitochondrial DNA mutations – includes 1 form of Wolfram syndrome, Pearson syndrome, Kearns-Sayre, diabetes mellitus, deafness c. Wolfram syndrome – DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness): WFS1-Wlframin chromosome 4p d. Thiamine responsive megaloblastic anaemia and diabetes 4. Drug or chemical induced a. Anti-rejection = cyclosporine, sirolimus b. Glucocorticoids (with impaired insulin secretion eg. CF) c. Many others 5. Diseases of exocrine pancreas a. CF-related diabetes b. Trauma – pancreatectomy c. Pancreatitis – ionising radiation d. Others 6. Infections a. Congenital rubella b. CMV c. HUS 7. Variants of type 2 diabetes a. Genetic defects of insulin action b. Acquired defects of insulin action i. Endocrine tumours – rare in children c. Phaeochromocytoma d. Cushings e. Others – anti insulin receptor antibodies 8. Genetic syndromes with diabetes and insulin resistance/ insulin deficiency a. Prader-willi syndrome b. Down syndrome c. Turner syndrome d. Klinefelter syndrome e. Others = Bardet-Biedel, Alstrom, Werner f. IPEX g. Celiac disease 9. Gestational diabetes 10. Neonatal diabetes - transient, permanent

Answer 33

1. Epidemiology a. Most commonly presents in childhood – ¼ are adult cases b. Most common form of diabetes in childhood c. Bimodal distribution – peak at 4-6 years of age, and another at 10-14 years of age 2. Inheritability a. 85% of newly diagnosed have NO family history b. Risk increases with increasing amounts of affects relatives 3. Aetiology a. Genetic susceptibility i. HLADR3/DR4 + DQ2/8 1. Results in 1/20 risk of T1DM compared with 1/300 population risk 2. In sibling, base line risk is 1-2 %, increases if they share these HLA types b. Other/environmental/unknown 4. Pathophysiology a. Thought to start with some sort of trigger in a susceptible host b. Leads to autoimmune destruction of beta cells  primarily T cell mediated damage c. Onset of clinical disease occurs when 90% beta cell mass is destroyed 1. ↑ serum glucose = glucosuria  polyuria, polydipsia, fatigue 2. Protein breakdown  weight loss, polyphagia 3. Lipolysis  FA + glycerol  ketones  ketoacidosis 5. Natural history a. Initiation of autoimmunity b. Preclinical autoimmunity with progressive destruction of beta cells i. May have episodic glycosuria when stressed ii. 80% have auto-antibodies to islet cell antigens iii. Eventual ↓ insulin response to glucose load c. Onset of clinical disease d. Transient remission = honeymoon period i. Improvement in residual beta cell function when therapy is commenced ii. 75% have ↓ insulin requirements, <5% will not need insulin e. Established disease f. Complications

Answer 34

1. Clinical manifestations a. Classic triad i. Polyuria 1. Serum glucose exceeds the renal threshold for glucose -> glycosuria 2. Glycosuria causes an osmotic diuresis and hypovolaemia 3. May present with – nocturia, bedwetting, daytime incontinence ii. Polydipsia 1. Enhanced thirst due to increased serum osmolality from hyperglycaemia and hypovolaemia 2. Patients may often not have classic signs of dry mucous membranes or decreased skin turgor iii. Weight loss 1. Results from hypovolaemia and increased catabolism 2. Insulin deficiency impairs glucose utilisation in skeletal muscle and increases fat and muscle breakdown 3. Initially appetite is increased, but over time children are more thirsty than hungry, and ketosis results in nausea and anorexia, contributing to weight loss b. Other symptoms i. Perineal candidiasis – relatively common in young children particularly girls ii. Visual disturbance – alteration in osmotic milieu of the lens c. Diabetic ketoacidosis d. Silent (asymptomatic) 2. Specific phenomenon a. Dawn phenomenon i. Early morning (2-8am) hyperglycaemia due to overnight GH secretion + ↑ insulin clearance ii. Occurs in peri-pubertal + pubertal years, may result in sub-optimal morning insulin levels iii. Manage with ↑ evening protophane dose b. Somogyi phenomena i. Rebound hyperglycaemia from late night/ early AM hypoglycaemia ii. Due to exaggerated counter regulatory response

Answer 35

a. Diagnostic criteria = one of the following i. Fasting (>8 hours) BSL >7 mmol/L on more than one occasion ii. Random BSL >11.1 mmol/L on more than one occasion in a patient with symptoms of hyperglycaemia iii. BSL >11.1 two hours after oral glucose load of 1.75 g/kg (max 75g) in OGTT (rarely done) iv. HbA1c >6.5 – not established as diagnostic for diabetes in children b. Autoantibodies i. Key points 1. Positivity at an early age is associated with rapid progression to clinical disease 2. The higher number of pancreatic autoantibodies and the younger the age at detection – increases risk of developing T1DM at a younger age ii. Islet cell antibodies = present in 70-90% (1 antibody = 30% progress to DM, 2 antibodies = 70% progress to DM, 3 antibodies = 90% progress to DM) iii. Progression of antibodies: insulin > GAD 65 > IA-2 Islet cell cytoplasmic antibodies (ICA) • First autoantibodies discovered • Measures a group of islet cell autoantibodies targeted against a range of islet cell proteins • 70% in newly diagnosed T1DM and their first degree relatives • Only a small percentage of individuals with ICA positivity will develop T1DM Anti-insulin antibodies (IAA) • Usually detected at T1DM diagnosis • Present in 50% of children • Tends to appear first – disappears with insulin therapy • Correlates inversely with age at onset of diabetes Anti-glutamic acid decarboxylase (anti-GAD) • Unclear significance • One of the most commonly detected antibodies • 70-80% have antibody detectable at time of diagnosis • Often present before clinical manifestations • Remain positive for a long time after diagnosis Anti-insulinoma protein 2 (anti-IA2) • Appears later than insulin and GAD • Present in 50-75% of newly diagnosed • Considered the best predictive marker for T1DM development Anti-zinc transporter (anti-ZNT8) • Present in 60-80% • Specifities of 99% and sensitivity of 70% • Levels decrease rapidly over time

Answer 36

Autoimmune thyroid disease • 20% of patients with T1DM have positive anti-thyroid antibodies (anti-thyroid peroxidase and/or anti-thyroid globulin) o 2-5% develop hypothyroidism o 1% develop hyperthyroidism (much rarer, but more common than general population) • Anti-TPO and thyroglobulin at diagnosis • All children should be screened regularly by measuring TSH Coeliac disease • 7-15% of children with T1DM develop celiac disease within the first 6 years of diagnosis • Clinical manifestations o Unpredictable BSL o Recurrent hypoglycaemia o Poor glycaemic control o Growth failure (GIT symptoms less likely) • Anti-tTG and IgA levels • If positive –biopsy • If negative – re-screening two years after diagnosis and then five years after diagnosis Adrenal disease • <1% of children with T1DM have autoimmune adrenalitis • 2% of children with T1DM have circulating antibodies to 21-hydroxylase • Clinical manifestations o Decreased insulin requirements o Increased frequency of hypoglycaemia Gastric autoimmunity • Circulating antibodies to gastric parietal cells and to intrinsic factor are 2-3x more common in patients with T1DM Vitiligo • Prevalence in general population 0.5% - 10-20x more common in those with T1DM • In children with T1DM prevalence of 6%

Answer 37

a. Aims of management i. Achieve normal physical and psychological development ii. As little restriction on lifestyle and occupation as possible iii. Minimize long term macrovascular and microvascular complications b. Management principles i. Multidisciplinary team – paediatrician, diabetes nurse educator, social worker + psychologist ii. Three key influences on blood glucose – exercise, insulin, diet iii. Usually 4 appointments per year c. Lifestyle = SNAPO i. Smoking – avoid ii. Nutrition – CHO 50% and low GI, fat 30% with saturated <10%, protein 20% iii. Alcohol – not recommended iv. Physical activity – recommended with company, rescue jelly beans, and testing before, during + after v. Obesity – avoid d. Dietary recommendations i. Include at least 1 low GI food at every meal and snacks ii. Never skip meals iii. Three major meals and 3 snacks iv. CHO counting 1. 500 rule: Rapid acting insulin:carbohydrate ratio = 500/TDD of insulin a. E.g. TDD 50 units. 500/50 = 10. 1 unit of insulin should cover 10g carbohydrate 2. 100 rule for corrections: 100/TDD = insulin sensitivity factor a. E.g. TDD 50 units. 100/50 = 2. Every 1 unit of insulin will lower your BGL by 2 units f. Regimens i. Basal bolus = usually lantus + TDS novorapid 1. TDD of 1 unit/kg/day 2. 0.4 unit/kg as basal insulin (long acting) at 2000-2100 3. Give the remainder as rapid acting insulin in 3 equal doses before meals (0.2 U/kg before each meal) 4. Good for motivated individuals 5. Much better control, ↓risk of Dawn / Somogyi phenomenon ii. BD = usually BD levemir + novorapid 1. TDD of 1 unit/kg/day 2. Usually commenced in children <10 years 3. Usually commenced with a total daily dose of 1 unit/kg/day a. 2/3 TDD in morning b. 1/3 TDD in evening 4. 2/3 intermediate acting, 1/3 short acting iii. Insulin pump g. Target BSLs = pre-prandial 4-8 - treat hypoglycaemia <4, ketosis >1 h. Side effects i. Hypoglycaemia ii. Lipohypertophy at injection sites iii. Hypersensitivity – uncommon iv. Insulin antibodies v. Nearly all develop antibodies after several moths vi. May promote unstable BSL (most = no effect)

Answer 38

a. HbA1c = glycosylated Hb i. Reflects last 2-3 month control ii. Target is 7.5, < 7 normal iii. Falsely low = haemolytic anaemias, pure red cell aplasia, blood transfusions, anaemias associated with haemorrhage, cirrhosis, myelodysplasias, renal disease treated with EPO b. Fructosamine = glycosylation of serum proteins i. Reflects 1-2 week control ii. Useful in haemoglobinopathies (HbA1c spuriously ↓/↑)

Answer 39

a. DKA is the leading cause of death in children and adolescents with T1DM b. In adults with T1DM – vascular complications, DKA and hypoglycaemia are all causes of death

Answer 40

1. RETINOPATHY a. Leading cause of blindness in young adults b. Risk after 15 years (98%) c. Associated with longer duration of diabetes and poorer glycaemic control e. Treatment i. Laser photocoagulation ii. Vitrectomy – advanced eye diseases with severe vitreous haemorrhage or fibrosis f. Diabetic maculopathy = severe macular edema manifested by impaired central vision 2. NEPHROPATHY a. Earliest sign of diabetic nephropathy is increased albuminuria – defined as albumin excretion between 30-300 mg/day (20-200 mcg/min) b. 30-40% of patients with T1DM develop ESRD c. Treatment i. Control of BSL ii. Control of BP iii. ACE-I iv. Dietary – reduced protein 3. NEUROPATHY a. Symptomatic diabetic neuropathy is uncommon in children and adolescents b. Increases with poor glycaemic control and duration of disease c. Peripheral neuropathy i. Earliest evidence is distal sensory loss (distal symmetric sensorimotor polyneuropathy) affecting ‘gloves and stockings’ distribution - best detected with monofilament d. Autonomic neuropathy i. Includes – abnormal HR variability and BP control, pupillary adaptation to darkness, and vibratory threshold ii. Puberty is a critical time for development of diabetic cardiac autonomic dysfunction 4. CEREBROVASCULAR a. Major cause of morbidity and mortality in adults with T1DM b. Children with T1DM have reduced LV size and decreased SV even in the absence of HTN or nephropathy c. Dyslipidaemia, atherosclerotic changes and vascular stiffness 5. OTHER a. Autoimmune diseases b. Growth i. Poor glycaemic control can result in poor linear growth, poor weight gain, and/or delayed skeletal and pubertal development ii. Excessive insulin and/or caloric intake can lead to weight gain 1. If obesity develops, this can lead to insulin resistance, complicating diabetes management c. Gastroparesis i. Post-prandial antral hypomobility occurs in 30-50% of individuals with longstanding T1DM ii. Results in N+V, abdominal pain and constipation following meals iii. Can contribute to poor glycaemic control and early satiety d. Necrobiosis lipoidica i. Inflammatory skin condition associated with diabetes seen in 1-2% of children ii. More common in those with poorer glycaemic control iii. Asymptomatic skin lesions usually occur on the shin as oval or irregularly shaped, indurated plaques with central atrophy and yellow pigmentation e. Limited joint mobility i. Primarily affecting hands and feet – skin usually thick and waxy in appearance f. Menstrual irregularity g. Paronychia h. Mauriac syndrome

Answer 41

1. Key points a. Severe hypogylcaemia most common during the night, when the glucose threshold for counter-regulatory hormone responses (sympathoadrenal) is lower  less likely to wake with symptoms b. Symptoms – correlate with sympathetic response; therefore autonomic neuropathy  decreased awareness due to decrease in adrenalin response to hypoglycaemia 2. History – recurrent hypoglycaemia a. Severe, moderate, mild b. Time of day c. Hypoglycaemic unawareness, blood glucose level where patient detects symptoms d. HbA1c e. Change in insulin dose, insulin type or insulin timing f. Exclude celiac disease, Addison’s disease, autoimmune thyroiditis 3. Symptoms a. Stimulation of sympathetic nervous system = anxiety, palpitations, tachycardia, pallor, perspiration, headaches, abdo pain b. Effects on CNS = lethargy, dizziness, ataxia, weakness, confusion, personality changes, visual disturbance, unconsciousness, localized and generalized convulsions 4. Causes a. Missed meal/snack b. Vigorous exercise c. Alcohol d. Too much insulin 5. Management – Acute a. All BSLs <4 mmol/L need to be treated regardless of the signs and symptoms b. Give 5-10g of high GI (quick acting) carbohydrate c. Wait 15 minutes – perform another BSL i. If <4 mmol/L – give another 5-10g of CHO ii. If >4 mmol – give 10-15 of low GI CHO d. Severe hypoglycaemia i. If BSL is <4 and child is unconscious, low GCS or having a seizure – give glucagon 1. 0.5ml = children <25 kg or <6 years 2. 1ml = children >25kg or >6 years ii. Takes 5-15 minutes to work

Answer 42

1. Cause = missing insulin, illness 2. Ketones should be checked when a. BSL >15 mmol/L b. Child appears unwell 3. Treatment required if ketones >1.0 mmol/L – dependent on BSL BSL >15 mmol/L • Give 10% of total daily insulin dose using rapid acting insulin (Novorapid or Humalog) immediately o If insulin is due, add 10% of total daily insulin dose to normal insulin dose o If insulin is not due, give 10% of total daily insulin dose as an extra injection immediately • Check ketones in 2 hours and seek medical advice if ketones remain > 1.0 mmol/L • Extra insulin may be required if BGL remains >15mmol/L & ketones remain > 1.0 mmol/L after 2 hours

Answer 43

1. General principles a. Treat underlying illness, facilitate regular intake b. Monitor BSLS 1-4 hourly, check ketones if BSL > 15 c. Do NOT omit insulin, may have to reduce dose d. Give extra insulin if BSL > 15 + ketones (short acting only, 5-20% more) 2. Illnesses causing high BSLs = bacterial and viral a. As above b. Encourage sugar free fluids to maintain hydration 3. Illnesses causing low BSLs = vomiting, diarrhoea, decreased appetite a. As above b. Sip on sugar containing fluids c. Mini doses of glucagon may be used to treat hypoglycaemia if unable o tolerate food or fluids

Answer 44

1. Overview a. Approximately 25% present in DKA – highest risk in toddlers and teenagers b. DKA definition = hyperglycaemia + metabolic acidosis + ketonaemia c. Biochemical criteria = venous gas <7.3 + blood or urinary ketones d. Cause i. May be first presentation for a child with previously undiagnosed diabetes ii. OR precipitated by illness or poor compliance e. Classifying severity i. Mild = pH 7.2-7.3, bicarb 10-15 ii. Moderate = pH 7.1 – 7.2, bicarb 5-10 iii. Severe = pH < 7.1, bicarb < 5 2. Pathogenesis a. ↓ INSULIN (NOTE: levels also inappropriately ‘normal’) i. ↓ glucose uptake + ↑ glucose production  HYPERGLYCAEMIA  glycosuria  osmotic diuresis  electrolyte depletion b. ↑ LIPOLYSIS/↓ lipogenesis  mobilisation of FFA/glycerol- substrates for gluconeogenesis + beta oxidation i. Glucagon excess  hepatic ketogenesis  FFA converted to ketones ( hydroxybutyrate  acetoacetate  acetone  ketonaemia and acidosis ii. Ketone bodies 1. Produced by acetyl-CoA mainly in the mitochondrial matrix of liver cells when CHO are scarce energy is obtained from FFA 2. Transported from the liver to the other tissues – amino acids and beta-OHB can be reconverted to acetyl-CoA to produce energy – heart + brain 3. Levels of acetone lower than those of the other two types of ketone bodies – excreted in urine; acetone is responsible for ‘fruity’ odour of breath c. Dehydration/hypovolaemia/haemoconcentration i. ↑ cellular K, ↑ cellular Na ii. Tissue hypoxia  lactic acidosis iii. Thrombosis iv. ↓Renal blood flow  pre-renal renal failure v. ↓ Cerebral blood flow

Answer 45

3. Precipitants a. Medication error / non-compliance (20%) b. New diagnosis (25%) c. Increased insulin requirement i. Infection (30%), vomiting, injury, emotional stress, alcohol, drugs, steroids, thiazides, d. No known precipitant (25%) 4. Clinical manifestations a. Hyperglycaemia – polyuria, polydipsia b. General – nausea, vomiting, abdominal pain c. Acidosis – Kussmaul’s breathing, ketotic breath, decreased GCS 5. Assessment a. Degree of dehydration i. None/Mild (< 4%): no clinical signs ii. Moderate (4-7%): easily detectable dehydration eg. reduced skin turgor, poor capillary return iii. Severe(>7%): poor perfusion, rapid pulse, reduced blood pressure i.e. shock b. Level of consciousness – GCS c. Investigations i. FBE ii. Blood glucose iii. UEC, CMP iv. Blood ketones (beta-hydroxy butyrate) 1. Not uncommon to have levels 0.2 mmol/L 2. Mild illness increases to 1.0 mmol/L 3. >=3 mmol/L at risk of DKA v. Urine ketones (acetoacetone) – not uncommon for children to have some ketones on waking vi. Venous blood gas (including bicarbonate) - metabolic acidosis with increased anion gap vii. Investigations for precipitating cause e.g. septic screen viii. For all newly diagnosed patients 1. Insulin antibodies, GAD antibodies 2. Coeliac screen (total IgA, anti-gliadin Ab, tissue transglutaminase Ab) 3. Thyroid function tests (TSH and FT4) ix. Urine = ketones, culture (if evidence if infection)

Answer 46

a. Airway / breathing b. Supportive measures to consider if appropriate i. Secure the airway and consider NG tube placement (to avoid aspiration) if low GCS ii. Keep NBM iii. X2 PIVC iv. Supplemental O2 = give oxygen to patients with severe circulatory impairment or shock v. Continuous cardiac monitoring (high/low K) vi. Abx if indicated vii. IDC = strict fluid balance c. Fluid Requirements i. Fluid boluses 1. Not all patients require fluid boluses (acidosis itself  poor peripheral perfusion + confounds accurate assessment of dehydration) 2. Peripheral perfusion improves with Tx of acidosis (with insulin) 3. If hypoperfusion present – 10 mL/kg N. saline bolus, further bolus if CRT >2 seconds 4. Patients with DKA rarely require >20 ml/kg in total as a bolus ii. Initial fluid replacement = normal saline + potassium 1. Adjust based on Na, K and glucose levels iii. Ongoing fluid management 2. Aim to keep the BSL between 5-12 mmol/L a. If BSL 12-15  add 5% dextrose b. If BSL <5.5 or falling rapidly  add 10% dextrose c. If continues to fall despite 10% dextrose – insulin infusion should be decreased (but only if metabolic acidosis continues to improve) 4. Corrected sodium should remain stable or rise as blood glucose level falls 5. N saline + dextrose should be continued if a. Hyponatraemia present b. Corrected sodium fails to stabilise or rise as the BSL increases c. Hyperosmolar and concerned about rapid shifts in osmolality 6. Fluids with a tonicity of < 0.45% saline should not be used iv. Rehydration may be completed orally after the first 24 - 36 hours if the patient is metabolically stable (this usually coincides with insulin therapy being switched to s.c. injections) d. Potassium i. Patients may present with low, normal or elevated K+ ii. Potassium replacement therapy is required for treatment of DKA 1. Generally total body deficit of K+ on presentation 2. Correction of acidosis results in hypokalaemia (K+ moves into cells) iii. Management 1. K > 5.5 mmol/L or patient anuric  defer initial replacement 2. Start KCl at 40 mmol/l if body weight < 30kg, or 40-60 mmol/l if > 30 kg a. Subsequent replacement is based on serum potassium levels b. Potassium replacement should continue throughout i.v. fluid and insulin therapy 3. Once insulin is commenced, a repeat K+ should be taken within one hour e. Insulin i. Add 50 units of clear/rapid-acting insulin (Actrapid HM or Humulin R) to 49.5 ml 0.9% NaCl (1 unit/ml solution) ii. Insulin dose 1. 0.1 units/kg/hr  newly diagnosed children AND established diabetes with BSL > 15 mmol/ 2. 0.05 units/kg/hour  established diabetes who have had their usual insulin and whose blood glucose level is < 15 mmol/l. iii. Adequate insulin must be continued to clear ketones and correct acidosis 1. Adjust the concentration of dextrose in the intravenous fluids, aiming to keep BSL 5-12 2. The insulin infusion can be discontinued when the child is alert and metabolically stable (pH > 7.30 and HCO3 > 15) iv. The best time to change to s.c. insulin is just before meal time 1. Insulin infusion should only be stopped 30 minutes AFTER the first s.c. injection of rapid-acting insulin f. Ongoing management i. Strict fluid balance ii. Hourly observations iii. Hourly glucose and blood ketones measurement while on insulin infusion iv. Re-check K+ within one hour of commencing insulin infusion v. Venous blood gas and lab glucose 2 hourly for initial 6 hours; then 2 - 4 hourly thereafter vi. Serum UEC 2 - 4 hourly for the initial 12 - 24 hours viii. Nurse head up g. Bicarbonate i. Bicarbonate administration is not routinely recommended as it may cause paradoxical CNS acidosis ii. Continuing acidosis indicates insufficient fluid and insulin replacement iii. Nonetheless, in rare circumstances, some extremely sick children may benefit from cautious administration (e.g. those with pH < 7.0 +/- HCO3 < 5mmol/L who require adrenaline for BP support or those with marked hyperkalemia)

Answer 47

a. Hyper / Hyponatraemia i. Measured serum sodium is depressed by the dilutional effect of the hyperglycaemia ii. To "correct" sodium concentration, use the following formula: 1. Corrected (i.e. actual) Na = measured Na + 0.3 (glucose - 5.5) mmol/l 2. i.e. 3 mmol/l of sodium to be added for every 10 mmol/l of glucose above 5.5 mmol/l. iii. If sodium does not rise as the glucose falls during treatment or if hyponatraemia develops, it usually indicates overzealous volume correction and insufficient electrolyte replacement 1. This may place the patient at risk of cerebral oedema b. Hypoglycaemia i. If blood glucose falls below 4.0 mol/l and patient is still acidotic, give i.v. 10% dextrose 2-5 ml/kg as a bolus and use a 10% dextrose concentration for ongoing iv fluids (with 0.45% NaCl and K+ supplements) ii. Do not discontinue the insulin infusion iii. If hypoglycaemia occurred despite use of 10% dextrose in the preceding 2 or more hours, the rate of the insulin infusion may be decreased iv. If blood glucose falls below 4.0mmol/l and most recent pH is >7.30, oral treatment for hypoglycaemia (jelly beans + 1 serve of complex carbohydrate) can be used instead of an i.v. bolus of dextrose 10% c. Cerebral Oedema i. Responsible for 50-60% of all T1DM related deaths ii. 1% of DKAs affected iii. Some degree of subclinical brain swelling is present during most episodes of diabetic ketoacidosis iv. Clinical cerebral oedema occurs suddenly, usually between 6 and 12 hours after starting therapy v. Mortality or severe morbidity is very high without early treatment (40-90% mortality) vi. Prevention 1. Slow correction of fluid and biochemical abnormalities 2. Optimally, the rate of fall of blood glucose and serum osmolality should not exceed 5 mmol/L/hr, but in children there is often a quicker initial fall in glucose 3. Patients should be nursed head up vii. Risk factors = first presentation, long history of poor control, young age (< 5 yr) viii. Warning signs 1. No sodium rise as glucose falls, hyponatraemia during therapy, initial adjusted hypernatraemia 2. Headache, irritability, lethargy, depressed consciousness, incontinence, thermal instability. 3. Very late signs - bradycardia, increased BP and respiratory impairment (Cushing triad) ix. Treatment 1. Mannitol 2. Reduce fluid input by 1/3 in the first instance d. Pre-renal failure due to ATN e. Pancreatitis f. Electrolyte abnormality leading to arrythmia

Answer 48

1. Key points a. Syndrome of insulin resistance + relative insulin deficiency leading to i. ↑ hepatic glucose output ii. ↓ muscle glucose uptake iii. ↑ lipolysis b. Suspect in adolescents with i. Strong family history ii. Phenotype of central adiposity iii. Show other signs of insulin resistance = acanthosis nigricans, skin tags iv. Have no insulin requirement of <0.5 units/kg/day after the partial remission (honeymoon phase) c. Risk of T2DM in adolescents is cumulative – therefore increased suspicion if multiple risk factors 3. Screening for T2DM in children a. Criteria i. Overweight, PLUS ii. Any 2 risk factors 1. Family history 2. Race/ethnicity – Hispanic, Polynesian, ATSIA, Indian, Chinese 3. Signs of insulin resistance = acanthosis nigricans, hypertension, dyslipidaemia, PCOS b. Age of initiation = 10 years or at onset of puberty (whatever is earlier) c. Frequency = every 2 years d. Test = fasting plasma glucose test preferred 4. Risk factors a. Obesity b. Positive family history i. Offspring of one parent with T2DM – 40% ii. Offspring of both parents with T2DM – 60% iii. Monozygotic twins – 90% chance c. Racial and ethnic groups d. Female gender – more likely than boys to develop T2DM during adolescence e. Conditions with insulin resistance – PCOS f. Prenatal exposures = low BW, gestational diabetes g. Other genetic associations i. GLUT2 defect: increased BSL, impaired secretion ii. Glycogen synthase gene polymorphism: difficulty storing glucose as glycogen, leads to ↑ BSL, insulin resistance

Answer 49

5. Clinical manifestations a. Asymptomatic = 40-50% b. Symptomatic (eg. polydipsia, polyuria) without ketonuria or acidosis = 50-70% c. DKA = 5-15% d. Hyperglycaemic hyperosmolar state = 5-15% e. Associated features i. Acanthosis nigricans – marker of insulin resistance found in 50-90% of youth with T2DM ii. Hyperandrogenism Diagnosis - Hyperglycaemia in the absence of any acute physiological stress +/- presence of symptoms of hyperglycaemia - Fasting glucose >7.0 - Randomg BGL >11.0 - Polyuria/polydipsia/weight loss/nocturia + random BGL >11.0 or HbA1c >6.5 Screen for comorbidities - Nephropathy (UEC, urine albumin) - Retinopathy (Dilated eye exam) - Dyslipidaemia (fasting lipids) - Hypertension - NAFLD (liver USS, LFTs) - PCOS - Sleep apnoea - Depression

Answer 50

a. Goals i. Lifestyle modification ii. Normalization of glycaemia – target HbA1c <6.5% iii. Management of comorbidities b. Lifestyle i. <10% of youth with T2DM reach glycaemic targets with lifestyle modification alone ii. Dietary recommendations = low GI foods iii. Exercise = moderate intensity exercise for 60 minutes/day iv. Screen time = <2 ours/day c. Normalization of glycaemia i. Oral hypoglycaemics 1. Metformin a. Metformin monotherapy is treatment of choice b. Action i. ↑ insulin sensitivity = ↑ insulin stimulated glucose uptake in fat and muscle ii. ↓ hepatic glucose production c. AE = abdominal pain, diarrhoea, lactic acidosis d. Aids in weight loss ii. Insulin 1. Indications a. Required for those with HbA1c >9% b. Severe hyperglycaemia (serum glucose > 15 mmol/L) c. Ketosis/ketoacidosis Other meds: - sulphonylureas - thiazolidinediones - acarbose - GLP analogues - DPP4 inhibitors - SLGT2 inihibitor ``` Manage comorbidities: HTN - 1/3 T2DM patients - lifestyle (weight loss, low salt diet, exercise) - ACE, ARB Dyslipidaemia - 2/3 patients - dietitian and dietary modification - statin Retinopathy - 10% at diagnosis, inc with time/hyperglycaemia - refer to ophthal (?laser) Nephropathy - 20% - ACE - treat HTN Depression - 15% - ref to MH ```

Answer 51

1. Key points a. Development of severe hyperglycaemia without significant ketosis, usually in setting of T2DM 2. Pathophysiology a. Insulin deficiency (NOT absence) i. Decreased glucose available to cells due to insulin deficiency ii. Activation of glycogenolysis, gluconeogenesis iii. Results in EXTREME hyperglycaemia – polyuria, polydipsia b. Lipolysis i. For GNG WTHOUT ketone formation due to presence of insulin c. Dehydration ++++ i. Due to osmotic diuresis from hypoglycaemia ii. Leads to: hypercoagulability, shock 3. Clinical features a. Trigger most commonly sepsis b. Presents late and worse prognosis than DKA c. Extreme dehydration d. No ketones Altered conscious state -> HONK (hyperosmolar hyperglycaemic nonketotic coma) 4. Assessment and management same as DKA except- a. Fluid resuscitation +++ b. Less insulin c. Treat underlying cause

Answer 52

1. Key features a. Non-insulin dependent diabetes b. Diagnosed at young age (<25 years) c. Autosomal dominant d. Lack of autoantibodies Types 1-6 - 3 most common (HFNA1), 2 second most common (GCK) Often a multigenerational family history 2. Epidemiology a. Most common form of monogenic diabetes – accounting for 2-5% of diabetes b. Very heterogenous – patients often misclassified as T1DM and T2DM 3. Genetics a. Mutations in hepatocyte nuclear-factor alpha (HFNA1) and glucokinase (GCK) mutations are most common b. Some family members may have the genetic defect but do not develop diabetes, unclear c. Other patients have classic MODY phenotype but do not have identifiable mutation 4. Treatment a. MODY1 and MODY3 = sulphonylurea to increase insulin secretion b. MODY 2 = diet

Answer 53

1. Key points a. Second most common form of MODY b. Mild and non-progressive 2. Pathogenesis a. Glucokinase = essential role in beta cell glucose sensing b. Heterozygotes = mild reduction in beta cell response to glucose i. Higher threshold for insulin release once BSL > 7 mmol/L c. Homozygotes = complete inability to secrete insulin in response to glucose resulting in permanent neonatal diabetes 3. Treatment a. Diet b. Pharmacotherapy – sulphonylurea if required

Answer 54

1. Key points a. Most common MODY b. May have renal problems c. Normal insulin secretion however fail to increase insulin secretion with increased plasma glucose 2. Pathogenesis a. Mutation in transcription factor HNF1alpha b. The precise mechanism by which a defect in HNF1A causes hyperglycemia is not clear 3. Clinical manifestations a. Symptomatic hyperglycaemia in 20s b. Secondary insulin resistance later develops 4. Treatment a. Sulphonylureas – very sensitive and can be treated with low doses

Answer 55

1. Key points a. Rare b. Maternal inheritance 2. Clinical features a. Diabetes b. Deafness c. Neurological defects

Answer 56

1. Epidemiology a. 20% by 20 years 2. Mechanisms a. Mainly insulin deficiency due to pancreatic insufficiency b. Liver disease contributes to insulin resistance c. Chronic use of steroids 3. Risk factors a. Increasing age b. Pancreatic insufficiency c. Delta F508 homozygous d. Female 4. Clinical manifestations a. Failure weight gain, decreasing growth velocity b. Delayed puberty c. Plateau/deterioration in lung function 5. Screening a. OGTT annually from 10years i. 2hrs 7-11.1mmol/L = IGT ii. 2hours >11.1mmol/L = DM b. Can do fasting venous glucose or HbA1c to confirm

Answer 57

1. Definition a. Hypoglycaemia is a Blood Glucose Level (BGL) low enough to cause signs and/or symptoms of impaired brain function and neurogenic response – generally BGL <3.3 mmol/L b. Symptoms of hypogylcaemia c. Resolution of symptoms with treatment to raise BSL 2. Key points a. Prolonged or recurrent hypoglycaemia, especially when associated with symptoms and signs  long term neurological damage or death b. Hypoglycaemia is the most frequent acute complication of type 1 diabetes either due to excess insulin or illnesses causing nausea, vomiting or diarrhoea and decreased oral intake c. Hyperinsulinism is the most common cause of persistent hypoglycaemia under 2 years i. The presence of ketonuria and/or ketonaemia makes this diagnosis very unlikely d. Accelerated starvation (previously known as “ketotic hypoglycaemia”) is the most common cause of hypoglycemia beyond infancy, usually presenting between 18 months to 5 years – prolonged fast usually precipitated by mild illness – documentation of low BSL with ketonuria and/or ketonaemia e. May be an early manifestation of other serious disorders (eg. sepsis, congenital heart disease, tumours) f. Hypogylcaemia in neonates, infants and children is almost ALWAYS a result of problems with fasting adaptation (post-prandial hypoglycaemia rare – post gastric surgery/fructose intolerance are main causes) ``` 3. Aetiology (by age) Neonate • Hyperinsulinism • GHD • GALT Infants • Inborn errors of metabolism o Fatty acid oxidation defect o Glycogen storage disease o Galactosaemia • Hyperinsulinism • Congenital hyperinsulinism Child • Accelerated starvation • Hypopituitarism Adolescent • Insulinoma • Adrenal insufficiency ```

Answer 58

5. Clinical manifestations a. Infant/neonatal i. Pallor ii. Poor feeding iii. Hypotonia / sleepiness iv. Jitteriness v. Hypothermia, apnea, bradycardia vi. Seizures b. Neuroglycopaenic i. Headache / Hunger ii. Poor concentration, confusion iii. Irritability iv. Visual changes v. Seizures / Stroke / Collapse vi. Coma c. Adrenergic i. Diaphoresis / pallor ii. Tachycardia / palpitations iii. Anxiety iv. Tremor / paresthesia 6. History a. Tolerance to fasting / illness b. Relationship to food i. Milk products (galactosemia) ii. Fructose e.g. juices (hereditary fructose intolerance) iii. Protein (amino acid or organic acid disorders) c. History of toxin ingestion – in toddlers or young children consider accidental ingestion of alcohol, oral hypoglycemic agents, aspirin, beta blockers, or toxins d. Past history i. Neonatal history of hypoglycemia ii. Episodes suggestive of hypoglycemia eg. undiagnosed seizure disorder iii. Previous gastric surgery, fundoplication (postprandial hypoglycemia) e. Family history i. Consanguinity ii. Unexplained infant deaths (may be from inborn errors of metabolism) iii. Hormonal deficiencies and hyperinsulinism

Answer 59

a. Raise BSL to 5-8 b. Mild to moderate i. 10-15g fast acting CHO (125-200mL juice or soft drink, 4 jelly beans) ii. 15g long acting (1 slice bread, 2 plain sweet biscuit or 1 fruit, 250mL milk) iii. Monitor BSL iv. Repeat short acting if required c. Severe i. IV dextrose- 2mL/kg 10% dextrose ii. Maintenance with 5-10% dextrose – aim BSL >4mmol/L iii. Increase rate/ repeat bolus if required – increase by 2mg/kg/min if BSL low iv. Glucagon infusion (impairs insulin release from B islet cells) d. Treat underlying cause i. Diazoxide infusion (potassium sensitive ATP B islet cell channel stimulation – inhibits insulin secretion, only if KATP intact) ii. Octreotide infusion (tachyphylaxis, impairs calcium stimulated insulin release B islet cell) iii. Surgery 1. Indications – diffuse form unresponsive diazoxide, focal lesion 2. Diffuse = sub-total pancreatectomy (95%), focal = focal resection

Answer 60

8. Investigation a. Indications to investigate i. Neonatal 1. Persistent beyond initial few days 2. Glucose requirement > 10-12 mg/kg/min (even initial days) 3. Babies with no identifiable risk factors (eg. mum with DM, HIE, SGA) ii. Older infant/child 1. Recurrent or severe hypoglycaemia b. Critical hypoglycaemia screen c. Bloods = see below d. Guthrie card = carnitine/ acylcarnitine e. Urine = glucose, ketones, reducing substances, amino acids and organic acids Bloods: - critical sample at time of hypo <2.6 - ketones, lactate, FFA, carnitine/acylcarnitine, ammonia, cortisol, insuline, C-peptide, GH, amino acids, electrolytes, LFT Controlled fast

Answer 61

1. Key points a. Children 18months – 5 years i. Pre-school years ii. Often gone by 10years b. Most common cause in this age group but diagnosis of exclusion c. Impaired fasting adaptation d. Idiopathic – mechanisms thought to not have increase in GNG in response to low glucose e. Resolves spontaneously 7-8years age f. Previously called ketotic hypoglycaemia but preferable NOT to use this term g. Diagnosis of EXCLUSION 2. Clinical features a. Precipitant – prolonged fasting, illness b. Usually first thing in morning c. Episodes unpredictable d. Thin/small body habitus e. Hypoglycaemia with ketones 3. Investigation a. May consider doing prolonged fast b. If can tolerate – HIGHLY unlikely to be organic cause 4. Diagnosis of exclusion a. Low alanine may be present 5. Management a. Avoid fasting b. Frequent feeding high protein/CHO

Answer 62

1. Key points a. Neonatal hypoglycaemia = < 2.6 mmol/L b. Incidence 1-3/1000 live births c. 10% neonates have transient hypoglycaemia 2. Normal perinatal physiology a. Transition from environment with continuous source of glucose (maternal blood) to one where glucose is in limited an intermittent supply b. Glucose is the preferred substrate for brain metabolism, which uses most of the 5-8 mg/kg/min produced by full-term neonate c. Glucose entry into brain cells is dependent on circulating arterial glucose (not insulin) concentration 3. Pathogenesis a. Loss of continuous transport of glucose, BGL falls in health newborn during first 2 hours post-delivery to a nadir of no less than 2.2, then stabilizes by 4-6 hours to 2.5-4.5 b. Immediately post birth, plasma BGL maintained by hepatic glycogen breakdown c. Glycogen stores used by first 8-12 hours, thereafter BGL maintained by synthesis of glucose from lactate, glycerol and amino acids

Answer 63

a. Transient i. Inadequate substrate/ immature function 1. Prematurity 2. SGA 3. Normal newborn 4. Increased usage – sepsis/ fever ii. Transient hyperinsulinism 1. Maternal factors – IDM, IV glucose during labour 2. Prematurity 3. SGA, discordant twin, birth asphyxia, maternal PET – depleted stores + hyperinsulinism 4. Beckwith Wiedemann syndrome 5. Increased utilization – sepsis, fever b. Persistent i. Hyperinsulinism 1. K(atp) channel defect – recessive/ dominant / focal 2. Glucokinase defect (dominant) 6. Beckwith -Wiedemann syndrome 7. Sulfonyurea drugs 8. Congenital disorders of glycosylation ii. Increased utility 1. Hypothermic 2. Anaerobic glycolysis due to reduced tissue perfusion 3. Sepsis 4. Polycythaemia iii. Ketotic hypoglycaemia 1. Inadequate substrate a. Prematurity/ SGA b. MSUD, PA, MMA 2. Counter-regulatory hormone deficiency a. Panhypopituitarism - often assoc with other midline abnormalities b. Isolated GH deficiency c. ACTH deficiency d. Addison disease 3. Glycogenolysis and gluconeogenesis disorders a. Range of disorders, usually associated with soft, massive hepatomegaly and FASTING hypoglycaemia with intact lipolysis + ketogenesis b. G6P deficiency – GSD 1a/ 1b c. Galactosemia d. Hereditary fructose intolerance iv. Fatty acid oxidation disorders 1. Short, medium, long chain fatty acid acyl-CoA dehydrogenase deficiency 2. Carnitine deficiency 3. Carnitine palmitoyltransferase deficiency v. Other etiologies 1. Liver disease 2. Amino acid and organic acid disorders 3. Systemic disorders

Answer 64

5. Clinical manifestations a. Frequently asymptomatic b. In symptomatic infant c. Neurogenic (autonomic) symptoms i. Jitteriness ii. Sweating iii. Irritability iv. Tachypnoea v. Pallor d. Neuroglycopenic symptoms i. Poor suck or poor feeding ii. Weak or high pitched cry iii. Change in level of consciousness (lethargy, coma) iv. Seizures v. Hypotonia 6. Examination a. Large for dates – hyperinsulinism b. Micropenis, midline defect – hypopituitarism c. Genital ambiguity, pigmentation – CAH d. Blindness – septo-optic dysplasia e. Hypotonia – FAO, GS f. Recurrent encephalopathy – FAO g. Jaundice – GSD III, FAO, galactosaemia h. Hepatomegaly – GSD, GNG defect i. Renomegaly – GSD I j. Myopathy – GSD, FAO defect k. Pigmentation – adrenal insufficiency

Answer 65

8. Management a. Mild to moderate – oral feeding if >1.6/1.8 asymptomatic or >2.2 if symptoms i. Fast acting CHO – glucose gel ii. Long acting CHO – feed +/- comp iii. Monitor BSL b. Severe <2.2 and symptomatic or <1.6/1.8 without symptoms i. IV dextrose- 2mL/kg 10% dextrose ii. Maintenance with 5-10% dextrose – aim BSL >4mmol/L iii. If persistently low 1. Repeat bolus 2. Increase rate of IV dextrose from 60 to 90mL/kg/day 3. Increase concentration of dextrose, max 20% (>12.5% needs central line) iv. 6-8 mg/kg/minute = substrate defect v. >12 mg/kg/minute = hyperinsulinism c. Specific management i. Hyperinsulinism 1. Glucose 2. Glucagon, diazoxide, ocreotide 3. Surgery ii. GSD/gluconeogenic defect 1. Continuous NG feed, corn starch 2. Allopurinol (GSD I) iii. Hypopituitarism 1. GH, cortisol iv. FAO defect 1. Avoid fasting 2. Carnitine v. Ketotic hypoglycaemic 1. Nocturnal feeds 2. Illness – increase CHO intake 3. Protein snack, ketone monitoring vi. Galactosaemia/ fructose intolerance 1. Dietary changes 9. Outcome a. Symptomatic hypoglycemia  brain injury (occipital most effected) b. Unknown what BSL or duration of low BSL leads to brain injury c. High risk for CP, developmental delay, small head circumference d. MCQ: Occipital lobe most vulnerable to hypogylcaemia – visuospatial impairment

Answer 66

1. Key points a. Most common cause of persistent hypoglycaemia in neonates and infancy b. Insulin suppresses ALL mechanisms of fuel generation -  glucose  GNG  FAO  ketogenesis c. Results in NO fuel to the brain d. Genetic disorder with familial and sporadic forms – highly heterogenous e. Characterised by dysregulated insulin secretion f. BSL <2.8 + detectable insulin = HYPERINSULINISM + no ketones i. ANY detectable insulin is inappropriate when hypoglycaemic g. Aim of treatment BSL > 4.0 mmol/L 2. Pathogenesis a. Normal relationship between plasma glucose concentration and insulin secretion is disturbed b. Inappropriate insulin secretion during periods of hypoglycaemia c. Disturbance of normal homeostasis caused by various mutations d. ATP-dependent potassium (KATP) channel of beta pancreatic cells i. Most common mutation iii. Inactivating mutations reduce the number of KATP channels OR mean they are persistently closed resulting in depolarisation of beta cells and persistent hypersecretion of insulin iv. CLOSURE of KATP channel results in insulin release e. Glutamate hydrogenase gene mutation f. Glucokinase gene mutation

Answer 67

a. Macrosomic baby (or SGA/ asphyxia) b. Early onset hypogylcaemia – often severe, recurrent c. Glucose requirement usually > 10 mg/kg/min d. Glycaemic response to glucagon e. Hypoglycaemia with detectable insulin and ABSENCE of ketones + FFA (insulin suppresses normal counterregulatory response) i. Ear crease anomaly, Exomphalos, hemihypertrophyy (BW syndrome) a. Key investigations i. Hypoglycaemia <2.2 mmol/L ii. Detectable insulin (Insulin > 14 pmol/L) iii. Absence of ketones (blood + urine) iv. Inappropriately low FFA Would do a critical sample screen +/- genetic studies (e.g. if BWS suspected)

Answer 68

a. Exogenous insulin b. Sulphonylurea ingestion c. Insulinoma d. Beckwith-Widman e. Kabuki syndrome f. Turner syndrome g. Congenital disorders of glycosylation ?Transient hyperinsulinism for neonates K-ATP mutations...

Answer 69

a. Aim BSL > 4.0 b. Glucose replacement i. 2-5 mL/kg of 10% dextrose 1. Aim for GIR of 8 mg/kg/min initially 2. Increase GIR by 2 mg/kg/min if subsequent BSL low c. Pharmacotherapy i. Glucagon 1. 5-20 mcg/kg/ hour 2. Very effective 3. Short-term use as IV or subcut infusion ii. Diazoxide 1. Mechanism = BLOCKS sulphonylurea receptor on beta cells  OPENS KATP  hyper-polarize beta cell  decreases insulin release 2. Only effective if KATP intact 3. Start with 10mg/kg/day in 3 divided doses and increase as necessary; if not responding to > 20mg/kg/day, consider the patient non-responsive 4. Adverse effects a. Most common i. Hypertrichosis – can be severe (excessive hair growth over and above the normal for the age, sex and race of an individual, in contrast to hirsutism, which is excess hair growth in women following a male distribution pattern) ii. Sodium and water retention 1. Can treat with thiazide which also aid in decreased insulin 2. Usually start both together iii. Thrombocytopaenia, leukoepnia b. Others: advanced bone age, hyperuricaemia, decreased IgG c. Rare but serious: ketoacidosis, heart failure, nonketotic hyperosmolar coma iii. Octreotide 1. Mechanism = long acting somatostatin analog 2. Dose 5-30 mcg/kg 3. Opens K+ channels + inhibits insulin release; can inhibit growth hormone release 4. Only subcut/ IV, can lead to tachyphylaxis 5. Adverse effects = modest increase in risk of NEC d. Surgical i. Indications 1. Diffuse form unresponsive to diazoxide 2. Focal lesion ii. Procedures 1. Diffuse = sub-total pancreatectomy (95%) 2. Focal = focal resection

Answer 70

* Deficiencies of ACTH/ cortisol or GH * Hypoglycaemia in growth hormone deficiency is due to decreased lipolysis (and glycogenolysis to a lesser extent) * Hypogylcaemia in ACTH/cortisol deficiency, hypoglycaemia results from increased insulin sensitivity, decreased GNG and increase glucose oxidation • Congenital hypopituitarism o May have associated cerebral or midline abnormalities o Septo-optic dysplasia o Micropenis in boys with GH deficiency o Some forms related to transcription factor mutations – PROP1, SOX2, SOX3, LHX3, LHX4 • Acquired hypopituitarism o Post-infections, haemorrhage o Older children – post surgery, irradiation, infiltration • Primary adrenal insufficiency o Newborn = CAH, congenital adrenal hypoplasia o Older child = Addison’s, ADL, TB, haemorrhage e

Answer 71

• Glycogen storage disorders (GSD) due to AR mutation in genes involved in glycogenolysis • Key features o Hepatomegaly (soft, often massive) o Hypoglycaemia with fasting  Usually presents in later infancy as inter-feed interval increases or during intercurrent illnesses o Lipolysis ad ketogenesis intact  LESS symptomatic than HI as alternative fuel available • Types o GSD1a  Impairment of both glycogenolysis and GNG – early hypoglycaemia can occur  GNG defect causes lactic acidosis  Completely dependent on exogenous glucose  Kidney involvement – RTA, microalbuminuria o GSDIII  Associated with muscle weakness, cardiomyopathy, hypotonia o GSD VI and IX – milder phenotypes o GSD 0  Defect in glycogen synthesis  Fasting hypoglycaemia and postprandial hyperglycaemia  CHO – lipolysis in liver – elevated lactate

Answer 72

a. Include i. Galactosaemia ii. Hereditary fructose intolerance – fructose 1,6-diphosphatase deficiency iii. PEPCK deficiency iv. Pyruvate kinase deficiency b. Features i. Glycogenolysis remains intact ii. Later onset – hypoglycaemia occurs in the setting of fasting or intercurrent illness iii. Positive glucagon response in the fed but not the fasted state iv. Keto and lactic acidosis, hyperuricaemia, hyperlipidaemia v. Hepatomegaly (lipid as opposed to glycogen)

Answer 73

a. Errors in pathway of i. Fatty acid uptake and activation ii. Mitochondrial oxidation b. Defects in i. Carnitine synthesis, CPT1 and 2 (transporters) ii. Acetyl-CoA dehydrogenase – SCAD, MCAD, LCAD iii. HMG-CoA lyase c. Features i. Delayed onset – after infancy – phenotype varies according to level of mutation ii. Often unmasked by fasting/ intercurrent illness iii. Skeletal and cardiac muscle and liver – target organs 1. Myopathy, cardiomyopathy 2. Hepatic failure iv. Encephalopathy – Reye like syndrome d. Investigations i. Low or absent ketones ii. Diagnosis – urinary organic acids, carnitine profiles

Answer 74

a. Clinical features i. Neonatal onset ii. Post-prandial hypoglycaemia iii. Neonatal cholestasis, diarrhoea b. Investigations i. Non-ketotic ii. Urine reducing substance +ve iii. Increased galactose-1-P iv. Low galactose-1 phosphate uridyl transferase (GALT) level

Answer 75

a. Clinical features i. Onset after weaning ii. Deficiency of fructose 1-phosphate aldolase (inhibits hepatic GNG) iii. RTA, cholestasis, FTT b. Investigations i. Non-ketotic ii. Urine reducing substance +ve iii. Hypo after fructose load

Answer 76

1. Pathogenesis a. Hyperglycaemia typically occurs when infants cannot adapt to a parenteral glucose infusion by decreasing endogenous glucose production or increasing peripheral glucose uptake i. Usually associated with prematurity or sepsis b. Hyperglycaemia is more common in preterm infants compared with term infants, multifactorial i. Poor insulin response ii. Incomplete suppression of glucose production iii. Increased secretion of counter regulatory hormones associated with stress 2. Aetiology a. Parenteral administration of glucose b. Prematurity c. Sepsis d. Stress = counter-regulatory hormones (adrenaline, cortisol) e. Drugs f. Neonatal diabetes mellitus

Answer 77

1. Epidemiology a. Incidence of 1/500,000 births 2. Definition a. Persistent hyperglycaemia in the first months of life that lasts for >2 weeks b. Requires insulin for management 3. Clinical presentation a. Weight loss b. Volume depletion c. Hyperglycaemia d. Glucosuria +/- ketonuria/ketoacidosis Can be permanent or transient

Answer 78

1. Etiology a. >50% have a permanent form primarily due to mutations in ATP-sensitive K+ channel ii. Diagnosis made in the first 2 months of life iii. Infants are SGA, but exhibit postnatal catchup with insulin therapy iv. Other features = neurological abnormalities including severe developmental delay, epilepsy, muscle weakness, and dysmorphic features (DEND syndrome = dev delay, epilepsy, neonatal diabetes) v. Treatment = oral sulphonylurea (insulin previously used) 2. Pathogenesis a. Activating mutations increase the number of open KATP channels at the plasma cell b. Results in hyperpolarization of the beta cells – preventing the release of insulin c. NOTE: inactivating mutations result in hyperinsulinaemic hypoglycaemia of infancy

Answer 79

1. Key points a. Appears within the first few weeks of life but is transient b. Affected infants go into remission within a few months c. Possible relapse to permanent 2. Clinical manifestations a. Hyperglycaemia (may have initial hypoglycaemia due to SGA) b. Dehydration c. FTT 4. Management a. Supportive b. Insulin c. Can get late onset T1DM

Answer 80

1. Key points a. Maternal diabetes i. Pre-gestational –T1DM, T2DM (1.8%) ii. Gestational (7.5%) b. Adequate glycaemic control before and during pregnancy critical to improve outcome c. Mortality i. Fetal mortality rate higher than non-diabetic mothers – especially after 32 weeks ii. Fetal loss throughout pregnancy associated with poorly controlled maternal diabetes and congenital abnormalities iii. Neonatal mortality rate >5x than infants of non-diabetic mothers (higher at all gestational ages + BW) d. Maternal risks i. Polyhydramnios ii. Pyelonephritis iii. Pre-eclampsia iv. Preterm labour v. Chronic hypertension 3. FETAL a. Maternal hyperglycaemia during first trimester and conception  major birth defects + spontaneous abortions b. Diabetic fetopathy occurs in 2nd and 3rd trimesters c. Fetal hyperglycaemia i. Stimulates glycogen storage in the liver, increased activity of hepatic enzymes involved in lipid synthesis and accumulation of adipose tissue  contribute to long-term metabolic outcomes d. Fetal hyperinsulinaemia i. Elevated insulin  elevated metabolic rate  increased oxygen consumption + fetal hypoxia ii. Consequences = increased mortality, metabolic acidosis, alterations in fetal iron distribution, polycythaemia, impaired lung maturation iii. Follow-on effect of above 1. Increased catecholamine production  hypertension and cardiac hypertrophy 2. Increased fetal red cell mass + iron redistribution  iron deficiency in developing organs, contributing to cardiomyopathy and neurodevelopment iv. Contributes to impaired or delayed lung maturation e. Macrosomia i. Excessive nutrients delivered from poorly controlled diabetic mother causes increased fetal growth, particularly of insulin-sensitive tissues (liver, muscle, cardiac muscle, SC fat)

Answer 81

a. Congenital anomalies i. Risk of 5-6%, increases to 10-12% in mothers requiring insulin ii. Congenital malformations account for 50% of deaths in IDM iii. Risk can be reduced by strict glycaemic control during the pre- and peri-conceptual time iv. Most (2/3) involve CNS and CVS 1. Cardiovascular malformations (3-9%) = TGA, DORV, VSD, truncus arteriosus, tricuspid atresia, PDA 2. Anencephaly and spina bifida 3. Flexion contractures of limbs, vertebral anomalies 4. Small left colon = rare condition which presents as transient inability to pass meconium [most cases occur in IDM] b. Prematurity c. Perinatal asphyxia i. Macrosomia  failure to progress and shoulder dystocia ii. Cardiomyopathy d. Macrosomia = >90th centile on population-appropriate growth weight or >4000g i. Increases risk of birth injury = shoulder dystocia (1/3 of IDM with macrosomia), brachial plxus injury, clavicular or humeral fractures, perinatal asphyxia, cephalhaematoma, subdural haemorrhage, or facial palsy ii. Subsequently more likely to have hyperbilirubinaemia, hypoglycaemia, acidosis, respiratory distress, shoulder dystocia and brachial plexus injury e. Respiratory distress i. RDS more likely as IDMs are more likely to be premature and maternal hyperglycaemia delays surfactant production ii. Other causes of RDS = TTN, cardiomyopathy f. Metabolic complications i. Hypoglycaemia = occurs in 25% 1. Caused by persistent hyperinsulinaemia – lasts for 2-4 days 5. Mechanism: Maternal hyperglycaemia  foetal hyperglycaemia  foetal hyperinsulinaemia ii. Hypocalcaemia 1. Lowest calcium occurs 24-72 hours after birth 2. Usually asymptomatic and resolves without treatment iii. HypoMg 1. Transient and asymptomatic, usually not treated g. Haematological complications – polycythaemia, hyperviscosity i. Chronic neonatal hypoxia results in increased EPO ii. Polycythaemia  hyperviscosity syndrome  vascular sludging, ischaemia and infarction iii. Higher rate of renal vein thrombosis h. Low iron stores i. Hyperbilirubinaemia j. Cardiomyopathy i. Increased risk of transient hypertrophic cardiomyopathy ii. Most prominent change is thickening of the interventricular septum iii. Usually asymptomatic 5. LONG TERM a. Diabetes b. Obesity and impaired glucose metabolism c. Impaired neurodevelopment

Answer 82

a. Maternal i. Close monitoring ii. Aim for strict BSL control b. Neonatal i. Initiate feeding within 1 hour ii. Screen glucose test within 30 minutes of first feed iii. Gavage feeding with breast milk or formula iv. IV glucose as needed

Answer 83

1. Hypothalamus a. Lateral nuclei of hypothalamus = hunger when stimulated b. Ventromedial nuclei = satiety c. Arcuate nuclei = where GI / adipose hormones converge to regulate food intake 2. Central neurotransmitters a. Anorexigenic = POMC neurons produce alpha- MSH + CART b. Orexigenic neurons = produce neuropeptide Y + AGRP 3. Short term players (less of a role in weight gain) a. Vagus nerve – stretch of GIT  inhibits appetite b. CCK released from enteroendocrine cells duodenum and jejunum in response to fat and protein  inhibits appetite, promotes bile/pancreatic enzyme secretion c. Peptide YY released from neuroendocrine cells ileum/colon in response to fat  inhibits appetite d. GLP released from pancreases in response to GI filling  inhibits appetite e. Ghrelin released from parietal oxyntic cells of stomach + intestine, rise during fasting  stimulates hunger and GH secretion 4. Long term factors = LEPTIN a. Peptide hormone in adipose tissue, signals satiety and appetite suppression b. ↑ adipose = ↑ leptin c. Acts via NPY, alpha-MSH receptors to decrease their usual orixogenic behaviour d. Stimulates POMC neurons to increase release of alpha-MSH (counteracts NPY action) e. ↑ metabolic rate and energy expenditure f. ↓ insulin secretion g. NOTE: can have leptin resistance and abnormalities in signaling in hypothalamus resulting in monogenic obesity (melanocortin 4 receptor)

Answer 84

Proopiomelanocortin (POMC) Precursor of ACTH, melanin, lipocortin, endorphin Obesity (no appetite inhibition) Pallor, red hair (no melanin) Adrenal insufficiency (no ACTH)

Answer 85

1. Diagnosis a. Age < 2 years = sex-specific weight for length is >97.7th centile on WHO charts b. Age > 2 years = BMI and CDC normative BMI centiles i. Overweight = BMI 85th to 95th centile ii. Obese = BMI > 95th centile iii. Extreme obesity = BMI >120% of 95th centile or >35 kg/m2 c. Other i. Age >6 years = waist to height ratio used as adjunct to BMI 1. Waist-to-height ratio of > 0.5 predicts cardiovascular risk in children 2. Half of height regardless of height d. NOTE: Height + weight in obesity i. A young child might exhibit high weight and high height because linear growth can increase early in childhood if a child consumes excess energy ii. At some point, the weight percentile exceeds the height percentile and the child’s BMI climbs into the obese range iii. Exogenous obesity drives linear height, so most obese children are tall for their age  most endocrine and genetic causes of obesity are associated with short stature 2. Investigation a. No routine laboratory investigations b. Comorbidities should be assessed c. Genetic obesity syndromes – indications for testing i. Extreme early onset obesity (<5 years of age) ii. Clinical features of genetic obesity syndromes – Hyperphagia iii. Family history of extreme obesity 3. Tracking a. Many, but not all, obese children will become obese adults b. The likelihood of persistence of childhood obesity into adulthood (sometimes called "tracking") is related to i. Age ii. Parental obesity iii. Severity of obesity iv. BMI trajectory during childhood 4. Red flags for underlying cause a. Short stature b. Abnormal physical signs c. Developmental disability d. Visual disturbance or headache (tumor)

Answer 86

5. Aetiology (genes+environment) a. Genetic 40-80% of variance in BMI i. Genetics accounts for 70-80% for body composition particularly in early years b. Environmental i. Decreased exercise ii. Decreased physical activity + increased sedentary activity iii. Energy dense food iv. Increased portion size 6. Medical causes of obesity = <5% a. Genetic i. Many and rare eg. POMC deficiency b. Syndromic i. Alstrom-Hallgren syndrome ii. Carpenter syndrome iii. Cohen syndrome iv. Bardet-Beidl syndrome v. Prader-Willi syndrome c. Endocrine (more likely to be short) i. Hypothyroidism ii. Cushing syndrome iii. PCOS iv. GH deficiency v. Pseudohypoparathyroidism vi. Insulinoma vii. Hypothalamic tumour / dysfunction d. Fat baby syndromes i. Prader Willi syndrome (big baby, hypotonia, small hands and feet) ii. Beckwith Wiedermann (macrosomia, hypoglycaemia, omphalocele, macroglossia) iii. Sotos (macrosomia, macrocephaly, large hands and feet) iv. Weaver (macrosomia, accelerated skeletal maturation, camptodactyly) v. Laurence-Moon/ Bardt-Biedel (obesity/ retinal pigmentation/ polydactylyl)

Answer 87

8. Prevention of obesity a. Dietary and activity education b. Healthy eating habits c. At least 20 minutes, optimally 60 minutes, of vigorous physical activity at least 5 days per week to improve metabolic health and reduce the likelihood of developing obesity d. Healthy sleep patterns e. Avoid technology-related screen time f. Involve the entire family g. Breastfeeding of infants 9. Intervention principles a. Family based lifestyle interventions b. Long term behavioural change c. Long term diet change d. Increase exercise and decrease sedentary behaviour e. Referral for multidisciplinary assessment 10. The simple 6 a. CHOOSE WATER AS YOUR MAIN DRINK b. EAT BREAKFAST EACH DAY c. EAT TOGETHER ONCE A DAY AS A FAMILY WITHOUT THE TV BEING ON d. LIMIT SNACKS e. SPEND 60 MINS OUTSIDE EVERY DAY PLAYING OR BEING PHYSICALLY ACTIVE f. LIMIT SCREEN TIME TO LESS THAN 2 HOURS PER DAY 11. Treatment a. Lifestyle =diet, exercise b. Pharmacotherapy – rarely used in children i. Metformin only in insulin resistance – shown in adults to delay progression to T1DM 1. Often used in adolecsents ii. Orlistat = lipase inhibitor 1. Results in diarrhoea 2. Weight loss 3. Not commonly used c. Bariatric surgery – rarely used in children i. The earlier – higher complication rate ii. Move to delay surgery until later in adolescence or early adulthood d. BEST = multidisciplinary team i. Hold BMI to hold centile while child grows

Answer 88

a. Diabetes/ Insulin resistance i. Prediabetes = moderate abnormalities in fasting glucose, glucose tolerance, or HbA1c ii. Fasting glucose and HbA1c are typically used for screening iii. NO validated test for measuring insulin resistance iv. In one study – 4% of adolescents with BMI >95th centile had asymptomatic T2DM v. Early diagnosis imperative as aggressive treatment can slow development of complications b. Metabolic syndrome i. ‘Metabolic syndrome’ is a term used to describe the clustering of metabolic risk factors for T2DM and atherosclerotic cardiovascular disease in adults c. Hyperandrogenism in females i. Adolescent girls with obesity are at an increased risk of hyperandrogenism and early onset PCOS (resulting in menstrual abnormalities ii. Diagnosis can be difficult to establish during adolescence d. Abnormalities in growth and development i. Obesity in children and adolescents may be accompanied by accelerated linear growth and bone age e. Other i. Pubertal advancement ii. Menstrual abnormalities iii. Reduced GH secretion + increased clearance

Answer 89

a. Obesity and children and adolescence linked with cardiovascular changes that are linked to increased cardiovascular risk in adulthood b. Hypertension = increased in obesity, correlates with the severity of obesity c. Dyslipidaemia = increased in obesity, particularly if central fat distribution d. Cardiac structure + function = associate with findings similar to seen in adults; increased LV mass etc. e. Coronary artery disease = increasing evidence suggests an association between obesity during childhood and cardiovascular disease during adulthood

Answer 90

a. NAFLD i. Obesity is associated with a clinical spectrum of liver abnormalities collectively known as NAFLD ii. 40% of obese children have fatty liver iii. 10% have mildly elevated serum aminotransferase concentrations – caused by NAFLD iv. Most common cause of liver disease in children v. Abnormalities include 1. Steatosis = increased liver fat without inflammation 2. Non-alcoholic steatohepatitis (NASH) = increased liver fat with inflammation vi. Diagnosis 1. Most patients asymptomatic – some have RUQ or abdominal discomfort 2. Elevation in transaminases, ALP an GGT 3. Imaging (USS) can confirm fatty liver – increased echogenicity 4. NO firm diagnostic criteria vii. Treatment = weight loss b. Cholelithasis i. Obesity is the most common cause of gallstones in children without predisposing conditions (eg. haemolytic anaemia, history of TPN) ii. One study found 10% of obese adolescents had gallstones iii. Risk for gallstones increases with BMI iv. Signs and symptoms are non-specific v. USS is the test of choice

Answer 91

NAFLD i. Obesity is associated with a clinical spectrum of liver abnormalities collectively known as NAFLD ii. 40% of obese children have fatty liver iii. 10% have mildly elevated serum aminotransferase concentrations – caused by NAFLD v. Abnormalities include 1. Steatosis = increased liver fat without inflammation 2. Non-alcoholic steatohepatitis (NASH) = increased liver fat with inflammation vi. Diagnosis 1. Most patients asymptomatic – some have RUQ or abdominal discomfort 2. Elevation in transaminases, ALP an GGT 3. Imaging (USS) can confirm fatty liver – increased echogenicity 4. NO firm diagnostic criteria vii. Treatment = weight loss

Answer 92

a. OSA = prevalence of OSA increased in obese children and adolescents b. Obesity hypoventilation syndrome i. Key criteria 1. Extreme obesity 2. Alveolar hypoventilation during wakefulness ii. More commonly, children and adolescents have hypoventilation during sleep in the absence of obstructive defect – perhaps due to restrictive ventilatory defect caused by obesity c. Asthma

Answer 93

a. SUFE i. Displacement of the capital femoral epiphysis from the femoral neck through the physeal plate ii. Typically occurs in adolescence, obesity is a significant risk factor iii. Require orthopaedic management b. Tibia vara (Blount disease) i. Progressive bowed legs and tibial torsion ii. Results from inhibited growth of the medial proximal tibial growth plate due to excessive weight baring iii. Tibia vara associated with obesity c. Fracture i. More susceptible to fracture – reduced bone mass when adjusted for body size

Answer 94

6. NEUROLOGIC a. Idiopathic intracranial hypertension i. Risk increases with severe obesity 7. DERMATOLOGICAL a. Intertrigo b. Furunculosis c. Hidradenitis suppurative = inflammatory nodules or deep fluctuant cysts in the interiginous skin of the axilla and groin d. Acanthosis nigricans e. Stirae densiae = mechanical factors 8. PSYCHOSOCIAL a. Teasing, discrimination, secondary disordered eating, poor self esteem, risk of depression

Answer 95

1. Key points a. Most common cause of infertility in women b. Frequently manifests in adolescent c. Characterised by ovulatory dysfunction and hyperandrogenism d. Lifelong implications with increased risk of metabolic syndrome, T2DM, and possibly CVD and endometrial carcinoma 2. Features a. Cutaneous signs of hyperandrogenism (eg. hirsutism, moderate-severe acne) b. Menstrual irregularity (eg oligo- or amenorrhoea, or irregular bleeding) c. Polycystic ovaries (one or both) d. Obesity and insulin resistance 3. Diagnosis a. Abnormal uterine bleeding pattern i. Abnormal for age or gynaecological age ii. Persistent symptoms for 1-2 years b. Evidence of hyperandrogenism i. Persistent testosterone elevation above adult norms – best evidence ii. Moderate-severe hirsutism is clinical evidence of hyperandrogenism iii. Moderate-severe inflammatory acne vulgaris – indication to test for hyperandrogenism

Answer 96

4. Clinical manifestations a. Cutaneous manifestations of hyperandrogenism i. Hirsutism = sexual hair in a male pattern ii. Acne iii. Other characteristics of hyperandrogenaemia = seborrhoea, hyperhidrosis, hidradenitis suppurativa iv. Frank virilisation is UNUSUAL in PCOS b. Ovarian findings i. Anovulation ii. Polycystic ovaries c. Associated metabolic features i. Obesity 1. Present in 50% of patients with PCOS 2. PCOS is the most common obesity-related endocrine syndrome in females ii. Manifestations of insulin resistance 1. Metabolic features of insulin resistance are common in adolescents with PCOS 2. Clinical manifestations of insulin resistance a. Acanthosis nigricans b. Metabolic syndrome c. Sleep disordered breathing d. NAFLD 6. Investigations a. Blood tests i. 75g OGTT with insulin levels ii. Fasting lipids iii. Testosterone = elevated in PCOS iv. SHBG v. Free androgen index vi. 17-OH-P = screening test for non-classical CAH secondary to 21-hydroxylase deficiency vii. DHEA = markedly elevated in adrenal tumour or cortisol reductase deficiency viii. FSH, LH ix. TSH x. Prolactin b. Pelvic USS

Answer 97

a. Physiological adolescent anovulation b. Virilising congenital adrenal hyperplasia i. Non-classical ‘late onset’ CAH is the second most common cause of androgen excess in adolescence ii. 3ß-hydroxysteroid dehydrogenase (3ß-HSD) 4. Investigations a. DHEAS level very elevated b. 17-hydroxypregnenolone elevation >10 SD above mean c. ACTH stimulation test d. Molecular testing iii. 11ß-hydroxylase c. Related congenital disorders of adrenal steroid metabolism or action i. Cortisone reductase deficiency ii. Apparent DHEA sulfotransferase deficiency d. Cushings syndrome e. Virilising tumours of adrenals or ovaries i. >50% malignant ii. Usually cause rapid onset of virilising symptoms including hirsutism, temporal hair recession, increased muscle bulk, voice deepening, clitoremegaly without genital ambiguity iii. Substantial minority are mildly hyperandrogenic and indolent in onset and mimic PCOS f. Ovarian steroidogenic block g. Hyperprolactinaemia h. Insulin-resistance disorders i. Acromegaly j. Thyroid dysfunction k. Drugs = anabolic steroids

Answer 98

a. Treatment is primarily directed against the major clinical manifestations b. Pharmacological i. Oral contraceptive pill 1. 1st line treatment is usually estrogen-progestin combined oral contraceptive pill (COC) – corrects both menstrual abnormalities and hyperandrogenaemia 2. Progestin component inhibits endometrial proliferation  preventing hyperplasia and reducing the risk of associated carcinoma 3. Estrogen component  reduces androgen excess  corrects menstrual abnormalities and improves hirsutism and acne (takes 3-6 months) ii. Anti-androgen 1. If hirsutism is not adequately controlled by cosmetic and COC treatment – anti-androgen can be added iii. Insulin sensitiser 1. Improve ovulation in half of cases and modestly reduce androgen levels 2. Not as effective as COC in controlling menstrual cyclicity or hirsutism 3. Metformin is suggested if abnormal glucose tolerance or lipid abnormalities of the metabolic syndrome that cannot be normalised by weight loss c. Non-pharmacological = lifestyle, weight loss i. Lifestyle modification is first line for overweight and obesity ii. Improves menstrual regularity, acanthosis nigricans, and hyperandrogenism

Answer 99

• Elevated o Insulinoma o Sulfonylurea intoxication o Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) o Insulin resistance states eg. obesity, Cushings o Chronic kidney disease • Decreased o Type 1 diabetes mellitus o Exogenous insulin injection (factitious) o Hypoglycemia due to insulin-like growth factor secreting tumor o Insulin-independent hypoglycemia

Answer 100

1. Situation a. Acute on chronic alcoholic who has a binge b. Then fasted, no oral intake c. +/- vomiting d. Usually not diabetic 2. Pathophysiology = ETOH + fasting a. Fasting i. Glycogenolysis / gluconeogenesis / lipolysis ii. Decreased insulin, increase glucagon iii. Insulin deficiency = lipolysis and ketone formation b. ETOH i. Metabolized in liver ETOH  acetylaldehyde  acetate, with NAD+ as cofactor (NAD NADH+ + H+) ii. Ratio of NADH/NAD+ rises iii. Result = inhibition of gluconeogenesis (requires NAD+), favors production of B-hydroybutyrate over acetoacetate  build up of ketones 3. Investigations a. BSL – low, normal, high b. Ketones – elevated c. Osmolarity – high d. UEC/CMP – Mg often low e. VBG – mixed metabolic acidosis (ketones) + metabolic alkalosis (vomiting) 4. Management a. Glucose/insulin infusion

Answer 101

i. Females 1. Gonads  ovaries 2. Paramesonephric (Mullerian) ducts  fallopian tubes, uterus, and upper vagina 3. Mesonephric (Wolfian) ducts persist in vestigial form 4. External genitalia a. Genital tubercle  clitoris b. Genital swellings,  labia majora c. Genital folds  labia minora ii. Males 1. Gonads  testes 2. Mesonephric (Wolfian) ducts  epididymis, vas deferens, seminal vesicles + ejaculatory ducts 3. Paramesonephric (Mullerian) ducts  regresses 4. External genitalia a. Genital swellings fuse  scrotum b. Genital folds elongate and fuse  shaft of penis and penile urethra c. Genital tubercule  glans penis d. Prostatic buds develop in the wall of the proximal urethra and elongate to form testes e. Testicular descent occurs in latter part of gestation

Answer 102

a. Key points i. All embryos start with bipotential gonads, Mullerian and Wolffian ducts ii. For the first 6 weeks of human gestation the two sexes develop in an identical fashion iii. Determination of the indifferent gonad into ovary or testis begins at 6 weeks following secretion of hormones by the fetal testes (ovary is usually silent) iv. Further features of the urogenital tract are completed by 12 weeks in males and slightly later in females v. Sex specific hormones from the gonads influence sexual differentiation c. Males i. Sex-determining region of Y chromosome (SRY) – directs development of gonads into testes 1. By 8-9 weeks have identifiable testes 2. Y chromosome is ESSENTIAL for testicular development ii. Hormones – 3 important 1. Anti-Mullerian hormone (= Mullerian Inhibiting Hormone/ Mullerian Inhibiting Substance) a. Produced by Sertoli cells of the fetal testis b. Causes regression of the Mullerian ducts  results in internal genital development c. If low levels in male = mullerian structures can remain 2. Testosterone a. Produced by fetal testes (Leydig cells) b. Stimulates Wolffian duct differentiation into epididymis, vasa deferentia, seminal vesicles and ejaculatory ducts c. Initially controlled by placental hCG and later by LH (produced by pituitary) 3. Dihydrotestosterone (potent testosterone) a. Formed by 5-alpha reductase acting on testosterone b. Regulates development of prostate and external genitalia – complete by 12th week d. Females (essentially lack everything above) iv. If male development is not initiated – ovarian development will occur around week 10 1. Need absence of SRY, testosterone and AMH

Answer 103

1. Genetic a. KAL-1, FGFR1, GnHR, DAX- 2. Organic a. Tumours i. Craniopharyngiomas ii. Germinomas, meningiomas, gliomas, astrocytomas b. Post head trauma c. Cranial irradiation d. Multiple pituitary hormone deficiency e. Isolated gonadotrophin deficiency (without anosmia) 3. Syndromal a. CHARGE b. Prader-Willi c. Kallman d. Bardet-Biedl 4. Chronic disorders a. Chronic systemic disease – IBD, renal failure, CF b. Malnutrition + AN c. Hypothyroidism, hyperprolactinaemia, poorly controlled diabetes, Cushing’s disease

Answer 104

1. Key points a. Cause of hypogonadotropic hypogonadism b. Occurs in males and females c. Classification i. 60% anosmia or hyposmia = Kallman syndrome ii. 40% normal smell = normosmic IGD 2. Genetics a. Sporadic or due to mutation in KAL1 gene (Xp22.3) or KAL2 3. Clinical manifestations a. Anosmia or hyposmia or normal smell b. Absent or partial puberty 4. Genetics a. Isolated gonadotropin deficiency (= hypogonadotropic hypogonadism without anosmia) i. Specific genetic defect is not found in most cases b. Kallman syndrome i. Autosomal (dominant or recessive) in 85% ii. X-linked 15% 1. Mutation in KAL1 gene 2. Leads to failure of olfactory axons and GnRH expressing neurons to migrate from their common origin in the olfactory placode to the brain 5. Investigations a. In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam b. In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts

Answer 105

Primary hypogonadism, i.e. issue in gonads 1. Etiology a. Congenital i. FSH and LH resistance ii. Mutations in steroid synthetic pathways iii. Gonadal dysgenesis iv. Klinefelter syndrome v. Noonan syndrome (PTPN-11 gene mutation in many cases) vi. Cystic fibrosis (infertility) b. Acquired i. Cryptorchidism (some cases) ii. Vanishing testes iii. Chemotherapy iv. Radiation v. Infection (eg. mumps) vi. Infarction (testicular torsion) vii. Trauma 2. Clinical Manifestations a. Primary hypogonadism suspected at birth if testes and penis small b. Often not noticed or diagnosed until puberty when secondary sex characteristics fail to develop i. Facial, pubic and axillary hair is scant or absent ii. Neither acne nor regression of scalp hair iii. Voice remains high pitched iv. Penis and scrotum remain infantile v. Fat accumulates in the hips and buttocks, sometimes the abdomen and breasts c. Epiphyses close later than normal – therefore have long extremities i. Arm span may be several inches longer than height ii. Upper segment <<< lower segment = eunuchoid 1. Ie. the ratio of upper to lower segment is <0.9 3. Diagnosis a. Hormone levels i. ↓ Serum total testosterone level – measured in morning (maximum at 0800) ii. ↑ FSH and LH iii. hCG stimulation test – only small or no rise in testosterone level iv. ↑ AMH – secreted by Sertoli cells and usually suppressed by testosterone

Answer 106

• 47,XXY – most common sex chromosome disorder in humans • Prevalence of 1/500 • Key features o Cognitive – normal intelligence, learning disability, autism, social problems o Cardiac – 55% mitral valve prolapse o Oncology – increased frequency of extragonadal germ cell tumour, breast cancer o Primary hypogonadism – small, firm testes, decreased virilisation, small phallus, hypospadias, cryptorchidism o Growth – tall, legs > trunk Clinical impairments become more severe with additional chromosomes

Answer 107

* 46,XX males – translocation of Y material including sex determining region (SRY) to the X chromosome during paternal meiosis * Essentially gives same phenotype as Klinefelter: Klinefelter: o Cognitive – normal intelligence, learning disability, autism, social problems o Cardiac – 55% mitral valve prolapse o Oncology – increased frequency of extragonadal germ cell tumour, breast cancer o Primary hypogonadism – small, firm testes, decreased virilisation, small phallus, hypospadias, cryptorchidism o Growth – tall, legs > trunk

Answer 108

Ie secondary hypogonadism (problem not with gonads) 1. Key points a. Deficiency of LH or FSH or both b. Primary defect either in the anterior pituitary OR hypothalamus c. Hypothalamic aetiology result in deficiencies of GnRH d. Usually recognized due to marked pubertal delay 2. Etiology a. Congenital i. Genetic defects 1. Kallman syndrome 2. Normosmic hypogonadotropic hypogonadism ii. Other genetic disorders associated with hypogonadotropic hypogonadism 1. Eg. Leptin gene, leptin receptor, DAX1, SF-1 iii. Inherited syndromes 1. Prada Willi 2. Bardet-Biedl 3. Laurence-Moon-Biedl 4. Alstrom iv. Isolated HH (hypogonadotropic hypogonadism) at pituitary level v. Multiple pituitary hormone deficiencies 1. Septooptic dysplasia 2. Other disorders of pituitary organogenesis vi. Idiopathic b. Acquired i. Anorexia ii. Drug use iii. Malnutrition iv. Chronic illness especially Crohn’s disease v. Hyperprolactinaemia vi. Pituitary tumours vii. Pituitary infarction viii. Infiltrative disorders (eg. histiocytosis) ix. Haemosiderosis and haemochromatosis x. Radiation 3. Clinical manifestations a. Absent or partial puberty in adolescents at presentation b. Incomplete sexual maturation on examination 4. Investigations a. ↓ Serum total testosterone level – measured in morning (maximum at 0800) b. ↓ FSH and LH (inappropriately low) 5. Treatment a. Usually managed with testosterone b. Sometimes treatment with gonadotropins

Answer 109

Defined as hypogonadism in a women <40 years, i.e. ovaries stop/don't function normally Turner syndrome is the most common cause of POI – ovaries are normal but accelerated depletion

Answer 110

Ie primary hypogonadism (issue is in gonads) 1. Key points a. Primary hypogonadism in women is defined as ovarian failure accompanied by high FSH concentration i. Primary ovarian insufficiency (POI) = defined as hypogonadism in a women <40 years b. Characterised by loss of oocytes, lack of folliculogenesis and ovarian oestrogen production, and infertility c. Diagnosis of hypergonadotropic hypogonadism before puberty is difficult d. Except in cases of Turner syndrome, most affected patients have no pre-pubertal manifestations e. Turner syndrome is the most common cause of POI – ovaries are normal but accelerated depletion 2. Pathogenesis a. Accelerated follicle depletion b. Decreased steroid production without oocyte loss

Answer 111

3. Etiology a. Genetic i. FSH and LH resistance ii. Mutations in steroidogenic pathways iii. 46 XXX gonadal dysgenesis iv. Turner syndrome and its variants v. Noonan syndrome vi. SF-1 gene mutation vii. Galactosaemia viii. Fragile-X associated disorders – carriers of FMR1 gene pre-mutation ix. Bloom syndrome x. Werner syndrome xi. Ataxia-telangiectasia xii. Fanconi anaemia b. Acquired i. Chemotherapy ii. Radiation therapy iii. Autoimmune ovarian failure from autoimmune polyendocrine syndromes 1 and 2 4. Etiology base on cause a. Accelerated follicular atresia i. Genetic defects 1. Turner syndrome 2. Fragile X permutation 3. X chromosome deletions and translocations ii. Ovarian toxins 1. Chemotherapeutic drugs (especially alkylating agents) 2. Radiation 3. Mumps or CMV iii. Autoimmune injury – as part of polyglandular autoimmune syndromes b. Abnormal follicular stimulation i. Intra-ovarian modulators – BMP15 ii. Steroidogenic enzyme defects iii. Gondaotropin receptor function

Answer 112

5. Clinical manifestations a. Change in menstrual cycle – irregular menstrual cycles b. Infertility c. Consequences of oestrogen deficiency – hot flushes, vaginal dryness, bone loss and osteoporosis d. Clues to underlying cause i. Prior ovarian surgery, chemotherapy ii. Symptoms of anorexia, weight loss, abdominal pain, weakness, skin pigmentation  primary adrenal insufficiency iii. History of autoimmune diseases  polyglandular autoimmune iv. Family history of POI – 10% cases familial v. Family history of fragile X 6. Investigations a. Hormone levels b. Identify underlying cause i. Adrenal autoantibodies ii. Other autoimmune screen iii. Karyotype – Turner syndrome iv. FMR pre-mutation 7. Treatment a. Puberty induction b. Transdermal patches = estradot i. Do not place on breast region iii. When spotting occurs, change to COC pill

Answer 113

• Inherited inborn error of metabolism affecting galactose pathway • Incidence 1/50,000 • Most commonly due to deficiency in galactose1-phosphate uridyl transferase (GALT) • Results in progressive ovarian fibrosis; testis spared • Primary ovarian insufficiency o Hypergonadotrophic hypogonadism occurs in 75-95% of homozygous galactosaemic women  Lower rates in affected males  FSH elevated, LH often normal o Variable age at presentation  Delayed puberty/ primary amenorrhoea  Secondary amenorrhoea in adult o Generally progressive ovarian dysfunction but levels may fluctuate • Treatment = induction of puberty

Answer 114

* Deposition of iron in gonad, usually ovary * Can also deposit in hypothalamus * Primary ovarian failure variable

Answer 115

1. Key points a. Hypogonadotropic hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is interrupted either at the hypothalamic or pituitary level b. Often difficult to distinguish between marked constitutional delay and hypogonadotropic hypogonadism 2. Etiology a. Hypothalamic i. Genetic defects 1. Kallman syndrome 2. Other gene defects 3. Inherited syndromes a. Prader-Willi b. Bardet-Biedl 4. Marked constitutional growth delay ii. Acquired (reversible) 1. Anorexia 2. Drug use 3. Malnutrition 4. Chronic illness – Crohn’s disease 5. Hyperprolactinaemia b. Pituitary i. Genetic 1. Isolated GnRH deficiency 2. Septo-optic dysplasia 3. Disorders of pituitary organogenesis ii. Acquired 1. Pituitary tumours 2. Pituitary infarction 3. Infiltrative disorders – histocytosis, sarcoidosis 4. Haemosiderosis, haemochromatosis

Answer 116

1. Key points a. Congenital disorders where there is atypical development of the chromosomal, gonadal or anatomic sex b. Incidence - 1/4500 c. Can present at any age d. Chromosomal anomalies found in 3% cryptorchidism, 7% hypospadias and 13% cryptorchidism + hypospadias e. Note: i. Infants with genital ambiguity and non-palpable gonads should be presumed to have CAH and observed for salt loss until diagnosis confirmed or excluded ii. Isolated micropenis – usually XY, suspect virilized female if hypospadias A palpable gonad is almost always testicular and implies Y chromosome material 2. Classification a. Virilised XX b. Undervirilised XY c. Mixed sex chromosome pattern 3. Clinical approach a. Is it XX or XY? b. 50% CAH the most common cause (need to exclude salt wasting) c. 40% mixed gonadal dysgenesis d. In 46 XY DSD a specific dx not found in up to 50% of cases Normal neonatal penis >2.4cm long >0.8cm wide Clitoral size 2-6mm 5. Consider DSD in infants with a. Bilaterally non-palpable testes b. Microphallus c. Scrotal or perineal hypospadias d. Clitoromegaly e. Posterior labial fusion f. Gonads palpable in the labioscrotal folds g. Hypospadias and unilateral non-palpable gonad h. Discordant genitalia and sex chromosomes 6. Common causes a. Virilising congenital adrenal hypoplasia >50% b. Mixed gonadal dysgenesis (46XX/46XY mosiacism) 35-40% c. Androgen insensitivity syndrome d. Clitoral/labial anomalies e. Hypogonadotropic hypogonadism f. 46XY SGA males with hypospadias

Answer 117

i. CAH 1. UEC, BSL – salt wasting 2. 17-hydroxyprogesterone a. Should be done in ALL infants with bilateral non-palpable gonads presenting with atypical genitalia – to exclude CAH due to 21-hydroxylase deficiency 3. Other hormones – 11-DOC 4. All infants should be tested for less common types of CAH a. DHEA b. 17-hydroxpregnenolone c. 11-deoxycrotisol 5. Urinary steroids – day 3 or later (otherwise maternal hormones) 6. ACTH + renin ii. Karyotype – including probe for SRY using FISH 1. Usually performed using peripheral leukocytes 2. In some complicated patients a karyotype of the gonadal tissue may be done 3. Due to the possibility of mosaicism at least 200 cells should be examined 4. SRY probe = SRY gene is a critical factor in testicular development and usually coincides with the presence of a Y chromosome iii. Hormone profile 1. Consider: LH, FSH, T, DHT, E1, AMH; inhibin B 2. Consider timing relative to mini-puberty/ puberty iv. Abdominal/pelvic USS 1. Important to determine the presence of gonads, a uterus and/or vagina a. Absence of uterus – means presence of AMH which means presence of testicular tissue b. If uterus – no AMH therefore may be XX or problem with AMH v. Laparoscopy + gonadal biopsy – 6 months and older vi. DSD gene panel vii. Bone age – older child

Answer 118

• Normal female internal organs – no AMH (as no Y chromosome) • Results from exposure to excess androgens during 9-13 weeks of gestation • 90% have CAH • Clinical spectrum o Depends on duration and extent of exposure to androgens o Clitoral enlargement o Posterior labial fusion o Phallus with penile urethra and fused scrotum with raphae o NOT micropenis without hypospadias 1. Androgen excess a. Foetal / placental source i. CAH 1. 21 hydroxylase deficiency 2. 11 beta hydroxylase deficiency 3. 3 beta hydroxysteroid dehydrogenase II deficiency 4. Cytochrome P450 oxidoreductase ii. Aromatase deficiency iii. Glucocorticoid receptor gene mutation b. Maternal source i. Virilising ovarian or adrenal tumour ii. Androgenic drugs 2. Disorder of ovarian development a. Ovotesticular DSD i. 75% are XX ii. True hermaphrodite iii. Both ovaries and testes iv. Risk gonads malignancy low b. Testicular DSD i. SRY translocation ii. SOX9 duplication c. Gonadal dysgenesis 3. Undetermined a. Associated with GU and GI defects Investigations - FISH (?SRY) - 17-OH-progesterone (?CAH) - USS (?internal organs) - AMH - Response to beta hCG

Answer 119

``` • Results from androgen deficiency • Clinical spectrum o Micropenis +/- hypospadias o Uni/bilateral undescended testes o Some cases complete female phenotype ``` 1. Defects in testicular development a. Denys-Drash syndrome – WT1 gene mutation b. WAGR syndrome: Wilms tumour, aniridia, genitourinary malformation, retardation c. 11p13 deletion d. SRY gene mutation e. XY gonadal agenesis f. XY pure gonadal dysgenesis = Swyer syndrome g. Campomelic syndrome (autosomal gene at 17q24.3-25.1) and SOX9 mutation 2. Deficiency of testicular hormones a. Leydig cell aplasia b. Mutation in LH receptor c. Lipoid adrenal hyperplasia d. 3 beta HSD II deficiency – high androstenedione above block e. 17 hydroxylase deficiency f. Persistent Mullerian system i. AMH gene mutations ii. Receptor defects for AMH 3. Defect in androgen action a. Dihydrotestosterone deficiency i. 5 alpha reductase II mutations ii. NOTE: this is the active form of testosterone iii. Will often have ambiguous or female external genitalia b. Androgen receptor defects i. Complete androgen insensitivity syndrome ii. Partial androgen insensitivity syndrome c. Smith-Lemli-Opitz syndrome i. Defect in converting 7-dehydrocholesterol to cholesterol Investigations - FISH (?SRY) - 17-OH-progenelone - USS (?testes) - AMH, beta hCG, androgens

Answer 120

1. Key points a. 46 XY subjects with bilateral testes and normal testosterone formation have impaired virilisation during embryogenesis due to defective conversion of testosterone to dihydrotestosterone (DHT) b. DHT is important for EXTERNAL genitalia during embryogenesis 2. Genetics a. Autosomal recessive (loss of function mutation in gene SRD5A2 ) 3. Clinical manifestations a. External genitalia are predominantly female at birth (or ambiguous) b. Internal urogenital tract is male – epididymides, vasa deferentia, seminal vesicles and ejaculatory ducts which empty into a blind-ending vagina i. Absence of mullerian duct derivatives indicates AMH is produced and acts normally c. Puberty i. Marked masculinisation ii. Phallic growth iii. Gender role change – most children raised as female  change gender to male during puberty d. Gynaecomastia is RARE 4. Investigations a. Biochemical diagnosis of 5-alpha reductase deficiency is characterised by: i. Normal testosterone level ii. Normal or low DHT level iii. Markedly increased and hCG-stimulated testosterone: DHT ratio (>17) iv. High ratio of urinary etiocholanolone to androsterone b. Genetic testing – SRD5A2 gene mutational analysis 5. Differential diagnosis a. 17-beta hydroxysteroid dehydrogenase 3 deficiency i. Hereditary disorder of testosterone biosynthesis b. Partial androgen insensitivity i. Usually associated with gynaecomastia at the time of puberty ii. Normal ratios of urinary 5-beta to 5-alpha reduce metabolites iii. Normal testosterone/DHT ratios 6. Management a. Dependent on phenotypic findings at birth b. Infants with this condition should be raised as males whenever possible c. Treatment of male infants with DHT results in phallic enlargement

Answer 121

1. Key points a. Loss of function mutations of the gene that encode the androgen receptor (AR) b. Individuals with 46,XY karyotype do not virilise normally despite the presence of bilateral testes and serum concentrations within or above normal male range c. Various phenotypes d. Testes develop and produce male hormones (AMH + T) but androgen insensitivity at receptor level e. Classification i. Partial = PAIS = variable clinical phenotype ii. Complete = CAIS = female external phenotype 2. Genetics a. X linked mutation in androgen receptor gene b. >50% of ‘presumed PAIS’ have no genetic confirmation of diagnosis c. Important impact for management (eg. predicting malignancy) 3. Diagnosis – considered in: a. Males and females of all ages, including newborns, who have ambiguous genitalia b. Girls with inguinal hernias or labial masses c. Women with primary amenorrhea d. Adolescent girls who become virilized and develop clitoromegaly e. Adolescent boys who fail to undergo normal male puberty or who have persistent gynecomastia f. Adult men with undervirilization or with infertility associated with azoospermia or severe oligospermia 7. Evaluation a. Hormone levels i. During first year of life = testosterone, LH, FSH ii. Children and adults 1. Capacity for testosterone synthesis should be assessed by the administration of hCG b. Genetic testing 8. Management a. Nil therapy to reverse the development that occurs during embryogenesis b. Gonadectomy i. Risk of tumorigenesis is increased in all post-pubertal subjects with cryptorchid testes ii. Tumours (germ cell tumours and gonadoblastomas) occur in 1.5-2% of undescended testes – more often in abdominal than inguinal testes; some become malignant iii. Gonadectomy is typically delayed until sexual maturation is complete c. Hormone replacement i. For CAIS and PAIS individuals who are phenotypically female – oestrogen replacement can be given to promote feminiziation + bone density d. Psychological support

Answer 122

a. Most often diagnosed in infancy or adolescence b. Female phenotype c. Many opt to leave gonads in situ (often inguinal/ labio-scrotal) d. Risk of osteoporosis – ultimately need estrogen e. Need to screen for malignancy f. Features i. Normal breast development due to aromatization ii. Testes produce AMH therefore no ovaries/uterus - blind/short vaginal pouch on examination iii. Primary amenorrhea iv. No virilisation despite high levels of testosterone - little or no axillary or pubic hair v. Often tall g. Investigations i. Serum testosterone concentrations in the normal adult male range ii. 46,XY karyotype

Answer 123

a. Associated with less severe impairments of AR function than CAIS b. Results in a spectrum of defects in virilisation c. Gonad(s) often palpable but NOT always; no uterus, variable external genital phenotype d. Difficult diagnosis e. Consider 46XY with genital ambiguity when i. Testosterone is normal (not low) and T:DHT is normal ii. +/- histologically normal testis on biopsy iii. Poor response to exogenous testosterone (if given for small penile size) – issue at puberty is to attain virilisation/ secondary sex characteristics f. Spectrum i. Female phenotype with mild virilisation ii. Predominantly male phenotype iii. Infertile male syndrome iv. Undervirilised fertile male syndrome

Answer 124

1. Key points a. Male undervirilisation due to low androgen exposure in utero 2. Genetics a. Autosomal recessive b. Affected 46XX – no phenotype (ie normal female) 3. Clinical manifestations a. Female external genitalia +/- mild clitoromegaly with undescended testes b. Normal AMH hence no Mullerian structures c. Puberty (larger Leydig cell volume) – considerable virilisation occurs in genitalia and male pattern hair growth; gynaecomastia is common d. Gender dysphoria and change to living as male reported 4. Investigations a. Suspect/ recognizing the genital ambiguity in the first instance b. 10-15 fold increase in usual androstenedione: testosterone ratio (although not uniformly seen); also get increased A:T if testes are dysgenetic hence need to assess for this also c. Incidence varies from 1:200 in Gaza to 1:167,000 in Netherlands

Answer 125

``` o Both ovarian and testicular tissues present, either in same or opposite gonads o Ovotestis is most common o Extremely rare o Karyotype:  Approx. 70% 46XX • Most sporadic, unknown • Cases of siblings • Approx. 10% have SRY gene on X  20% 46XX/46XY mosaicism • ½ of these are chimeras, i.e. fusion of 2 zygotes  <10% 46XY  NOTE: peripheral blood karyotype may not match gonadal ``` * Rare * “True hermaphroditism” * Both ovarian and testicular tissue in same individual * Clinical phenotype is variable and may change over time * Presence of Y material = increased risk of malignancy

Answer 126

o 45X Turner o 47XXY Klinefelter o 45X/46XY o 46XX/46XY

Answer 127

Gonadal dysgenesis is the name given to any of a multitude of conditions that can cause impaired development of the gonads, i.e., the testes or ovaries 1. Key points a. Abnormalities of sex determination b. Can be isolated or associated with syndromes i. Examples – Denys-Drash, WAGR, Frasier syndrome; or SRY or SOX9 mutation/ deletions; SF1 mutations - adrenal failure and sex reversal c. Karyotype varies i. 45XO 1. Ovarian insufficiency 2. External genitalia female 3. Usually Turner syndrome phenotype ii. 46XY 1. External genitalia often appear asymmetrical 2. Often one gonad palpable 3. 75% have a uterus/ Mullerian remnant (low AMH) iii. 46XX 1. Typical external genitalia 2. Present with absent puberty iv. 45X/ 46XY 1. Gonadal development ranges from streak to testis or ovotestis a. Male phenotype most commonly 45X/46XY – 90-95% (important given increase in antenatal NIPT) b. Remaining 5-10% account for 40% of all ambiguous genitalia 2. Classification a. Partial gonadal dysgenesis i. Gonads contain recognizable testicular or ovarian elements ii. Commonly asymmetric with streak on one side and dysgenetic gonad on other iii. Can have female phenotype or varying degrees of virilisation (depending on Leydig cells in dysgenetic testis) b. Complete i. ‘Streak’ gonads ii. XX or XY (Swyer) – primary amenorrhoea, scanty or absent pubic hair, absent breast development iii. Often not diagnosed in newborn period iv. Risk of gonadoblastoma if Y material – needs screening or gonadectomy 3. Investigations a. Karyotype and FISH for Y (rapid) b. Pelvic USS including Inguino-scrotal region c. +/- MRI/ urogenital sinugram d. Serum LH and FSH e. AMH f. Testosterone +/- DHT, estrogen 4. Management a. Monitoring for malignancy – may need gonadectomy (if no inherent gonadal function but high malignancy risk) b. Management of puberty with hormonal replacement as needed

Answer 128

1. Key points a. Proliferation of mammary glandular tissue in male i. Presence of palpable fibroglandular mass at least 0.5cm in diameter located concentrically beneath the nipple or areolar region ii. Usually bilateral, but can be asymmetrical and even unilateral b. Common condition in male c. True gynaecomastia requires differentiation from pseudogynacomastia (accumulation of adipose tissue) d. If non-pubertal consider Klinefelters e. Mechanism: decrease in androgen production, increase in oestrogen production 2. Natural history a. Trimodal distribution in neonates (prevalence 60-90%), pubertal period (30-60%), and older males (30-60%). b. In neonates, it is because of the high oestrogenic period of pregnancy i. It usually regresses 2-3 weeks post-delivery 3. Classification a. Physiological i. Neonatal gynaecomastia ii. Pubertal gynacomastia 1. Peaks at age 13-14, and usually regresses within 18 months 2. During puberty, oestradiol (E2) rises to adult levels before testosterone – this imbalance accounts for the development of gynaecomastia. 3. It is typically painful, tender gynaecomastia b. Pathological i. Fetal androgen deficiency ii. Pre-pubertal androgen deficiency iii. Adult androgen deficiency

Answer 129

a. Fetal i. Fastest period of growth iii. Size at birth is determined by: 1. Mother’s size 2. Placental nutrient supply v. Growth affected by nutrition and IGF2 (LIVER) 1. Hypothyroid – normal birth length 2. GH deficiency – normal birth length 3. GH resistance in Laron dwarfism (therefore no IGF) – short birth length b. Infancy i. Linear growth velocity rapid in first year of life (dependent upon nutrition and genetics)- 10cm/year 1. Nutrition is the main driver ii. Weight doubles by 6 months, triples by 12 months iii. Rapid, but decelerating growth rate c. Childhood i. Slow, steady growth phase – average 5 cm/year ii. During early childhood, nutrition is the most important factor (first three years of life) 1. Later  GH has greater role (GH deficiency does not present until >3 years) iii. Requirements for normal growth = nutrition, thyroid hormone, vitamin D ,steroids d. Puberty i. Most rapid postnatal linear growth phase 1. Due to pulsatile release of FSH/LH (pituitary) resulting in testosterone (testicles) and oestrogen (ovaries) to facilitate puberty 2. Synergistic with GH secretion 3. ↑ GH secretion leads to back lengthening ii. Increase in sex hormones have direct effect on bone growth but also cause peak in IGF1 and GH iii. In girls 1. Growth spurt starts age 9 (stage 3 puberty) 2. Peak growth velocity 8.5cm a year at age 11-13years 3. Average age of menarche 12-12.5 4. After menarche, linear growth velocity 5-6cm/year iv. In boys 1. Growth spurt starts age 11 (stage 4 puberty) 2. Peak growth velocity 9.5cm a year at age 13-15years v. Epiphyses fuse 1. Age 15 for girls 2. Age 17 for boys

Answer 130

Genetic/Chromosomal Most important factor • Familial height • Tallness: Fragile X, Klinefelters (47 XXY) • Shortness: Turners (45XO), Achondroplasia (dominant) Nutritional • Second most important • Undernutrition causes growth failure • Placental insufficiency  IUGR • IUGR in utero often does not catch up (cf. SMA) • Overnutrition may cause life-long obesity Hormonal • GH & Insulin-like Growth Factor 1 (GH-IGF1) axis • Thyroid hormone: physical & mental growth • Testosterone & Adrenal hormones: anabolic & growth promoting, causing bone maturation • Oestrogen: inhibit growth & cause early epiphyseal fusion • Emotional environment also regulates

Answer 131

a. Key points i. Peptide hormone ii. Chromosome 17 iii. Released from anterior pituitary somatotropes - hypothalamus release growth hormone releasing hormone to stimulate ant pit production GH iv. Very short lived – weak plasma protein binding, released into tissues rapidly i. Pulsatile secretion – 10 pulses per day b. Mechanism of action i. Direct effects of growth hormone ii. Indirect effects of IGF-1 (converted from GH) - IGF1 negatively feeds back to hypothalamus, causes release of growth hormone inhibiting hormone to inhibit GH release from ant pit c. Summary of actions i. Insulin and glucose 1. ↓ glucose uptake throughout the body (opposes action of insulin – but by doing so ↑ glucose levels in blood stimulates insulin secretion = diabetogenic effect) 2. ↑ glucose production through gluconeogenesis ii. Other metabolic effects 1. ↑ protein synthesis, ↑ protein synthesis 2. ↑ lipolysis, mobilizes FFA iii. Stimulates bone growth – 2 mechanisms: 1. Encourages long bone growth at epiphyses + cartilage deposition 2. Stimulates osteoblasts

Answer 132

* Mediates most of GH’s growth-promoting effects * 75% bound to IBFBP3 * Majority circulating IGF1 produced in liver * Most tissues produce IGF1 in response to GH but does not enter circulation (may act locally in paracrine fashion) * Control of IGF1 depends upon nutritional factors, age and tissue-specific stimulatory factors (i.e. In testes and ovaries) in addition to GH

Answer 133

* Production does not depend on GH * Important during foetal development * Uncertain significance in adult life

Answer 134

Weight = (Age + 4) x 2 • Weight loss in first few days 5-10% of birth weight (preterms lose more) • Return to birth weight 7-10days of age (preterms take longer) - weight gain 15-30g/d first 3 months • Double birth weight 4-5 months Triple birth weight 1 year Quadruple birth weight 2years • Daily weight gain 10g/kg birth weight for first 3-4 months (30g/day) 5g/kg birth weight 3-4 months until 12 months (20g/day) • Average weight gains 3.5kg at birth 10kg at 1 year 20kg at 5 years 30kg at 10years

Answer 135

* Changes over first 6-18months that reflect stabilization at genetic potential compared with in utero environment * Usually doesn’t cross 2 centiles, developmentally normal

Answer 136

a. Arm span: height should be 1: 1 at all ages i. Abnormal in Marfans/Klinefelters/dwarfism ii. Arm span < height = skeletal abnormalities b. Upper: lower i. Upper = crown to pubic symphysis ii. Lower segment = pubic symphysis to ground iii. Changes with age 1. 1.7:1 as a neonate 2. 1.4:1 4-5 years 3. 1:1 at 10-12 years iv. Proportionate = familial short stature

Answer 137

a. Females = (M + F -13 )/ 2 +/- 9 cm (3rd to 97th centile of anticipated adult height) b. Males = (M+F +13) / 2 +/- 10 cm (3rd to 97th centile of anticipated adult height)

Answer 138

a. XR of hand and wrist b. Physiological maturity by epiphyseal fusion c. Indicates stage of bone development vs. chronological age (<1 year delay is normal) d. Indicates underlying disease and predicts mature height e. Delayed or advanced age >20% above or below chronological age

Answer 139

a. Measurement of rate of growth b. Inaccurate if interval of less than one year c. Reaches nadir by late childhood; pubertal associated growth spurt than decreases by age 15-16 d. Do not take over <4 months e. Need > 1 measurement a year for accuracy f. Impaired if the height for age has crossed more than 2 major centile lines g. Or if child growing slower than: i. 2-4 yo = < 5.5cm/yr ii. 4-6 yo = < 5cm/yr iii. 6yo-puberty = < 4cm/yr for boys + < 4.5cm/yr for girls h. Or utilize height velocity chart: < 10th centile warrants thorough investigation for growth failure

Answer 140

1. Questions a. How short is the child? b. Is the child’s height velocity impaired? c. What is the child’s likely adult height? 2. Definitions a. > 2SD below the mean (Z-score -2) ==> corresponds to below the 3rd centile b. Extreme short stature = height < 1st centile - higher index of suspicion for pathological growth failure 3. Key points a. If equal reduction in parameter  TORCH/chromosomal b. If height more affected  endocrinopathies/skeletal dysplasia c. If weight most affected, height less and HC normal  malnutrition d. Girls = Turners until proven otherwise e. Boys = more often physiological  Girls are more likely to get early puberty; boys are more likely to get late puberty  Precocious puberty in a girl is UNLIKELY to be pathological  Boys with precocious puberty have a brain tumour until proven otherwise  Delayed puberty in a girl is Turner’s until proven otherwise 4. Red flags a. Height > 3 SD below mean > 6 cm below 3rd centile b. Growth rate <25th percentile after 1 year of observation 5. Etiology a. Physiological i. Constitutional delay of growth and puberty ii. Familial short stature b. Pathological = EPICNICS (endocrine, psychosocial, intra-uterine, chromosomal/genetic, nutritional, iatrogenic, chronic disease, skeletal)

Answer 141

EPICNICS ``` Endocrine • Cushing’s syndrome • Hypothyroidism • Pseudohypoparathyroidism • Rickets • IGF1 deficiency • Sexual precocity ``` Psychosocial • Deprivation Intra-uterine (Symmetrical) • Fetal abnormalities = congenital infections/ IUGR • Placental abnormalities (commonest cause) = impaired uteroplacental function • Maternal disorders = malnutrition, diabetes, HTN, alcohol drugs ``` Chromosomal/genetic • Russel-Silver syndrome • Noonan syndrome • Turner • Down’s • SHOX mutation • Prader Willi • (Skeletal dysplasias) ``` Nutritional • Anorexia • Malabsorption Iatrogenic • Radiation • Steroids ``` Chronic disease • Gastrointestinal • Rheumatological • CKD • Cardiopulmonary disease • Immunologic disease • Cancer ``` Skeletal (Height > weight, Disproportionate body segment (limb < length)) • Skeletal dysplasias • Osteogenesis imperfecta • Achondroplasia – commonest, AD but 90% sporadic mutation (FGFR mutation)

Answer 142

7. Investigations a. Clinical features warranting investigation i. Extreme short stature ii. Height significantly below target height iii. Subnormal height velocity iv. History of chronic disease v. Obvious dysmorphic syndromes vi. Precocious or abnormally delayed puberty vii. ? Extreme parental concern b. Bone age = commonest investigation i. Index of physiological maturity, indicated by state of bony epiphyseal maturation ii. Advances with puberty ( ↑ in precocious puberty) iii. XR of L wrist compared to age and sex matched iv. If GV is <25th percentile for bone age, or the height is out of keeping with the genetic potential, further tests are indicated c. FBE/ ESR/ CMP/ Vit D/ UEC/ ferritin/ LFT i. FBE/ESR – IBD d. Coeliac screen e. Karyotypes – for all short girls (lack of dysmorphism does NOT exclude Turner’s) f. TFTs – TSH is the usual screening test g. Cortisol, Prolactin h. Skeletal survey if dysmorphic + CMP/vitamin D/ ALP i. If above normal, assessment of GH axis i. Baseline IGF1 – interpreted in the context of bone age ii. Stimulated growth hormone studies – most definitive test [basal GH not helpful due to pulsatile release] 1. Exercise 2. Pharmacological – glucagon (RCH), clonidine, insulin, arginine 8. Management a. Most families need reassurance and no investigation or treatment b. Treat cause

Answer 143

Short stature homeobox (SHOX) insufficiency - located on X chromosome - The protein product of the SHOX gene plays a role in the growth and maturation of the skeleton

Answer 144

IGF-1 deficiency | - renal failure distorts GH-IGF axis leading to high GH and inappropriately low/normal IGF-1

Answer 145

Familial short stature • Short parent(s), often below the 10th percentile • Adult height short for population, but within the range predicted by parents' height o Determine parental target height o Growth velocity o Not an absolute diagnosis – if the parents are short and the child is short then may be due to the inheritance of a genetically transmitted disorder  Eg. endocrine causes – pseudohypoparathyroidism, thyroid problems – osteochondroplasias, renal disease, blood disorders (eg. thalassaemia)  Cause by may not yet be discovered o Key features  Several adult family member are short  Skeletal proportions and GV are normal  Bone age is equivalent to chronological age o Some children from short families also have a constitutional delay in maturation Constitutional delay of growth and puberty • Normal height for bone age but not for chronological age. Often family history of delayed growth and/or puberty. Adult height usually normal. o Exclusion of other causes of short stature along with late maturation o FH delayed puberty is often present o Parental anxiety/ distress to child should not be underestimated o Bone age delay > 2 years – can be pathological (eg. GH deficiency, hypothyroidism) Small for gestational age infant, with catch-up growth • Most SGA infants catch up by two years of age; the remainder have slower or absent catch-up growth that can be considered pathologic Ix: - hx, ex - bone age No treatments required

Answer 146

``` Familial short stature Child short Parents short Normal growth Normal puberty BA not delayed Poor height prognosis ``` ``` Constitutional delay of growth Child short Parents normal height Slow growth Delayed puberty Delayed bone age Good height prognosis ```

Answer 147

1. Overview a. 1/3500-4000 2. Clinical manifestations a. Typical presentation i. Neonatal presentation = hypogylcaemia, micropenis, jaundice ii. Adolescence = failure to have normal growth spurt b. Variable clinical presentation i. Mild 1. Usually present > 5 years 2. Less severe short stature 3. Subnormal HV over 12 months 4. Isolated GH insufficiency 5. Normal subcutaneous fat distribution 6. Delayed skeletal maturation 7. Delayed puberty ii. Severe 1. Presents < 3 year old 2. Obvious short stature 3. Subnormal HV from birth 4. Other features = hypoglycaemia, Micropenis 5. Excess subcutaneous fat 6. +/- ant pit deficiencies 7. +/- mid-facial hypoplasia/ features of septo-optic dysplasia 8. +/- delayed skeletal maturation 4. Investigations a. TFT and cortisol (prior to stim tests) b. IGF1/IGFBP3 – can be used to monitor the effect of GH replacement – reflect GH status as long as GH receptor function normal; helpful for excess c. Stimulation tests = BEST i. PULSATILE – peaks every 3hours ii. Insulin – not used iii. Exercise – can diagnose 80-90% iv. Glucagon / Arginine – can measure GH and cortisol 1. GH <10 deficient 2. GH 10-20 insufficient 3. GH >20 normal 5. Etiology a. Idiopathic multiple anterior pituitary hormone deficiencies b. Genetic (rare) i. GH-1 gene mutation (recessive, dominant, X-linked types), GHRH receptor mutations c. Congenital i. GHRH receptor deficiency – ‘idiopathic isolated GH insufficiency’ (majority) ii. Structural defects – septo-optic dysplasia, agenesis of the corpus callosum, holoprosencephaly iii. Intra—uterine infection d. Acquired i. CNS tumours (cranio, germinoma, optic nerve glioma (NF)) ii. Histiocytosis (with DI) iii. Cranial irradiation iv. Head injury v. Inflammatory/ granulomatous disease e. Transient i. Psychosocial deprivation ii. Pre-pubertal iii. Hypothyroidism

Answer 148

1. Congenital = genetic a. GH1 gene mutation i. Results in failure to produce GH ii. GH1 gene is one of a cluster of 5 genes on chromosome 17q22-24 vi. Most children with GH1 gene deletion respond well to recombinant GH – some dev antibodies 2. Acquired a. GH axis more susceptible to disruption by acquired conditions than other hypothalamic-pituitary axes b. Common causes i. Post radiotherapy 1. GH most susceptible – almost universal 5 years after therapy > 35 Gy 2. ↓ growth during radiation/chemo, Improves for 1-2 yrs then ↓ again with ↓ pituitary function (2˚ to ↓ hypothalamus) 3. Greater dose = greater risk – GH most common although others noted (TSH, ACTH) 4. May get precocious puberty (as puberty is under –ve regulation from hypothalamus) ii. Meningitis iii. Inflammation/granulomatous disease iv. Histiocytosis v. Trauma

Answer 149

1. Abnormality of GH release hormone receptor (GHRH) = GHRH mutation a. Inhibits somatotrope proliferation - variable inheritence/multiple mutations 2. Abnormality of GH receptor = GHR mutation  Laron syndrome b. Children resemble severe IGHD (ie. the same as having no growth hormone) c. Birth tends to be 1 SD below the mean, and severe short stature develops by 1 year of age d. ↑ GH, ↓ IGF e. Do not get a normal pubertal growth spurt as you require normal sex steroids AND GH 3. Abnormality of GH signaling (ie. normal receptor then something goes wrong) a. Mutation in post-receptor signaling i. Severe growth failure, ↑GH, ↓ IGF, normal GH binding protein levels iv. Phenotype similar to Laron syndrome b. IGF-1 gene abnormality i. Produces severe prenatal and postnatal impairment ii. Results in microcephaly, intellectual disability and deafness iii. Respond to recombinant IGF-1 c. IGF-binding protein abnormalities d. IGF-1 receptor abnormality

Answer 150

a. Idiopathic i. Familial – normal GV and bone age ii. Precocious puberty (start out tall, end up short) – temporary iii. Obesity – temporary  lifestyle related obesity is associated with increased stature in childhood, but normal adult final height b. Endocrine i. Hyperthyroidism ii. Pituitary gigantism (juvenile acromegaly) c. Syndromes i. Marfan = arachnodactyly + ligament laxity + chest deformity + cardiac AR/dissection + subluxation lens + high arched palate ii. Klinefelter = low IQ iii. Triple X = low IQ iv. XYY = low IQ v. Homocystinuria = Marfanoid features + low IQ d. Large babies/infants i. Gestational diabetes ii. Cerebral gigantism of Sotos iii. Beckwith-Wiedemann

Answer 151

2. Key Questions a. Is the child's height abnormal for the population? i. Normal range = within 2 SD from the population mean (2.3 to 97.7th centile) ii. Tall stature > 97.7th centile b. Is the child's growth abnormally rapid? i. Height velocity 2. Child growing >95th centile rate for HV c. Is the child's growth within the range for the family? i. Mid-parental height +/- 8.5 cm – represents 3rd to 97th centile d. Is there evidence of accelerated growth? Bone age 3. Assessment a. History b. Examination – dysmorphism, neurological, ophthalmological i. Upper segment to lower segment ratio 1. Normal in familial or pituitary gigantism 2. ↓ in syndromes ii. Limb span to height ratio ↑ in Marfan’s, homocystinuria, Klinefelter’s c. Development and pubertal d. Accurate height charted, MPH, height velocity, height age, arm span:height, upper:lower body segment ratios

Answer 152

4. Investigations a. If physical examination normal, no intellectual delay and tall family – NONE b. Bone age c. Thyroid function d. Karyotype e. Urine metabolic screen/antithrombin II/coagulation/lipids (homocystinuria) f. 3 hours OGTT assessing for failure of suppression of GH/IGF1 if acromegaly is suspected g. MR pituitary/ other assessment of pituitary function indicated if test consistent with GH excess 5. Treatment a. Treat specific cause b. Counselling c. Rarely accelerate puberty in boys or girls with either testosterone or estrogen respectively

Answer 153

1. Role a. Autonomic nervous system regulation b. Temperature regulation c. Water balance d. Food intake and energy balance e. Emotions and behaviors f. Endocrine secretions from the pituitary gland 2. Location a. Forms floor and walls and of the third ventricle of the brain b. Superior to sphenoid sinus and pituitary gland 3. Controls the pituitary via a. Anterior pituitary = all hormones peptides except dopamine (catecholamine) i. Thyrotropin releasing hormone (TRH- 3AAs)- controls the release TSH ii. Corticotropin releasing hormone (CRH)- controls the release of ACTH iii. Growth hormone releasing hormone (GHRH) which causes release GH and SS which inhibits release growth hormone iv. Gonadotropin releasing hormone (GnRH) which causes release of LH + FSH v. Dopamine- with inhibits PRL secretion b. Posterior pituitary = due to nerve signals from the hypothalamus that terminate in the posterior pituitary 4. Communication between hypothalamus and pituitary a. Posterior = via neurosecretion along magnocellular neurons originating from hypothalamus b. Anterior = hypophyseal portal system i. Capillary plexus where factors are secreted – balance of stimulating and inhibiting factors mediate release of the pituitary hormones

Answer 154

● All hormones under control by hypothalamus ● All positive control except prolactin – all hormones except prolactin fall to very low levels without hypothalamus Anatomy ● Located at the base of the skull in the sella turcica (sphenoid bone) ● Suspended from the hypothalamus by a pituitary stalk – the infundibulum ● The pituitary is EXTRA-DURAL and not in contact with CSF ● Divided into anterior (adenohypophysis) and posterior (neurohypophysis) ● Anterior pituitary = derived from pharyngeal arches ● Posterior pituitary = outpouching of the brain Anterior Pituitary 1. Embryology a. Derived from Rathke’s pouch = invagination of the oral ectoderm c. By 6 weeks of gestation the connection between the Rathke pouch and the oropharynx is obliterated e. Permanent remnants of the original connection b/n the Rathke pouch and the oral cavity: craniopharyngiomas 2. Blood supply a. Arterial blood supply of the pituitary gland originates from the internal carotid 3. Cell types a. Somatotrophs (50% cells) = release human growth hormone b. Lactotrophs (10-25% cells) = release prolactin c. Thyrotrophs (10% cells) = release thyroid stimulating hormone d. Gonadotrophs (10-15% cells) = release follicle stimulating hormone and lutenizing hormone e. Corticotrophs (10-15% cells) = release of POMC (Pro-opiomelanocortin)/ACTH Posterior Pituitary 1. Overview a. Origin – arises as down growth of ventral hypothalamus and 3rd ventricle of brain c. Embryologically an outpouching of the brain d. Secrete two hormones (differ only by 2 amino acids) i. Supraoptic nerve terminals = ADH ii. Paraventricular nerve terminals = oxytocin

Answer 155

b. Gene = GH1 (five genes that are very similar) on chromosome 17 c. Secreted in a pulsatile fashion = basal concentrations of growth hormone in blood are very low, the most intense period of growth hormone release is shortly after the onset of deep sleep d. Factors controlling release i. Stimulation 1. GHRH 2. Ghrelin 3. Hypoglycaemia 4. Sleep, exercise, stress, nutritional deficiency, estrogen or testosterone ii. Inhibition 1. Somatostatin 2. Hyperglycaemia 3. Steroids 4. Hypothyroidism 5. GH and IGF1 – acts at the hypothalamus and pituitary as negative feedback e. Mediators i. Direct effects of growth hormone ii. Indirect effects of insulin-like growth factor iii. Ratio of GH to IGF depends on physiological state of body – in fasting state, GH predominant, in fed state IGF predominant f. Mechanism ii. Primarily acts through synthesis of somatomedins, particularly IGF-1 at the liver iv. Largely protein bound to IGF-BP3, this is decreased in GH deficient children g. Actions (think burns fat, builds muscle) i. Metabolic effects (mainly GH = diabetogenic = insulin antagonist) 1. Stimulates protein synthesis and decreases breakdown 2. Stimulates lipolysis (metabolism of fatty acids from adipose tissue), increased FA in the blood and increased use of FA for energy 3. Decreases glucose uptake in tissues, increase gluconeogenesis in the liver results in increased blood glucose – diabetogenic effect – increase insulin ii. Cartilage and bone growth (largely mediated by IGF-1 = insulin synergistic) 1. Increased protein production for bone growth, increase rate of osteogenic cell production and conversion of chondrocytes into osteogenic cells

Answer 156

a. Secreted from lactotropes b. Unique regulation – consistently secreted UNLESS it is inhibited by dopamine produced by the hypothalamus c. Therefore, any disruption in the hypothalamus or pituitary stalk -> elevated PRL levels d. Factors controlling release i. Stimulation 1. Many hormones from the hypothalamus – TRH, GnRH, VIP 2. Peripheral – stimulation of the nipples during breastfeeding, stress and sleep ii. Inhibition = Dopamine e. Actions i. Initiation and maintenance of lactation ii. Stimulates development of milk-secretory apparatus iii. NOTE: oestrogen and progesterone during pregnancy inhibit lactation

Answer 157

a. 2 glycoprotein chains: alpha subunit (identical to FSH/LH/hCG) + beta subunit b. Stored in secretory granules primarily released in response to TRH (thyrotropin releasing hormone) stimulation d. Factors controlling release i. Stimulation 1. TRH 2. Cold (increased body temp to increase metabolic rate) 3. Stress (SNS activation) 4. Circadian rhythm (max 0000 and 0400) 5. Caloric intake ii. Inhibition 1. Thyroxine (negative feedback) 2. Dopamine 3. Somatostatin + glucocorticoids e. Actions i. Stimulates iodine pump ii. Production thyroglobulin iii. Tyrosine iodination iv. Hypertrophy of follicular cells v. Hyperplasia of follicular cells

Answer 158

b. Synthesized as POMC (proopiomelanocortin), broken down into LPH (lipotropin) + MSH (melanocyte stimulating hormone) + beta-endorphin + ACTH c. Secreted in diurnal pattern – cortisol levels highest in the morning at the time of waking, low in the late afternoon and evening, and reach their nadir 1-2 hours after sleep d. Factors controlling release i. Stimulation = CRH, vasopressin, oxytocin, angiotensin II, CCK ii. Inhibition = ANP, opioids , cortisol f. Action i. Adrenal cortex: cortisol synthesis + secretion ii. Pigmentary hormone

Answer 159

a. Glycoproteins contain same alpha unit as TSH, different beta subunits b. FSH i. Receptors on ovarian granulosa cells + testicular Sertoli cells ii. Stimulate follicular development + gametogenesis iii. ↓ by inhibin c. LH i. Promotes luteinisation of ovary + Leydig cell function in the testis ii. ↓ by androgens/ estrogens e. Regulation i. Stimulation = GnRH ii. Inhibition 1. Males a. Testosterone from Leydig cells (LH) b. Inhibin from Sertoli cells (FSH) 2. Females a. INHIBITORY PHASE – follicular part of cycle i. Estrogen from thecal/granulose cells inhibits FSH ii. Inhibin from follicles inhibits LH b. POSITIVE PHASE - ovulation = at threshold, estrogen acts as positive feedback to stimulate LH and FSH release c. INHIBITORY PHASE – luteal phase = estrogen, progesterone, inhibin from CL negative feedback for FSH/LH

Answer 160

a. Short half-life (5 mins) and responds quickly to change in hydration status b. Vasopressin is synthesized in the paraventricular and supraoptic nuclei of hypothalamus, stored in posterior pituitary e. Mechanism i. Released in response to osmolality ii. V2 receptors located primarily on the collecting tubule, the thick ascending loop of Henle, and the periglomerular tubules iii. Activation of V2 receptor 🡪 G proteins 🡪cAMP production 🡪 aquaporin-2 insertion into the membrane 1. This allows water movement along the osmotic gradient into the hypertropic inner medullary interstitium from the tubule and excretion of concentrated urine f. Actions i. V(1a) receptors = arterial smooth muscle vasoconstriction and hepatic glycogenolysis ii. V(1a) receptors = actions at corticotrophs (anterior pituitary) to increase ACTH secretion iii. V(2) receptors = as above iv. OTHER 1. Mediates von Willebrand factor + tPA g. Regulation i. Simulation 1. ↑ plasma osmolality = detected by osmoreceptors in hypothalamus a. Very sensitive, detects 1-5% change 2. ↓ blood volume = detected by carotid arch baroreceptors a. Not as sensitive, detects 15-30% change 3. OTHER = pain, stress, hyperthermia ii. Inhibition 1. ANP – produced by the cardiac atrial muscle a. Stimulates natriuresis (Na+ secretion), inhibition of Na resorption, and inhibition of ADH secretion 2. OTHER = ethanol, alpha agonists, caffeine

Answer 161

a. Regulation i. Intercourse = facilitates sperm through the uterus by increasing motility ii. Parturition = dilation of the cervix during birth iii. Nipple stimulation = breast feeding resulting in “let down” reflex iv. Hypertonicity = cross over function with ADH b. Actions i. Smooth muscle contraction during suckling (let-down reflex) – breast myoepithelial cells ii. Rhythmic smooth muscle contraction during parturition – uterus iii. Actions in anxiety, trust, love, maternal behaviour etc postulated

Answer 162

1. Key points a. Hypopituitarism = denotes underproduction of GH alone or in combination with other pituitary hormones b. Panhypopituitarism = all hormones affected c. Affected children have a postnatal growth impairment that is specifically corrected by GH replacement d. Congenital hypopituitarism is rare – 1/4000 to 1/1000 live births e. Acquired hypopituitarism has a later onset and different causes i. Any lesion that damages the hypothalamus, pituitary stalk, or anterior pituitary hormone ii. As lesions are not selective, multiple hormone deficiencies are usually observed iii. Diabetes insipidus is MORE frequent in acquired than in congenital hypopituitarism iv. The most common lesion is craniopharyngioma 2. Etiology a. HYPOTHALAMIC i. Mass lesions = benign (craniopharyngioma) and malignant tumours ii. Radiation iii. Infiltrative lesions = sarcoidosis, Langerhans cell histiocytosis iv. Infection = tuberculous meningitis v. Other = TBI, stroke b. PITUITARY i. Congenital 1. Genetic = Pit1, Prop1 (homeobox genes), isolated GH deficiency, multiple pituitary hormone deficiency 2. Midline defects a. Cleft palate (6% associated with GH deficiency), single maxillary incisor, choanal atresia, encephalocele b. Septo-optic dysplasia (ON hypoplasia, absent septum pellucidum, panhypopituitarism = nystagmus, visual failure) 3. Structural a. Pituitary stalk transection b. Ectopic posterior pituitary gland (absent of normal appearance “bright spot” on MRI which is post pit) ii. Acquired 1. Brain damage = TBI, SAH, neurosurgery, stroke, irradiation 2. Pituitary tumours = adenomas, others 3. Non-pituitary tumours = craniopharyngiomas, meningiomas, gliomas etc 4. Infection = abscess, hypophysitis, meningitis, encephalitis 5. Infarction = apoplexy, Sheehan’s syndrome 6. Autoimmune disorders 7. Other = haemochromatosis, granulomatous disease, histiocytosis, perianal insults

Answer 163

Hormones affected (most->least common) a. GH b. Gonadotrophins c. Thyroxine d. ACTH e. NOTE: Prolactin – negatively regulated i. Only hormone purely negatively regulated (by dopamine) ii. Therefore hypothalamus damage (eg. radiotherapy, physical trauma), the prolactin level will elevate iii. High prolactin may not be a prolactinoma, it may be a marker of hypothalamic damage 2. Clinical manifestations - GH: hypoglycaemia, micropenis, growth failure, cherubic appearance, delayed bone age - Gonadotropins: delayed puberty - Thyroxine: growth/development failure, weight gain, constipation, cold intolerance - ACTH: hypoglycaemia, shock - PRL: elevated, galactorrhoea - +/- diabetes insipidus: polyuria, polydipsia a. Congenital hypopituitarism i. Usually normal size/weight a birth ii. Neonatal emergencies – apnoea, cyanosis, severe hypoglycaemia with or without seizures iii. Prolonged jaundice – conjugated and unconjugated iv. Nystagmus – suggests septooptic dysplasia v. Micropenis vi. Dysmorphism b. Acquired hypopituitarism i. Child is normal initially ii. With complete or almost complete destruction pituitary insufficiency results in clinical features iii. Atrophy of the adrenal cortex, thyroid and gonads 🡪 loss of weight, asthenia, sensitivity to cold, mental torpor, absence of sweating, failed sexual maturation or regression (atrophy of gonads, amenorrhoea, loss of pubic hair) iv. Hypoglycaemia v. Growth slows dramatically vi. Diabetes insipidus – may be present but tends to improve spontaneously with development of central adrenal insufficiency vii. Craniopharyngioma – visual field defects, optic atrophy, papilledema, Cn palsy

Answer 164

a. Endocrinological i. Non-provocative 1. TFT – note TSH unhelpful a. Central hypothyroidism – therefore unhelpful b. Must get FT4 2. Prolactin – hypothalamic damage 3. FSH/LH – if low may be normal (if pubertal low be abnormal) ii. Provocative (pulsatile hormones) [need to ensure child euthyroid; false positive results if hypothyroid] 1. GH, ACTH (via cortisol) – exercise/ glucagon/ arginine/ clonidine a. Glucagon has added advantage as it also simulates ACTH 2. ADH – water dep iii. Other 1. IGF1 and GH-dependent IGF-BP3 b. Central imaging i. Craniopharyngioma (associated with calcification), bony changes (histiocytosis) c. Bone age – decreased

Answer 165

a. Hypothyroidism = T4 i. Full replacement b. ACTH deficiency i. Hydrocortisone 50% of maintenance (half of 10-15 mg/m2) ii. If adrenal insufficiency – use full replacement iii. Adrenal glands still function with minimal stimulus from pituitary gland; therefore if you use full replacement 🡪 completely switch of adrenal gland and can be growth inhibitory c. GH deficiency i. If growing slowly – daily GH ii. Recombinant IGF-1 1. Given subcutaneously twice per day 2. Risk of hypoglycaemia reduce if given with food d. Delayed puberty i. Testosterone or estrogen ii. Previously tried to hold off to get maximum growth – eg. age 14, 15 years iii. Now try and treat at appropriate age – start 11-12 years iv. Concurrent treatment of GH + GnRH used to help interrupt puberty and delay epiphyseal fusion thus prolonging growth v. Results in increased adult height e. Diabetes insipidus i. DDAVP 0.05 ml BD (desmopressin)

Answer 166

1. PROP1 a. Deficiency = GH, TSH, LH, ACTH b. Mechanism i. Role in turning on POUF1 expression ii. Found in nuclei of somatotrophs, lactotropes and thyrotropes c. The most common explanation for recessive MPHD d. Clinical manifestation i. Anterior pituitary hormone not usually evident in neonatal period ii. Median age at GH deficiency diagnosis is 6 years Others: - PIT1 (POU1F1) - HESX1 - LHX3/4 a. Pituitary hypoplasia i. Can occur as part of an isolated phenomena OR in association with other developmental abnormalities (anencephaly, holoprosencephaly) ii. Midfacial anomalies (cleft lip, palate) or the finding of a solitary maxillary central incisor – indicate a high likelihood of GH or other anterior or posterior hormone deficiency iii. Many genes identified and implicated

Answer 167

1. Congenital = genetic a. GH1 gene mutation i. Results in failure to produce GH ii. GH1 gene is one of a cluster of 5 genes on chromosome 17q22-24 vi. Most children with GH1 gene deletion respond well to recombinant GH – some develop antibodies 2. Acquired a. GH axis more susceptible to disruption by acquired conditions than other hypothalamic-pituitary axes b. Common causes i. Radiotherapy for malignancy ii. Meningitis iii. Histiocytosis iv. Trauma

Answer 168

Optic nerve hypoplasia, midline defects, hypopituitarism 1. Key points a. Incidence 1 in 10 000 live birth b. Phenotypically variable disorder c. Diagnosed on a clinical basis, with ongoing debate as to the exact diagnostic criteria d. Features i. Optic nerve hypoplasia – from mild CNVI palsy to blindness ii. Midline defects – corpus callosum, septum pellucidum iii. Pituitary hypoplasia – results in hormone abnormalities ranging from isolated GHD to panhypopit 2. Genetics - mostly unknown (<1%) 3. Clinical manifestations a. Visual: impairment, strabismus, nystagmus, wandering eyes b. Pituitary: hypoglycaemia, jaundice, micropenis +/- undescended testes (GH def most common) c. Midline defects: cleft palate d. Other i. Visual impairment ii. Developmental delay iii. Seizures 4. Investigations a. Ophthalmology to assess degree of eye involvement b. MRI brain c. Pituitary screen – TSH, FT4, cortisol, GH and IGF-1 if hypoglycaemia 5. Treatment a. Treat hormone deficiency

Answer 169

1. Key points a. Clinically manifests as polyuria and polydipsia b. Results from vasopressin deficiency (central) or insensitivity at the level of kidney (nephrogenic) c. Polyuria = >4mL/kg/hour over 6 hours d. Nocturia = waking at night >1 time to pass urine f. Definition i. Serum osmolality > 300 mOsm/kg ii. Urine osmolality < 300 mOsm/kg (inability to concentrate urine) 2. Classification a. Central DI = deficient secretion of ADH i. Idiopathic – 10%, Genetic (autosomal dominant), Acquired 1. Trauma (eg post neurosurgery) 2. Congenital malformations 3. Neoplasms 4. Infiltrative/ autoimmune/ infectious diseases b. Nephrogenic DI = resistance to effect of ADH on body i. Genetic (XL, AR, AD) ii. Acquired 1. Hypercalcemia/ hypokalemia - interferes with Na Cl reabsorption which interferes with ADH’s ability to increasing collecting tubule water permeability 2. Drugs – lithium, clozapine, rifampin, amphotericin 3. Kidney disease – obstruction, PCKD, Sjogren’s 3. Physiology a. Key points i. Extracellular water tonicity almost exclusively controlled by water intake and excretion ii. Extracellular volume is controlled by sodium intake and excretion b. Summary i. Baroreceptors or osmoreceptors 🡪 posterior pituitary 🡪 ADH release ii. ADH acts on V2 receptors in the kidney (collecting tubule, thick ascending loop of Henle and periglomerular tubules) 🡪 aquaporin 2 insertion into the apical membrane allowing water resorption

Answer 170

4. Investigations a. UEC = renal function + sodium i. Should not be high if no cognitive impairment – thirst response ensures euvolaemia ii. Risk in infants as cannot get their needs across b. CMP = identify hypercalcaemia c. Urine MCS = identify glycosuria or infection, SG <1.005 d. Paired urine + serum sodium and osmolality i. Low plasma sodium with a low urine osmolality 🡪 water overload from primary polydipsia ii. High-normal plasma sodium (>142), with urine osmolality lower than serum 🡪 DI iii. Normal plasma sodium and urine osmolality > 600mosmol/kg 🡪 excludes DI e. Water deprivation test 5. Management a. Goal is to minimise polyuria and avoid hypernatraemia + volume depletion b. Acute therapy i. Rehydration = if Na >150, rehydration over 48hours ii. DDAVP (desmopressin) = if Na >145 + specific gravity <1.005 + UO >4mL/kg/hr for 6 hrs iii. Strict fluid balance iv. Regular monitoring UEC c. Long term i. Fluid therapy – large volumes required to compensate for losses 1. May require NG ii. Renal diet 1. Low salt, low protein diet decreases urine output – the reduction will be directly proportional to decrease in solute intake and excretion (in DI UO proportional to solute excretion) 2. Salt restriction <2.3gm/day, and protein <1.0g/kg a. Every gram of protein in the diet 🡪 4 mmol urea iii. Central = DDAVP replacement 1. Can be given IN 2. Oral tablets = need 10 x dose of intranasal spray 3. To prevent water intoxication patients should have at least 1 hour of urinary breakthrough between doses each day and be advised to drink in response to thirst 4. Synthetic aqueous vasopressin: for post neurosurgery causes – continuously iv. Nephrogenic 1. Treat underlying cause – offending drug, hypercalcaemia, hypokalaemia, or ureteral obstruction 2. Congenital nephrotic DI is difficult to treat 3. Aim for foods with high calorie to osmotic load ratio (maximise growth, minimize urine volume) 4. Pharmacological a. Thiazide diuretics = enhance sodium excretion at the expense of water b. DDAVP = high dose DDAVP may be useful in patients with V2 receptor problems (affinity for binding overcome) c. NSAID = inhibition of renal prostaglandin synthesis, PG’s usually act to anatagonise ADH, and therefore NSAIDs increase urine concentrating ability i. Indomethacin > ibuprofen for effectives

Answer 171

1. Key points a. Involves water restriction followed by administration of DDAVP b. Not necessary if clear in paired urine/serum Na/osmolality c. Normal response = increase in plasma osmolality 🡪 ADH secretion 🡪 increase in urine osmolality as more water is reabsorbed 2. Continue until maximal ADH secretion is occurring a. Urine osmolality clearly normal > 600mosmol/kg (or SG > 1.020) b. Urine osmolality stable despite increasing plasma osmolality c. Plasma osmolality > 295-300, or Na > 145 3. Abnormal response a. Central DI i. Serum osmolality will ↑ quickly as urine will not concentrate adequately ii. Additional DDAVP will ↑ urine osmolality b. Nephrogenic DI i. Submaximal rise in urine osmolality depending on whether partial vs complete resistance ii. Additional DDAVP – no effect in complete nephrogenic DI, small rise in partial DI c. Partial central vs. partial nephrogenic DI i. Central DI – will achieve urine osmolality >300 with water restriction ii. Nephrogenic – persistently dilute urine that rises but remains suboptimal despite DDAVP 4. Water deprivation is stopped when a. Urine osmolality >600mosmol/kg – adequate concentrating by secretion and effect of ADH b. Plasma osmolality >300 or plasma sodium >145 – inadequate response of ADH to water deprivation c. Urine specific gravy >1.02 d. 5% loss of body weight e. Reaches time limit for study 5. DDAVP a. Once the plasma osmolality reached 295-300 (275-290), and plasma Na >145, effect of ADH on kidneys is maximal i. Central DI 🡪 reduced UO ii. Nephrogenic DI 🡪 no response b. NOT done in children with suspected hereditary nephrogenic DI – just give DDAVP, if no significant response (indicating nephrogenic DI, proceed to genetic testing)

Answer 172

● More often seen in adolescents/adults | ● Driven by excess water intake, this can be in response to a dry mouth

Answer 173

1. Key points a. Syndrome of inappropriate ADH secretion 2. Pathophysiology a. Excess/inappropriate ADH secretion i. Normally: excess water intake 🡪 suppression of ADH release b. Consequences i. Low volumes of high osmolarity urine ii. Low plasma osmolarity iii. Increase urinary sodium iv. Euvolemic hyponatremia

Answer 174

``` CNS ● Meningitis / encephalitis ● Tumors ● Vascular abnormalities ● Hydrocephalus ● Head injury/ haemorrhage ● Post pituitary surgery (part of triple response – phase 2) ``` ``` Respiratory ● Lung infection ● Asthma ● Pneumothorax ● Pneumonia ● TB ● Lung abscess ● PPV ``` ``` Tumour ● Bronchogenic carcinoma ● Oat cell carcinoma of lung ● Duodenal ● Pancreatic ● Neuroblastoma ``` Metabolic ● Hypothyroid ● Hypoadrenalism ``` Drugs ● SSRIs ● Vincristine ● Cyclophosphamide ● Carbamazepine, valproate, OXC ● TCAs ``` Endocrine ● Hypothyroidism ● Cortisol deficiency

Answer 175

4. Clinical manifestations/investigations a. Blood i. Hyponatraemia +/- hypokalaemia ii. Osmolality – low iii. Uric acid – low b. Urine i. Urine output – normal or low ii. Urine osmolality - inappropriately concentrated urine (>100 mOsm/kg) iii. Urine sodium – high (>40) c. Paired urine + blood i. Elevated urinary vs. plasma sodium + osmolality 5. Management a. Fluid restriction b. High salt c. Fluid balance, daily weight d. Monitor electrolytes e. 3% saline may be needed +/- loop diuretic f. Demeclocycline – can inhibit ADH action at kidney

Answer 176

1. Key points a. Up to 15% of all intracranial tumors b. Peak 5 – 14 years 2. Tumor of Rathke’s pouch a. Cells between the adeno and neurohypophysis b. Can cause hypopituitarism c. Benign histologically but locally invasive especially upwards into optic nerves d. Cystic and solid component – contains thick oil substance 3. Clinical features a. Endocrinological i. Growth failure = 90% 1. Note that linear growth often continues normally despite absence of secretion 2. IGF-1 levels may be normal 3. Usually associated with obesity ie. nutritional over-regulation of IGF-1 ii. Hypothyroid = 40% iii. Cortisol deficient = 25% iv. Diabetes insipidus = 10% (posterior pituitary usually intact) b. Non-endocrinological i. Visual disturbance = 70% ii. Headache = 50% c. Hyperprolactinaemia NOT common feature as no stalk involvement d. Diabetes insipidus uncommon 4. Investigations a. Hormone studies (see pan-hypopit) b. Lateral skull XR – 90% seen as calcification c. MRIB 5. Post-operative a. DI common b. Triple response to cutting pituitary stalk i. Original DI (polyuria) ii. SIADH (antidiuretic phase) iii. Permanent central DI c. Damage to OVLT in floor of third ventricle leads to loss of thirst – may be very hypernatraemic and can feel completely fine d. Usually combined with diabetes insipidus - needs strict fluid intake plus DDAVP

Answer 177

1. Key points a. Rare in childhood b. Increase in incidence towards adolescence 2. Clinical presentation a. Often secretary b. ACTH producing most common in young children i. No familial association ii. Weight gain, drop in linear height, hypertension, glucose intolerance, delayed puberty and amenorrhoea iii. Management – transsphenoidal adenectomy c. GH and PRL second most frequent – usually familial d. Prolactinomas 50% pituitary adenomas – most common older children i. Adolescence ii. F>M iii. MEN1, Carney complex, familial isolated pituitary adenoma iv. Growth arrest, pubertal delay, amenorrhoea, hypogonadism v. Local effects headache, visual loss, CN compression vi. Management – dopamine agonist to reduce tumor size and control PRL levels (bromocriptine) +/- surgery

Answer 178

● Types o Glioma (associated NF1 have lower mortality) o Germinoma o Hamartoma Hamartoma ● Young girls 2-4years ● Mass effect ● Precocious puberty + gelastic seizures ● Composed of mature neurons in clusters of axons ● Circular midline on MRIB ● Only remove if seizures

Answer 179

a. Peptide i. Includes 1. Somatostatin, GnRH, RGF, GHRP, CRF, TRH 2. GH, ACTH, TSH, FSH, LH, Prolactin, ADH 3. Insulin, glucagon, IGF 4. PTH, calcitonin b. Steroid i. Cholesterol derived ii. Eg. cortisol, sex steroids, aldosterone, thyroid hormones (closely related to steroid hormones) c. Amine eg. dopamine d. Eicosanoid eg. prostaglandin 3. Mechanism of action a. Endocrine = released in one place and act elsewhere b. Paracrine = released and act locally (eg. IGF, IGF binding protein) 1. Hormone receptors a. Steroid hormones – move into the cell, usually bound by binding protein inside cell, carries them into DNA – bind to DNA and trigger off transcription effect i. Results in long-lasting effects b. Peptide hormones – cannot move through cell membrane, bind to cell surface receptor and stimulate signal transduction i. Example – seven transmembrane/GPCR/cAMP, cytokine receptors (Jak/stat), insulin/IGF (tyrosine kinase)

Answer 180

Multiple endocrine neoplasia Types: 1, 2A, 2B MEN1 = 3Ps Parathyroid hyperplasia Pituitary adenoma Pancreatic islet cell tumour MEN2A = 2Ps 1M Parathyroid hyperplasia Phaeochromocytoma Medullary thyroid carcinoma MEN2B = 1P 2 Ms Marfanoid habitus + mucosal neuromas Phaeochromocytoma Medullary thyroid carcinoma

Answer 181

3Ps: parathyroid, pituitary, pancreas 1. Key points a. Rare disorder; 2 per 100,000 2. Clinical definition a. Occurrence of two or more primary MEN1 tumour types b. In family members of a patient with a clinical diagnosis of MEN1 – the occurrence of one of the MEN-1 associated tumours 3. Genetics a. Autosomal dominant b. Mutation in MEN1 gene 4. Clinical manifestations a. 3P’s = pituitary tumour, parathyroid hyperplasia, pancreatic tumour b. Endocrine i. Primary hyperparathyroidism (90%) ii. Entero-pancreatic tumours (30-70%) 1. Gastrinoma (30-40%) 2. Insulinoma (10%) 3. Non-functioning (20-55%) 4. Other – glucagonoma, VIPoma, somatostatinoma iii. Foregut carcinoid 1. Thymic carcinoid non-functioning (2%) 2. Bronchial carcinoma (2%) 3. Gastric enterochromaffin like tumour non-functioning (10%) iv. Anterior pituitary tumour (30-40%) 1. Prolactinomas (20%) 2. Others – GH + PRL, GH, non-functioning (each 5%) 3. ACTH (2%), TSH (rare) v. Adrenal cortical tumour non-functioning (40%) c. Non-endocrine i. Lipomas (30%) ii. Facial angiofibromas (35%) iii. Collagenomas (70%) iv. Phaeochromocytoma (<1%) v. Ependymoma (1%) 5. Management a. Screening for tumours

Answer 182

Medullary thyroid carcinoma is common 1. Epidemiology a. 1/30,000 2. Genetics a. Mutation in RET proto-oncogene b. Autosomal dominant pattern c. Very high penetrance 3. Classification a. MEN2A i. MEN2A classical = medullary thyroid carcinoma, phaeochromocytoma, hyperparathyroidism ii. MEN2A with cutaneous lichen amyloidosis iii. MEN2A with Hirschsprung disease iv. Familial medullary cancer without phaeochromocytoma or parathyroid hyperplasia b. MEN2B i. Medullary thyroid carcinoma ii. Phaeochromocytoma iii. Other 1. Mucosal neuromas 2. Intestinal ganglioneuromas 3. Marfanoid habitus

Answer 183

1. Key points a. Rare, often fatal, X linked syndrome b. Typically presents in infancy with classic triad i. Enteropathy = results in life-threatening chronic diarrhoea ii. Autoimmune endocrinopathy = neonatal type 1 diabetes or thyroiditis iii. Dermatitis = usually eczematous 3. Genetics a. Mutations in the gene for transcription factor FOXP3 – fundamental to the function of Tregs 5. Clinical manifestations a. Chronic diarrhoea due to autoimmune enteropathy b. Type 1 diabetes mellitus – most common with onset generally during first year of life c. Dermatitis – usually eczematous d. Severe food allergies e. Thyroiditis – may result in hyper or hypothyroidism f. Immune-mediated cytopaenias g. Increased infections h. Nephritis i. Failure to thrive j. Developmental delay 6. Investigations a. Diagnosis established by mutational analysis of FOXP3 gene b. Extensive investigations in any suspected diagnosis 7. Management a. Immune suppression b. Dietary modification to avoid food allergies c. HSCT – only curative therapy 8. Prognosis a. Untreated – infants with IPEX usually die in early childhood

Answer 184

``` Type 1, HAMP Hypothyroidism Addison’s Mucocutaneous candidiasis Parathyroid – hypo ``` Type 2, HAD Hypothyroidism Addison’s Diabetes (T1DM) ``` Type 3, TVAP Thyroiditis Diabetes Pernicious anaemia Vitiligo ```

Answer 185

1. Key points a. Wide variation in clinical presentation and course of disease 2. Genetics a. Mutation in Autoimmune Regulator (AIRE) gene d. Expression of the autoantigen is controlled by transcription AIRE 4. Clinical manifestations a. Mucocutaneous candidiasis + hypoparathyroidism + adrenal failure b. Classic triad i. Chronic mucocutaneous candidiasis 1. Oral cavity, nails, skin, less frequently oesophagus, vagina and gastrointestinal tract 2. Presenting features in 60%, present in all patients by age 40 3. Candida albicans most common infection ii. Hypoparathyroidism 1. Most common endocrine abnormality and second most common feature of AIRE 2. Presenting feature in 30%, >80% eventually affected 3. Results in hypocalcaemia and hypoMg – can result in seizures iii. Adrenal failure 1. Third most common features 2. Occurs in 5% at presentation, but >60% by age 115 c. Other manifestations i. Other endocrinopathies = T1DM, hypothyroidism, GH deficiency, Addison’s disease, ovarian failure, male hypogonadism ii. Other autoimmune manifestations = vitiligo and alopecia areata (>30% after age 20), pernicious anaemia (>20% by age 30) iii. Complications due to chronic Candida infection = keratoconjunctivitis resulting in blindness, esophageal stricture, squamous cell carcinoma of mouth and esophagus iv. Antibody deficiency to polysaccharide antigens v. Other oral and gastrointestinal manifestations = enamel abnormalities, chronic diarrhoea, constipation vii. Pulmonary disease, interstitial nephritis, encephalopathy

Answer 186

1. Key points a. Primarily occurs in adulthood – around 3rd-4th decade of life 2. Genetics a. HLA DR3 and DR4 strongly linked 3. Clinical manifestations a. Classic triad i. Addison’s ii. Autoimmune thyroid disease iii. T1DM b. Oher features i. Vitiligo ii. Chronic atrophic gastritis iii. Hypergonadotropic hypogonadism iv. Chronic autoimmune hepatitis v. Alopecia vi. Hypophysitis vii. Myasthenia gravis viii. Rheumatoid arthritis ix. Sjogren’s syndrome x. Celica disease 4. Investigations a. Features of above conditions

Answer 187

• Most studies look at children with ALL who had cranial irradiation as part of treatment compared with those without • Growth hormone deficiency most common endocrinopathy following cranial irradiation • Significant reduction in adult height, and thought to contribute to metabolic / effects on cognitive function • Damage usually at level of hypothalamus o Low dose radiation <30Gy – GH deficiency in about 30% o 30-50Gy – GH deficiency 50-100%, gonadotropin 20-30%, TSH 3-9%, ACTH 3-6% • Precocious puberty reported, not delayed puberty • Subclinical hyperprolactinaemia also reported • Diabetes insipidus rarely complication of cranial irradiation • Frequently due to pituitary/hypothalamic tumors or following surgery

Answer 188

1. Key points a. Cytotoxic agents can cause gonadal dysfunction/failure in males and females i. Low dose – loose pubertal inhibition ii. High dose – delayed/failure of puberty 2. Risk factors for poor fertility a. Cyclophosphamide or other alkylating agents b. Hypothal/pit tumour 3. Multiple issues possible a. Growth hormone deficiency most common b. TSH deficiency c. Gonadotrope deficiency 4. Males a. Worse outcomes of chemo post puberty than pre-puberty b. Spermatogenesis more likely to be disrupted than testosterone production because the germinal epithelium of the testis is more sensitive to damage from cytotoxic drugs than are the Sertoli and Leydig cells c. Management = GH +/- testosterone 5. Females a. Ovaries = affected by both CTx and RTx b. Uterus = ONLY affected by RTx c. Mx = GH +/- other

Answer 189

PTH (inc Ca - bones/kidneys) Vit D (inc Ca - GIT) Calcitonin (red Ca) Calcium sensing receptor – on parathyroid gland and in kidney Poorly absorbed via the GIT (↑ absorption with vitamin D); only 20-30% absorbed iii. Distribution 1. 99% bone = hydroxyapatite (mineralized CaPO4) and calcium carbonate 2. 1% serum a. 50% ionised = physiologically active b. 40% is mostly bound  80% albumin + 20% globulin c. 10% complexed = phosphate, citrate, bicarbonate, lactate d. Most important influence on protein binding is plasma pH – alkalosis encourages binding of calcium as more anionic sites – decreasing ionized calcium v. Excretion 1. 10% excreted in urine 2. Protein bound Ca not filtered by glomerular capillaries 3. Usually 99% of calcium is reabsorbed a. 90% proximal tubules, loop of Henle + early distal tubules b. Final 10% in late tubules/ early collecting ducts  this part of reabsorption is variable depending on Ca ion concentration

Answer 190

b. Phosphate i. Normal intake = 100 mg / day, easily absorbed via the gut ii. 85% stored in bones (hydroxyapatite), 14-15% in cells, < 1% in ECF iii. Regulation = renal tubular reabsorption 1. ↓ by phosphatonin ( eg FGF 23) 2. ↓ by PTH

Answer 191

4. Bone a. Essentially = collagen matrix strengthened by Ca+ phosphate deposits b. 3 different types c. Haversian systems (bone formed around blood vessels) d. Key cells i. Osteoblasts = secrete collagen molecules and ground substance 1. Become quiescent and stuck in osteoids once collagen polymerises – in this stage called an osteocyte ii. Osteoclasts = responsible for bone resorption e. Turnover i. Mineralization 1. Process whereby calcium, phosphate, and other ions absorbed from blood and incorporated into bone as hydroxyapatite 2. Osteoblasts lay down collagen, then mineralization can occur with calcium phosphate ii. Resorption 1. Process where calcium phosphate is dissolved from bone and released into circulation 2. Osteoclasts facilitate this process

Answer 192

e. Production i. Parathyroid gland produce pre-pro-PTH + pro PTH 1. Parathyroid glands form from 3rd and 4th branchial arches ii. Broken down to PTH which is stored in cell vesicles f. Secretion i. Stimulation 1. ↓ ionised calcium levels – main stimulus [SECONDS] 2. ↑ phosphate levels – binds to calcium thereby stimulating PTH release ii. Inhibition 1. Calcitriol 2. ↑ Ionised calcium levels 3. 1,25-D directly suppresses PTH secretion by the parathyroid gland g. Action i. OVERALL = ↑ Ca ↓ PO4 ii. SUMMARY 1. ↑ bone resorption – occurs in minutes - Initial rapid phase (mins-hours) = activation of osteoclasts to promote calcium + phosphate release - Second slower phase (days-weeks) = binds to osteoblasts stimulating RANKL to differentiate into mature osteoclasts that promote resorption (longer term); also inhibits osteoblasts 2. ↑ intestinal absorption of calcium via increased production of calcitriol – takes days 3. ↓ urinary calcium excretion due to stimulation of calcium reabsorption in the distal tubule – occurs in minutes a. ↓ Ca excretion by stimulating calcium reabsorption in the distal tubule b. ↑ Phosphate excretion by inhibiting phosphate reabsorption in proximal tubule

Answer 193

b. Secreted by C cells of thyroid gland c. Secretion i. Release stimulated by ↑ calcium levels , independent of PTH + vitamin D d. Inhibition i. Low calcium levels ii. PTH e. Actions i. OVERALL = ↓ Ca ↓ PO4 ii. BONE = Stimulates Ca 2+ deposition in the bones (inhibits resorption) 1. Stimulates osteoblasts 2. Inhibits osteoclasts iii. RENAL = ↑ renal excretion of Ca

Answer 194

a. Source – mostly sun exposure (>80%), diet (< 20%) (minimal intake in breast milk 25 IU/L) i. Few dietary sources – fish liver, fatty fish, egg yolks, formula ii. Breastmilk contains almost no vitamin D iv. Dietary vitamin D3 b. Production – involves SKIN > LIVER > KIDNEY i. Sunlight = 7-dehydrocholesterol > cholecalciferol (vitamin D3) ii. Oral intake = cholecalciferol (vitamin D3 – fish and meat), vitamin D2 (vitamin supplementation) iii. Liver = cholecalciferol (vitamin D3) > 25-hydroxy-vitamin D (calcidiol) via 25 hydroxylase iv. Kidney = 25-hydroxy-vitamin D (calcidiol) > 1,25-dihydroxy-vitamin D (calcitriol) via 1 alpha hydroxylase c. Actions i. OVERALL = ↑ Ca ↑ PO4 ii. INTESTINE 1. Promotes Ca and phosphate absorption (note most phosphate absorption is independent of vitamin D) 2. Occurs over 2 days with effects lasting 1-2 weeks iii. KIDNEY = increases Ca2+ and PO4 reabsorption in proximal convoluted tubule iv. BONE = simulates bone demineralisation – binds to osteoblasts which releases RANKL promoting differentiation of osteogenic stem cells into osteoclasts v. OTHER 1. Increases muscle strength, effect on RAAS, mood, immune system 2. Suppresses PTH

Answer 195

Glucocorticoids oppose vit D Glucocorticoids affect vitamin D metabolism at different levels of the enzymatic cascade, thereby decreasing the synthesis of active vitamin D and impairing its biological action at the tissue level. Glucocorticoids directly inhibit osteoblast proliferation/differentiation -> bone resorption and suppressed bone formation Reduced Ca absorption d/t reduced vit D Increase renal excretion d/t reduced Ca absorption

Answer 196

a. Similar to PTH – has same first 13 amino acids b. Gene is on chromosome 12 c. Can activate PTH receptors on kidney + bone cells to ↑ renal production of 1,25-OHD d. Often implicated in paraneoplastic phenomena

Answer 197

Mostly PTH/vit D Neonatal - transient - permanent Hypoparathyroidism - Genetic (DiGeorge, mutations in PTH production, HDR syndrome, mutations in Ca sensing receptor, mitochondrial disorders) - Autoimmune (APS1) - Other (parathyroid/thyroid surgery, infiltration of PTH gland (iron, copper)) Hyperparathyroidism - vitamin D deficiency / impaired metabolism (insufficient intake, low sun exposure, decreased absorption, liver/renal disease, 25-hydroxylase deficiency, - pseudoparathyroidism (type 1, type 2) Miscellaneous - hungry bone syndrome - osteopetrosis - sepsis, other acute illness - hyperphosphataemia - alkalosis (more anion binding sights therefore increase protein binding and decrease ionized calcium) - IV citrate/lactate - pancreatitis - hypomagnesaemia

Answer 198

1. Clinical features a. Seizures b. Apnoea c. Weakness and tiredness d. Carpopedal spasm i. Trousseau’s sign = carpal spasm from inflated BP cuff for 3-5mins >15mmHg above SBP; sensitive and specific (1% false positive) ii. Chovstek’s sign = facial spasm from tapping facial nerve in front of ear e. Stridor f. Irritability and other behavior problems g. Soft tissue and basal ganglia calcification with longstanding hypoparathyroidism or pseudohypoparathyroidism h. Features of cardiac failure 2. Investigation a. Biochemistry: Ionised Ca, UEC, LFT, CMP, ALP, Total calcium/albumin: 1. CORR Ca = Ca TOTAL + (40 – Alb) x 0.02 v. Urinary calcium/creatinine ratio vi. vit D b. Other tests as indicated i. Maternal vitamin D ii. FBE/ blood film/ iron studies iii. PTH autoantibodies iv. Fat soluble vitamins (other than vit D) c. Imaging i. Long bones ii. Skeletal survey d. ECG = prolonged QT interval i. Low calcium results in decreasing potential and hyper-excitability 3. Management a. Treat cause b. Consider replacement of vitamin D and magnesium c. Mild / moderate i. Oral supplementation calcium (calcium carbonate or calcium gluconate) and vitamin D 1. Calcium carbonate 1-2mmol/kg/day ii. Cholecalciferol stoss or regular d. Severe – symptomatic i. IV calcium gluconate / calcium chloride (10% CaCl usually) ii. Need telemetry for monitoring QT interval iii. Can precipitate arrythmias + can cause calcium burns (need central line) 4. Complications a. Nephrocalcinosis b. Pancreatitis

Answer 199

1. Key points a. Common metabolic problem in newborns 2. Clinical manifestations a. Usually identified by screening b. Neuromuscular irritability c. Jittery, muscle jerking d. Generalised or focal seizures e. Rare presentations – laryngospasm, bronchospasm, pylorospasm 3. Management a. Treat cause b. Maternal hyperparathyroidism or late hypocalcaemia (onset >72 hours due to impaired renal sensitivity to PTH) may need treatment with calcium + vitamin D supplements

Answer 200

Undetectable or low PTH Hypoparathyroidism HypoMg (important cofactor – calcium sensing receptor) Normal PTH Abnormal calcium sensing receptor (new ‘set point’ – activating mutation) High PTH Vitamin D deficiency/ impaired Pseudohypoparathyroidism Renal failure

Answer 201

EARLY HYPOCALCAEMIA • Occurs in first 2-3 days after birth • Exaggeration of the normal decline in calcium after birth Prematurity • Very common – 1/3 of preterm infants and majority of VLWB infants have hypocalcaemia • Multifactorial – hypoalbuminaemia, reduced intake of Ca due to low milk intake, possible impaired response to PTH, increased calcitonin, increased urinary losses accompanying high Na excretion Fetal growth restriction • Decreased transfer of Ca across the placenta Infants of diabetic mothers • Occurs in 10-20% of IDM • Low PTH concentrations after birth in IDM compared with normal infants Birth asphyxia • Multifactorial – increased phosphate load caused by tissue catabolism, decreased intake due to delayed initiation of feeding, renal insufficiency, increased calcitonin Hypoparathyroidism • Hypoparathyroidism associated with excess phosphorous intake is common • Also due to lack of parathyroid gland (eg. CATCH-22) Maternal hyperparathyroidism • Increased transplacental transport of Ca caused by high maternal Ca concentrations  fetal hypercalcaemia which suppresses fetal and neonatal PTH HypoMg • HypoMg causes resistance to PTH and impairs PTH secretion – both resulting in low Ca • Most common is transient hypoMg

Answer 202

LATE HYPOCALCAEMIA • Occurs after 2-3 days, typically at the end of the first week • Infants with late-onset hypocalcaemia typically present with signs of hypocalcaemia (neuromuscular excitability + seizures) • Cause o Transient hypoparathyroidism o Transient parathyroid hormone resistance o High phosphorous intake – infants fed bovine milk o Low Mg o Maternal vitamin D deficiency o DiGeorge = hypoplastic or absent parathyroid glands

Answer 203

``` Transient Hypoparathyroidism • Premature • Growth retarded 30-90% • Infant of diabetic mother +/- low Mg • Infant of vitamin D deficient mother ``` Permanent • Primary hypoparathyroidism • Di George – most common, usually becomes less severe • HDR – with deafness/ renal dysplasia

Answer 204

* Hallmark = LOW calcium + HIGH phosphate * Impaired synthesis or secretion of PTH due to lack or loss of parathyroid gland (tissue) or due to a defect in the synthesis or release of PTH – primary or acquired * Defect in calcium-sensing receptor (CaSR) or related proteins Aetiology: Congenital - many - DiGeorge/velocraniofacial syndrome i. Deletion mutation in chromosome 22q11, 25% inherited from parent ii. 1/4000 newborns iii. 60% have neonatal hypocalcemia (often transitory) 1. Can recur or have onset later in life iv. Associated abnormalities: 1. 3rd and 4th pharyngeal pouch abnormalities 2. Heart defects 3. Cleft palate 4. Renal anomalies 5. Thymus aplasia with immunodeficiency - X-LINKED RECESSIVE HYPOPARATHYROIDISM, autosomal recessive hypoPTH - mitochondrial disorders FAMILIAL HYPOCALCAEMIA (AUTOSOMAL DOMINANT HYPOCALAEMIA) i. Activating mutation of the CaSR PTH NOT released at serum concentrations that normally trigger PTH release iii. Clinical features 1. Often asymptomatic with mild to moderate hypocalcemia 2. Become symptomatic with stress (febrile illness/ tetany) 3. Recurrent nephrolithiasis – particularly if treated with vitamin D iv. Investigations 1. Hypocalcaemia 2. Normal or low PTH, relative hypercalciuria 3. High or high normal urinary calcium excretion v. Treatment 1. No treatment required if asymptomatic (vitamin D results in nephrocalcinosis) Aetiology: AUTOIMMUNE a. APECED/AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1 Aetiology: 3. ACQUIRED a. SURGICAL i. Removal or damage of the parathyroid glands can complicate thyroidectomy ii. Symptoms of tetany can occur abruptly post-operatively b. OTHER ACQUIRED i. Iron deposition in the setting of chronic transfusions ii. Copper deposition in Wilson’s disease iii. Infection resulting in impaired PTH secretion

Answer 205

1. VITAMIN D DEFICIENCY a. Suspect in darker skinned infants or presenting age 6-12 months b. NB may occur in younger children where mother wears covering clothing and is also vitamin D deficient – these infants are born without vitamin D stores and can present as early as 3 months c. The most common cause d. Risk factors i. Dark skin ii. Maternal history iii. Malabsorption e. Clinical features i. Can present as early as 3 months ii. Rickets 2. ABNORMAL VITAMIN D METABOLISM a. Hepatic dysfunction b. Renal dysfunction c. 1-alpha hydroxylase deficiency = VDDR 1 type 1 iii. Investigations = ↓ (or N) Ca, ↓ (or N) PO4, ↑ PTH iv. 25 vit D will be normal but 1,25-OH-vit D will be low v. Treatment = calcitriol 1. Aim to keep Ca low normal, PTH high 2. Excessive calcitriol can drive hypercalciuria + nephrocalcinosis d. Hereditary resistance to vitamin D (HRVD) = VDDR type 2 i. Rare AR disorder, Due to abnormal vitamin D receptor – in hormone binding domain or DNA binding domain 3. END ORGAN RESISTANCE TO PTH = PSEUDOHYPOPARATHYROIDISM a. Key features i. Hypocalcaemia ii. Hyperphosphataemia iii. Elevated PTH b. Types i. Type 1A – Albrights hereditary osteodystrophy + biochemical + resistance to other hormones ii. Type 1b – biochemical, normal phenotype, post receptor defect iii. Type 1c – different receptor mutation, phenotypically the same as 1a, distal defect iv. Type 2 – Do not have features of AHO, post receptor defect c. Type 1A (accounts for the majority of patients)

Answer 206

AKA Type 1A pseudohypoparathyroidism Inactivating mutation GNAS1 gene (same gene as Mcune Albright syndrome but inactivating rather than activating mutation) - inheritance determines syndrome: maternally inherited = pseudohypoPTH 1a/b/c, paternally inherited = pseudopseudohypoPTH Manifestations - Obesity - Short stature - Round facies - Subcutaneous ossification - Brachydactyly type E (shortening mainly of 4th+/-5th metacarpals/tarsals) - IUGR - Developmental delay - Tetany - End organ resistance to several hormones, e.g. PTH, TSH (2nd most common)

Answer 207

Variant of pseudohypoPTH Mutation of same gene (inactivating GNAS) but paternally inherited - maternally inherited = pseudohypoPTH - activating mutation = McCune Albright syndrome Manifests - anatomic stigmata of pseudohypoPTH, but serum Ca/PO4 normal - PTH may be slightly elevated

Answer 208

* Phase of avid bone mineralisation with hypocalcaemia due to rapid movement of calcium from the bone to the skeletal compartment * Tends to occur during early phases of recovery from a severe mineralisation defect or after a prolonged period of calcium resorption from bone * A parallel increase in uptake of Mg leading to hypoMg may increase severity of hypocalcaemia * Examples = vitamin D therapy in the setting of severe rickets, parathyroidectomy

Answer 209

1. Causes hypocalcemia by a number of mechanisms a. Reduced responsiveness to PTH b. Impaired PTH release c. Impaired formation of 1,25 vit D 2. Clinical manifestations a. Carpopedal spasm b. Tetany and/or seizures c. Anorexia and hypokalemia d. Tachycardia with prolonged QT and PR intervals 3. Causes a. Congenital i. Intestinal absorption defect ii. Magnesium losing kidney b. Acquired i. Malabsorption ii. Renal tubular damage eg. cisplatin iii. Impairment of PTH secretion and action

Answer 210

In order of frequency: - hyperparathyroidism - 1,25 vitamin D excess, granulomatous disease - subcutaneous fat necrosis - vitamin D intoxication - acute/chronic renal insufficiency Neonatal - fat necrosis (inc 1,25 vit D) with normal PTH - Williams syndrome - familial hypocalciuric hypercalcaemia - hypophosphatasia (normal serum phosphate and ALP but elevated urine phosphatase) - renal failure All ages - abnormalities of calcium detection (familial hypocalciuric hypercalcaemia, neonatal hyperparathyroidism, antibodies to Ca sensing receptor) - vitamin D related (Williams, vit D toxicity, sarcoidosis, granulomatous disease, lymphoma, fat necrosis) - increased bone turnover (immobilisation, vit A toxicity) - hyperparathyroidism (primary, secondary (appropriate response to hypocalcaemia), tertiary (chronic secondary -> hyperplasia and autonomous secretion)) - PTH receptor abnormality - malignancy - other (hypophosphatasia, thyrotoxicosis, tumour lysis)

Answer 211

1. Clinical features a. Generally rare b. Neonatal severe hyperPTH = anorexia, irritability, lethargy, constipation c. Stones, bones, thrones, abdominal groans, psychiatric moans d. Bones = bone pain, osteoporosis e. Gastrointestinal (groans) = constipation, nausea, vomiting, pancreatitis f. Renal (thrones - toilet) = polydipsia, polyuria, renal calculi g. MSK = weakness, hypo-reflexia h. CVS = cardiac arrest, short QT, HTN i. Other = failure to thrive j. CNS = confusion, apathy, drowsiness, impaired consciousness k. Long-standing = cognitive impairment, convulsions, blindness l. Psychiatric manifestations = depression, confusion, dementia, stupor and psychosis 2. Investigations a. UEC/ CMP/ ALP b. ECG iii. High calcium results in increasing potential and decreased excitability c. PTH d. Vitamin D e. Plain films - ?resorption of subperiosteal bone f. Urinary Ca/Cr ratio, PO4/Cr ratio g. Skeletal survey h. Renal USS = evidence of nephrocalcinosis

Answer 212

a. Most important to REHYDRATE b. Acute i. Mild <3mmol/L = no treatment 1. Avoid high calcium diet, thiazide diuretics, bed rest/inactivity, hydration ii. Moderate 3-3.5mmol/L = as above unless acute rise/symptomatic iii. Severe >3.5mmol/L 1. IV N/Saline + 5% Dex hydration to euvolemic state +/- frusemide a. Infants <2 years – use 0.45% N saline + 5% dextrose b. Rehydrate: drives co-excretion of Na+ and Ca 2. Corticosteroids (decrease GIT absorption, increase renal excretion, oppose vitamin D - also increase bone resorption but net effect reduces Ca) 3. Bisphosphonates = usually longer term 4. Calcitonin = immediate effect over 48hours (tachyphylaxis) 5. Diuretics = indicated if a. Acute hypercalcaemia – frusemide given to reduce fluid overload while patient aggressively b. Chronic hypercalcaemia with hypercalciuria c. Long term i. Low Ca diet (Lowcosol) ii. Steroids iii. Bisphosphonates 1. Conditions associated with increased bone resorption (ie immobilisation, PTHrP associated malignancies) 2. Onset of effect 24-48 hours, peak effect within 1 week 3. Pamidronate 4. Zoledronic acid

Answer 213

1. Neonatal hyperparathyroidism 3q13 Genetic, mutation leading to abnormal Ca sensing receptor d. Clinical manifestations i. Symptoms develop shortly after birth – anorexia, irritability, lethargy ii. FTT e. Investigations i. X-ray = subperiosteal bone resorption, osteoporosis, pathological fractures ii. ↑ Ca, inappropriately normal/ ↑ PTH f. Inappropriately ↓ Ca in urine 2. Transient neonatal hyperparathyroidism a. Occurs in infants born to mothers with hypoparathyroidism or with pseudohypoparathyroidism b. Chronic intrauterine hypocalcemia drives parathyroid hyperplasia c. In newborns, manifestations mainly involve the bones and healing occurs between 4-7 months 3. Williams syndrome a. Abnormally sensitive to vitamin D, ↑calcitriol leads to hypercalcemia b. Other features i. Cocktail party manner ii. Supravalvular aortic stenosis iii. ID iv. Elfin face c. Treatment = decrease calcium intake 4. Fat necrosis a. Hypercalcemia in neonates must exclude fat necrosis b. Trauma of delivery results in fat necrosis – granulomatous tissue breakdown results in increased activity 1 alpha hydroxylase resulting in increased production of active calcitriol and hypercalcaemia through GIT absorption Macrophages make 1 alpha hydroxylase

Answer 214

Cause of hypercalcaemia a. Due to adenoma or hyperplasia b. Parathyroid gland  excessive secretion of PTH  elevated calcium c. Most common in MEN1 i. 90% MEN1 d. Less common in MEN2 – more likely malignant (more malignant driven)

Answer 215

Hypercalcaemia Heterozygotes: a. AD inheritance b. INACTIVATING mutation in the Ca-sensing receptor (chromosome 3) c. Change in set point  PTH release fails to release with increased levels of high Ca d. Usually asymptomatic e. Investigations i. ↑ Ca ii. Inappropriately normal PTH

Answer 216

1. Source a. 80% sun exposure (UVB) (NB. sunscreen does not affect) b. <20% diet i. Few dietary sources – fish liver, fatty fish, egg yolks, formula ii. Breastmilk contains almost no vitamin D 3. Summary of forms of vitamin D a. Cholecalciferol = vitamin D3 i. Animal products ii. Some vitamin D supplements iii. Formed in the skin from 7-dehydrocholsterol b. Ergocalciferol = vitamin D2 i. Plant dietary sources ii. Most vitamin D supplements c. Calcidiol = 25-hydroxyvitamin D = 25(OH)D i. Storage form of vitamin D ii. Formed in the liver after vitamin D (cholecalciferol produced in skin/ingested OR ergocalciferol) undergoes 25-hydxosylation d. Calcitriol = 1,25-hydroxyvitamin D = 1,25(OH)2D i. Formed in the kidney after 25(OHD) undergoes 1-alpha-hydroxylation ii. Driven by PTH and other mediators (eg. hypophosphataemia, growth hormone) 4. Production = involves SKIN  LIVER  KIDNEY a. Sunlight = 7-dehydrocholesterol  cholecalciferol (vitamin D3) b. Oral intake = cholecalciferol (vitamin D3) OR ergocalciferol (vitamin D2) c. Liver = cholecalciferol (vitamin D3)  25-hydroxy-vitamin D (calcidiol) via 25 hydroxylase d. Kidney = 25-hydroxy-vitamin D (calcidiol)  1,25-dihydroxy-vitamin D (calcitriol) via 1 alpha hydroxylase 5. Sources based on age a. Older children = cutaneous synthesis most important b. Infancy = cutaneous synthesis + intake i. Formula fed - adequate vitamin D, even without cutaneous synthesis ii. Breast fed - low vitamin D content of breast milk -> rely on cutaneous synthesis or vitamin supplements c. <3mo = transplacental transport (mostly 25OHD) typically provides enough vitamin D for the first 2 mo of life unless there is severe maternal vitamin D deficiency

Answer 217

a. Decreased synthesis i. Skin pigmentation – produce less vitamin D in response to light ii. Low sun exposure b. Decreased intake i. Primary source = oily fish, cod liver oil, liver and organ meats, egg yolk iii. Vitamin D fortified in many foods – milk, milk products, orange juice, bread, cereals c. Perinatal factors i. Maternal vitamin D deficiency 2. Vitamin D transferred from mother to fetus across the placenta 3. If a women has severe vitamin D deficiency during pregnancy offspring can have signs of rickets at birth or during the first 3 months of life 4. Particularly common among dark-skinned pregnant women ii. Prematurity 1. Less time to accumulate vitamin D from the mother through transplacental transfer 2. Third trimester is critical time for transfer as fetal skeleton is calcified at this time 3. Fetal vitamin D levels are directly proportional to maternal levels iii. Exclusive breastfeeding 1. Vitamin D content of breast milk is low (15 to 50 IU/L) d. Obesity i. Inverse relationship between obesity and 25(OH)D ii. Vitamin D sequestered in fat e. Malabsorption i. Conditions with impaired fat absorption result in inadequate vitamin D absorption ii. Examples = coeliac disease, IBD, exocrine pancreatic insufficiency (CF), cholestasis f. Genetic disorders i. 25-hydroxylase deficiency (vitamin D dependent rickets type 1B) ii. 1-alpha hydroxylase deficiency (vitamin D dependent rickets type 1A) iii. Hereditary resistance to vitamin D (vitamin D dependent rickets type 2) g. Medications i. Anticonvulsants ii. Glucocorticoids = inhibit intestinal vitamin D-dependent calcium absorption [decrease expression of calcium channels in the duodenum] iii. Ketoconazole and other antifungal agents = block 1-alpha hydroxylation iv. Isoniazid, rifampicin

Answer 218

a. General i. Non-specific bone / muscular pain; fatigue with exercise ii. Symptoms of low calcium: muscle cramps, tetany, seizures (rare beyond 6 months of age) b. Examination i. Osseous 1. Swelling of wrists and ankles 2. Delayed fontanelle closure (normally 2 years) 3. Delayed tooth eruption (no incisors by 10 months, no molars by 18 months) 4. Leg deformity (genu varum, genu valgum, windswept deformity) 5. Rachitic rosary (enlarged costochondral joints) 6. Frontal bossing 7. Craniotabes – softening of skull bones, palpation of cranial sutures in first 3 months (like a ping pong ball) ii. Non-osseous 1. Delayed gross motor 2. Poor linear growth 3. Raised ICP 4. Dilated cardiomyopathy c. Rickets = failure of mineralisation of growing bone and cartilage d. Osteomalacia i. In older children and adolescents once growth is complete and epiphyseal plates are closed, usually reserved mineral which prevents bony deformities ii. Impaired mineralisation in older children and adults causes osteomalacia – asymptomatic or result in generalised muscle and bone pain

Answer 219

9. Biochemical changes a. Low Vitamin D  impaired calcium and phosphorous absorption b. ↑ PTH  normalization of calcium levels or moderately decreased c. Advanced vitamin D deficient rickets may present with severe hypocalcaemia during periods of rapid growth (infancy or adolescence) d. Measuring vitamin D levels i. Laboratory test of vitamin D is 25-hydxoy vitamin D 25(OH)D = stored form ii. Recommended level >50 nmol/L 1. Severe deficiency = <12.5 nmol/L 2. Moderate deficiency = 12.5-29 nmol/L 3. Mild deficiency = 30-49 nmol/L 4. Sufficient = >50 nmol/L 5. Elevated = >250 nmol/L 10. Investigations a. Infants i. Exclusively breastfed with at least one other risk factor WITHOUT symptoms/signs – usually appropriate to start supplements without investigations ii. Infants WITH symptoms/signs need urgent review b. Children i. Measure vitamin D, CMP, ALP ii. Symptoms/signs of deficiency = PTH iii. Rickets = UEC, X-ray and clinical photography

Answer 220

11. Management a. Children i. Aim to restore and maintain Vitamin D levels in the normal range (≥ 50 nmol/L) ii. Options are either 1. Daily low-dose supplements a. 5000 IU/day for rickets initially b. Maintenance 400-800 IU/day 2. High-dose intermittent therapy (≥50,000IU/dose) a. Major problem is hypocalcaemia post vitamin D (hungry bone syndrome) b. Repeat every 6 weeks to 6 months iv. Ensure adequate Calcium Intake - cheese, yoghurt and fortified soy dairy are useful sources of calcium in children who dislike cow milk - consider supplements if poor intake b. Infants i. There is inadequate evidence to support high dose treatments in infants aged < 3 months ii. Exclusively breastfed infants of mothers with Vitamin D deficiency, with at least one other Risk Factor should be given 400 IU daily for at least the first 12 months of life iii. Infants on full formula feeds should receive adequate vitamin D from this source iv. Those on mixed feeds or solids may have inadequate intake: consider checking levels or adding daily supplements in babies with risk factors c. If rickets = calcium co-treatment – monitor for hungry bones affect: calcium drops quickly with refeeding 12. Monitoring a. Moderate/severe deficiency – repeat bloods 3/12 after initial review b. Mild deficiency – not necessary to re-check for response c. One practical approach is to test yearly or second-yearly at the end of Summer (peak annual levels)

Answer 221

1. Key points a. Normal bone growth and mineralisation requires adequate calcium and phosphate b. Deficient mineralisation can result in rickets and/or osteomalacia c. Rickets = deficient mineralisation at the growth plate + architectural disruption of this structure d. Osteomalacia = impaired mineralisation of the bone matrix e. Rickets and osteomalacia usually occur together as long as the growth plates are open f. Rickets is disease of GROWING BONE only – cannot be seen in children who are not growing (eg. pre liver transplant) g. Only osteomalacia occurs after growth plates have closed 2. Pathophysiology a. Growth plate thickness is determined by two opposing processes i. Chondrocyte proliferation and hypertrophy ii. Vascular invasion of the growth plate followed by conversion into primary bone spongiosa b. Vascular invasion requires mineralization of the growth plate cartilage and is delayed or prevented by deficiency of calcium or phosphorus c. Consequences i. Growth plate cartilage accumulates and the growth plate thickens ii. Chondrocytes of the growth plate become disorganized iii. At the metaphysis mineralization defect  accumulation of osteoid d. Abnormalities alter the overall geometry of the involved skeletal sites  secondary increases in the diameters of the growth plate and metaphysis e. Bone stability is compromised and, if the underlying condition does not improve, bowing occurs

Answer 222

Deficient mineralisation at the growth plate + architectural disruption of this structure

Answer 223

Impaired mineralisation of the bone matrix

Answer 224

a. Initially manifest at distal forearm, knee and costochondral junctions (sites of rapid bone growth) where calcium and phosphorous are required for mineralisation b. Skeletal findings = similar for calcipenic and phosphopenic rickets i. Delayed closure of the fontanelles ii. Parietal and frontal bossing iii. Craniotabes (soft skull bones) iv. Enlargement of costochondral junction visible as beading along the anterolateral aspects of the chest (the "rachitic rosary") v. Formation of Harrison sulcus (or groove) at the lower margin of the thorax caused by the muscular pull of the diaphragmatic attachments to the lower ribs vi. Widening of the wrist and bowing of the distal radius and ulna vii. Progressive lateral bowing of the femur and tibia c. Factors affecting site and type of deformity i. Dependent on age and weight-bearing patterns ii. Infants = deformities of the forearms and posterior bowing of the tibia iii. Toddler who is weight bearing = exaggeration of the normal physiological bowing (genu varum) iv. Older child = valgus deformities of the legs or a windswept deformity (valgus deformity of one leg and varus deformity of the other) d. Extraskeletal findings i. Hypoplasia of the dental enamel – calcipenic ii. Dental abscess – heritable phosphopenic rickets iii. Decreased muscle tone and delayed milestones – calcipenic rickets iv. Hypocalcaemic seizures v. Increased sweating due to bone pain vi. Increased infections – calcipenic

Answer 225

4. Investigation a. ↑ ALP – good marker of disease activity, elevated in both types of rickets b. Ca/PO4/PTH/vit D (variable depending on calcipenic/phosphopenic) - calcipenic: PTH high, Ca/PO4 normal/low - phosphopenic: phos low, PTH normal/mild elevated, Ca normal 5. Radiographic findings a. Changes of rickets are best seen at the growth plate of rapidly growing bones = distal ulna, knee b. Features i. Osteopenia ii. Fractures of different ages iii. Metaphysis widening, cupping (concave metaphysis, normally convex/flat), fraying (loss of sharp border), stippling, cortical spurs – results from disorganization of the growth plate iv. Rachitic rosary and chest deformity v. Pathological fractures and Looser’s zones (Milkman pseudofractures) 1. Looser zones are pseudofractures – fissures/radiolucent lines with sclerotic borders and are characteristic of osteomalacia; bilateral and symmetrical viii. Deformity of shafts

Answer 226

1. Key points a. Definition = intestinal absorption of calcium is too low to match calcium demands imposed by bone growth b. Most cases of acquired rickets are calcipenic c. Usually due to insufficient intake or metabolism of vitamin D d. Occasionally insufficient intake or absorption of calcium in the setting of normal vitamin D 2. Etiology a. Vitamin D deficiency (aetiologies as per vit D def notes) b. Calcium deficiency i. Rickets can occur despite vitamin D if calcium intake very low ii. Does not usually occur unless calcium intake is VERY low because vitamin D increases intestinal calcium absorption iii. Most children with calcium deficiency rickets have normal serum 25OHD and high serum 1,25 OH2D - indicating adequate vitamin D levels 3. Investigations a. ↑ PTH (usually) b. ↓ Ca (usually) c. ↓ 25OHD (usually; in nutritional rickets)

Answer 227

1. Key points a. Usually due to renal phosphate wasting b. Always characterised by low phosphate levels c. Short with PROFOUND skeletal bowing d. Key is to assess renal handling of phosphate – and identify inappropriate losses/ phosphaturia e. Nutritional phosphate deprivation can be distinguished by the finding of low urine phosphate (elevated renal tubular reabsorption of phosphate [TRP]), whereas those due to renal phosphate losses usually manifest increased urine phosphate clearance (low TRP) 2. Etiology a. Hereditary (multiple, X-linked/AD/AR) v. Overproduction of phosphatonin – tumor induced rickets (NF, epidermal naevus syndrome, McCune Albright syndrome) b. Inadequate intake i. Prematurity c. Renal loss i. Fanconi – waste PO4 in urine, glucosuria, aminoaciduria, tubular proteinuria + proximal RTA ii. Distal RTA iii. Dent disease – similar to Fanconi 3. Investigations a. Normal (usually) or mild ↑ PTH b. ↓ Phosphorous c. N Ca (usually) 4. Treatment a. Need to ensure very regular phosphate – multiple times per day b. FGF23 Ab therapy now approved by FDA c. Avoid secondary hyperparathyroidism

Answer 228

a. Two main physiological events of puberty i. Gonadarche = activation of the gonads by pituitary hormones resulting release of LH/FSH 1. Girls – breast development, female body habitus, increased size of uterus, menarche 2. Boys – pubic/axillary hair, facial hair, muscularity, deepening of voice, increase in testicular volume and penile size ii. Adrenarche = release of adrenocortical androgens (DHEA/ DHEAS) 1. Results in development of pubic/axillary hair, oiliness of hair/skin, acne, body odour a. ↑ DHEA/ DHEAS also occurs around 6-8 years – prior to gonadarche c. Before earliest changes of puberty are apparent b. Terms to describe specific components of puberty i. Thelarche = breast development, primarily due to the action of oestradiol from the ovaries ii. Menarche = first menstrual bleed iii. Spermache = first sperm production (heralded by nocturnal sperm emissions), due to effects of FSH and LH via testosterone iv. Pubarche = first appearance of pubic hair due to effects of androgens from adrenal gland; term also applied to first appearance of axillary hair, apocrine body odour, and acne c. Puberty i. ↑ pulsatile GnRH ii. ↑ LH release responsiveness to GnRH iii. ↑ secretion LH/ FSH , pulses 2/24 iv. ↑ GH + IGF-1 v. ↑ androgens/ estrogens d. Over time i. FSH becomes less responsive to GnRH , ↑ LH:FSH ratio ii. Gonadal maturation = ↑ sex steroids iii. Acceleration of growth 1. Oestrogen > epiphyseal closure (also in boys) 2. Oestrogen > GH > growth spurts Girls: thelarche->pubarche->growth peak->menarche Boys: testicular volume->pubarche->growth peak->sperm in urine

Answer 229

= DHEA/DHEAS i. ↑ before LH , 5-6 in F, 7-8 in M ii. May cause premature adrenarche iii. Measuring DHEAS = more reliable reflection of androgen production iv. Function 1. Pubic hair 2. Acne 3. Axillary hair + hirsutism 4. Genital enlargement

Answer 230

i. Types = beta-estradiol (most potent), estrone, estriol ii. Functions 1. Stimulates development of genitalia, breast, female fat distribution 2. Stimulates epiphyseal closure 3. Stimulates GH  growth spurt 4. Growth of follicle, endometrial proliferation iii. Role in menstrual cycle: 1. Stimulates upregulation of oestrogen, LH, progesterone receptors 2. Initially provides negative inhibition of FSH/LH 3. At set point, feedback changes to +ve LH feedback = LH surge stimulating ovulation iv. Regulation 1. May be high in first few years (premature thelarche) 2. Another rise in puberty 10-11 years of age)

Answer 231

i. Made by Leydig cells (in utero some placental gonadotropin converted to testosterone) ii. Synthesized via 5-alpha reductase into dihydrotestosterone in target tissues iii. Functions 1. Descent of testes (in utero) 2. Differentiation of epididymis, vas, seminal vesicles 3. Deepening of voice 4. Closure of epiphyseal plates (less action than oestrogen) 5. Libido 6. ↑ basal metabolic rate iv. Regulation 1. High in fetus due to placental hCG + fetal pituitary stimulation 2. Persists until 10 weeks of life, then decreases 3. Increases again in puberty

Answer 232

= LH, FSH i. Overall ↑ testicular volumes/ ovaries ii. In males 1. FSH  Sertoli cells  spermatogenesis 2. LH  Leydig cells  testosterone iii. In females 1. FSH  follicular stimulation  thecal cells: oestrogen/ progesterone 2. LH  corpus luteum iv. Normal fluctuations in levels: 1. Fetus: peak secretion after 16-18 weeks 2. Neonate: ↑ FSH/LH (withdrawal from maternal oestrogen) 3. Early puberty: ↑ FSH/LH rise (initially at night)

Answer 233

i. Produced by Sertoli cells/ follicles | ii. Provide negative feedback to FSH

Answer 234

i. Progesterone + 17 alpha hydroxyprogesterone ii. Main source = corpus luteum iii. In follicular phase, mainly converted to estrogen by granulosa cells iv. ↑ in luteal phase v. Promotes breast development and uterine shedding

Answer 235

i. 17-18% of final adult height accrues across puberty ii. Growth spurt typically lasts for 2 years in both sexes iii. Occurs 2 years earlier in girls than boys iv. Increase in height affects axial (trunk) and appendicular (limb) components 1. Limbs accelerate before trunk, with distal portions before the proximal portions v. Disparity in mean adult height occurs due to timing and magnitude of growth spurt between sexes vi. Girls 1. Peak height velocity occurs 0.5 years before menarche 2. Usually age 11-12 years 3. Peak rate = 8.5 cm/year vii. Boys 1. Pubertal growth spurt starts 2 years later – additional two years of pre-pubertal growth (rate of 3-8cm per year) 2. Usually age 13-14 years 3. Peak rate = 9.5-10cm/year ii. 40-50% of bone mass is accrued during puberty

Answer 236

a. Kisspeptin produced in arcuate nucleus stimulates GnRH release – influenced by i. Estradiol (negative feedback in prepubertal years) ii. Nutritional status via leptin and ghrelin b. Neuroglial cell products i. TGF-alpha, TGF beta, and others act on GnRH cells to stimulate cell growth and function ii. Dynamic direct apposition of glial cells with GnRH cells stimulate GnRH secretion – inhibited by estradiol

Answer 237

Precocious (2SDmean) - Girls >12 - Boys >14

Answer 238

a. Thelarche (breast bud) usually first sign of puberty (8-12 years) b. Pubarche = 3-6 months post thelarche c. Menarche = 2 years post thelarche d. Peak height velocity = occurs early (when breast stage II-III) and ALWAYS precedes menarche i. Mean age 11-12 years with maximum velocity of 9 cm/ year (generally stops by 16 years) ii. During puberty gain approximately 25cm in height

Answer 239

a. Follicular phase = day 0-13 = follicle growth + endometrium proliferation i. FSH binds to granulosa cells within the follicles which synthesize estradiol and estrone by converting androgens to estrogens via the aromatase enzyme ii. Between 3-30 follicles are recruited between day 8-10 iii. Estradiol levels increase from day 1 and peak at day 12 iv. Granulosa cells also produce inhibin, which negatively feeds back onto pituitary to inhibit FSH v. FSH levels decline after day 5 vi. Most of the follicles regress, but one follicle, the dominant follicle, emerges at day 10-14 vii. At low levels estrogen inhibits LH, but at high levels it has a simulatory effect viii. Estradiol peak induces a huge LH surge in the late follicular phase b. Ovulation = day 14 i. Ovulation occurs 10-12 hours after LH surge, and 24-36 hours after estradiol peak c. Luteal phase = day 15-28 = endometrium secretory + corpus luteum formation i. Follicle becomes leutinised 1. Granulosa cells form corpus luteum  progesterone ii. Initially progesterone converted to oestrogen iii. Corpus luteum degenerates if ovary not fertilized  declining progesterone and estrogen  menses (high FSH and LH, new follicle) iv. The luteal phase is constant – ovulation ALWAYS occurs 2 weeks prior to the first day of the next cycle (therefore a longer cycle only lengthens the follicular phase of the cycle) 4. Summary of hormones a. FSH i. Stimulates follicular growth ii. ↑ granulosa cells = ↑estrogen iii. Slight negative feedback from estrogen initially b. LH i. Stimulates theca cells to produce androstenedione, converted to estrogen ii. Estrogen = normally has -ve feedback, reaches set point where feedback = +ve  LH surge c. Estrogen i. Induces endometrium to grow ii. ↑ under FSH/LH stimulus iii. Reduces when follicle becomes corpus luteum d. Progesterone i. Increases blood flow to endometrium + ↑ uterine secretions ii. Produced by corpus luteum iii. -ve feedback to FSH/ LH e. Inhibin also produced – negative feedback to FSH

Answer 240

a. First sign = testicular growth (> 4ml) and thinning of scrotum first sign ( 11-12 years) b. Pubarche = occurs 6 months after testicular enlargement c. Spermache = 2 years post pubarche d. Facial hair = 3 years post pubarche e. Peak height velocity = occurs LAST i. Acceleration of growth begins AFTER puberty – approximately 2 years after starting ii. Maximal at genital stage IV-V , begin growth at a later stage than females iii. Peaks at 13-14 year at ~10 cm/ year, then slows to a stop at 18 years

Answer 241

a. Nocturnal emissions at 13 years of age b. GnRH released in pulsatile fashion, stimulates LH/ FSH c. LH  Leydig cells  testosterone (negative feedback) d. FSH  Sertoli cells  spermatogenesis, regulated by inhibin (-ve feedback) i. Testosterone also diffuses across from the Leydig cell to stimulate spermatogenesis

Answer 242

Central (gonadotropin dependent = true precocious puberty) - idiopathic - organic brain lesions - hypothalamic hamartoma (A hamartoma is a noncancerous tumor made of an abnormal mixture of normal tissues and cells from the area in which it grows) - brain tumours, hydrocephalus, trauma - hypothyroidism (prolonged and untreated) Combined central+peripheral - treated CAH - McCune Albright syndrome (late) - familial male precocious puberty Peripheral (gonadotropin independent = precocious pseudopuberty) GIRLS - Isosexual (feminising): McCune Albright, ovarian cysts/tumours, granulosa cell tumour, adrenal tumour, exogenous steroids - Heterosexual (masculinising): CAH, adrenal tumours, ovarian tumours, glucocorticoid receptor defect, exogenous androgens BOYS - Isosexual (masculinising): CAH, adrenocortical tumour, Leydig cell tumour, hCG secreting tumour (CNS, hepatoblastoma), familial male precocious puberty, a/w pseudohypoparathyroidism, glucocorticoid receptor defect, exogenous androgens - Heterosexual (feminising): feminising adrenocortical tumour, exogenous oestrogens Incomplete (partial) - premature thelarche - premature adrenarche - premature menarche

Answer 243

a. Central precocious puberty = central = gonadotropin-dependent ↑ LH/FSH ↑ estradiol/testosterone i. Early maturation of the hypothalamic-pituitary-gonadal axis ii. Sequential maturation 1. Boys: premature testicular enlargement followed by development of pubic hair 2. Girls: premature breast development followed by development of pubic hair iii. Sexual characteristics are appropriate for a child’s gender = isosexual iv. Pathological in 40-50% of boys compared with 10-20% of girls b. Peripheral precocity = peripheral = gonadotropin-independent ↓ LH/FSH ↑ estradiol/testosterone i. Caused by excess secretions of 1. Sex hormones (estrogens or androgens) from the gonads 2. Exogenous sources of sex steroids 3. Ectopic production of gonadotropin from a germ cell tumour (eg. hCG) ii. Not true puberty as hypothalamic-pituitary-gonadal axis is not activated iii. May be isosexual or contrasexual iv. Incorrect sequence c. Benign/ non-progressive pubertal variants i. Girls = premature thelarche ii. Boys + girls = premature Adrenarche

Answer 244

a. FSH / LH + estrogen/ testosterone  differentiates central vs peripheral b. GnRH test – FSH/LH response i. Pubertal response predominant FSH ii. Pre-pubertal response predominant LH c. hCG in boys d. Oestrogen levels e. TFTs, cortisol f. Plasma DHEAS (adrenarche) g. X-ray – bone age h. Pelvic/abdominal US (?tumor ?cyst) i. +/- MRI brain – if suspect central cause

Answer 245

a. Consider use of GnRH agonist i. Physiolgical GnRH is pulsatile in manner  continuous administration results in ‘desensitization’/ negative feedback on the gonadotropic cells of the pituitary  inhibit endogenous GnRH production i. Overcomes the pulsatile nature of GnRH ii. EG – leuprolide acetate, goserelin (Zoladex) iii. Induces response in 1-6 months: 1. Tanner stage II-III breast development may regress. If III-IV, tends to remain 2. Menses cease 3. Pubic hair tends to stay the same 4. ↓ hormone profile but LH does not return to return to prepubertal levels iv. Menarche tends to occur 18 months after ceasing therapy v. No long term therapy related b. Bone health i. Without treatment, 30% of girls will be < 5th percentile in height ii. Aim to slow before epiphyseal fusion c. Mental health i. Compatible with chronological age

Answer 246

1. Key points a. Breast development <8 years in girls b. Testicular development (volume >=4ml) <9 years in boys c. GnRH dependent d. KEY = due to early activation of the hypothalamic-pituitary-gonadal axis e. More common in girls f. Idiopathic in 80-90% of girls and only 25-60% of boys g. 75% of boys have CNS abnormality h. NOTE: Mutation in MKRN3 imprinted gene is the most common cause of precocious puberty which is familial 2. Aetiology a. Idiopathic (80%) i. Almost all idiopathic cases are girls b. Organic brain lesions c. Hypothalamic hamartoma d. Brain tumours, hydrocephalus, severe head trauma e. Hypothyroidism prolonged and untreated f. Acquired CNS insults i. CNS irradiation – commonly associated with GH deficiency ii. Hydrocephalus, subarachnoid cysts, CP, tuberous sclerosis g. NF type 1 h. Previous excess sex steroid exposure eg. CAH i. Genetic (rare) = gain of function kisspeptin gene or receptor

Answer 247

3. Clinical manifestations a. All components of puberty normal but early b. Girls = early development of breasts, early menstrual cycles c. Boys = early development of testes, early spermatogenesis d. Both i. Height, weight and osseous maturation are advanced  early closure of epiphyses 1. Without treatment 1/3 girls and most boys = <5th centile height as adults ii. Mental development compatible with chronological age NOT pubertal development 4. Investigations a. Key = elevated basal LH and/or stimulated LH concentration post GnRH b. Sex hormone concentrations – usually appropriate for the stage of puberty c. GnRH stimulation test (GnRH administered) or GnRH agonist (leuprolide) – helpful diagnostic test d. Pelvis USS = may show enlarged ovaries, enlarged fundus and the whole uterus e. X-ray bone age = advanced bone age f. MRI = CNS pathology, may show physiological enlargement of pituitary (normal in puberty) 5. DDx a. Organic causes more likely in boys + girls with rapid breast development, estradiol concentration > 30 pg/ml or are <6 years b. Gonadotrophin-independent causes of isosexual precocious puberty must be considered in DDx i. Girls – consider tumour of ovaries, autonomously functioning ovarian cyst, feminizing adrenal tumour, McCune-Albright syndrome, exogenous estrogens ii. Boys – consider CAH, adrenal tumours, Leydig cell tumour, chorionic gonadotropin producing tumours, exposure to exogenous androgens, familial male precocious puberty

Answer 248

a. GnRH agonists = mainstay of treatment i. Physiolgical GnRH is pulsatile in manner  continuous administration results in ‘desensitization’/ negative feedback on the gonadotropic cells of the pituitary  inhibit endogenous GnRH production ii. Examples = leuprolide, histrelin, goserelin iii. Decision to treat based on chronological age at presentation + height preservation iv. Treatment results in decrease of growth rate, decrease in the rate of osseous maturation – results in enhancement of predicted height v. Protocol = 11.25 mg IM dose 3 monthly 1. Review at 3/12 with LH level 1-hour post 2. Adequate suppression = LH <2 3. If not suppressed, consider increasing dose 4. Annual GnRH test and bone age vi. Length of treatment 1. Normal age of onset of puberty (<14 years) 2. Patient/parent preference 3. Anticipated time of menarche = mean time from end of treatment to menses 16 months 4. Chronological age 5. Bone age b. Effect of treatment i. Girls 1. Breast develop may regress if Tanner stages II-III (or unchanged in III-V) 2. Pubic hair remains stable or may progress slowly during treatment 3. Menses if present cease 4. Greatest height gain seen in girls with onset age <6 months (average gain 9-10cm) ii. Boys 1. Decrease of testicular size 2. Variable regression of pubic hair 3. Decrease in frequency of erections iii. If treatment effective, sex hormones decrease to pre-pubertal levels 1. Testosterone <10-20 ng/dL 2. Estradiol <5-10 pg/mL 3. LH and FSH decrease to <1 IU/L in most patients c. Adverse effects = nil serious (apart from reversible decrease in bone density) d. Other i. Structural abnormalities present = surgery, chemotherapy, radiotherapy 1. HOWEVER would not do surgery for hypothalamic hamartoma if only feature is precocious puberty – treat medically ii. Progestogen sometimes used iii. GH sometimes used if markedly advanced bone age, prediction of short stature

Answer 249

Glioma, germ cell tumour, hamartoma a. Etiology i. Glioma – note those with NF-1 have lower mortality 1. Optic tract tumours are highly prevalent with NF-1  3% incidence of precocious puberty in NF-1 ii. Hypothalamic hamartomas 1. Ectopic neural tissue 2. Glial cells within the hamartoma produce transforming growth factor alpha  activate GnRH pulse generator 3. Note can also be associated with gelastic or psychomotor seizures iii. Germ cell tumours 1. 5% of intracranial neoplasms in children 2. Peak incidence in puberty 3. Males >> females 4. Majority are midline 5. Pineal region (50%), suprasellar, hypothalamic or third ventricle 6. May initially be small 7. Secrete hCG  LH receptors in the Leydig cells of the testes [peripheral precocious puberty] iv. Any insult involving hypothalamus – scarring, invasion, pressure eg. tuberculous meningitis, tuberous sclerosis, severe head injury, hydrocephalus, neoplasm b. Clinical manifestations i. Tumour may result in signs ii. For lesions causing neurological symptoms, the neuro-endocrine manifestation may be present for 1-2 years before the tumour can be detected radiographically iii. Hypothalamic signs or symptoms = diabetes insipidus, adipsia, hyperthermia, unnatural crying or laughing (gelastic seizures), obesity, cachexia iv. Visual signs = proptosis, decreased visual acuity, visual field defects v. Sexual precocity is ALWAYS isosexual c. Investigations i. MRI = hypothalamic hamartoma  small pedunculated mass attached to the tuber cinerum or the floor of the third ventricle d. Treatment i. GnRH agonists ii. Stereotatic radiation therapy – for patients with gelastic or psychomotor seizures iii. GH therapy if GH deficiency

Answer 250

a. Key points i. Radiation therapy for leukaemia or intracranial tumours increases the risk of precocious puberty 1. Low dose 18-24 Gy  affects females only 2. 25-47 Gy  both males and females ii. Type of sexual precocity is often associated with GH deficiency +/- hypothyroidism iii. NOTE: hypopituitarism with gonadotropin deficiency may subsequently develop as a late effect of high dose CNS irradiation in patients with or without a history of precocious puberty, requiring substitution with sex steroids b. Treatment i. GNRH analogues ii. Concomitant GH +/- Thyroid hormones

Answer 251

Hypothyroidism is the only condition resulting in precocious puberty with SLOW GROWTH a. Note this is central puberty without true gonadotropin dependency b. In children with untreated hypothyroidism, onset of puberty is usually delayed until epiphyseal maturation reaches 12-13 years of age c. Can occur in up to 50% of children with longstanding hypothyroidism (usually Hashimoto’s) d. Clinical features i. Breast enlargement/ menstrual bleeding ii. Multicystic ovaries seen on USS iii. Boys – testicular enlargement with minimal penile enlargement/ pubic hair iv. SLOW GROWTH (usually grow FAST with precocious puberty) e. Pathogenesis i. High levels of TSH interact with FSH receptor, but not the LH receptor ii. FSH receptor  estradiol secretion by ovaries iii. In boys testicular enlargement without substantial testosterone secretion f. Investigations i. TSH – elevated ii. LH/FSH – low iii. MRI brain – enlargement of the sella – typical of longstanding primary hypothyroidism g. Treatment i. Treatment of hypothyroidism ii. Results in return of normal biochemical and clinical features iii. MAY induce rapid bone age advancement

Answer 252

1. Key points a. Caused by excess secretion of sex hormones (estrogens and/or androgens) derived from i. Gonads ii. Adrenal glands iii. Exogenous sources b. Low or suppressed gonadotropin concentrations with elevated sex hormone levels c. Pubertal status needs to be monitored for 6/12 after treatment as treatment of peripheral precocity can trigger central precious puberty d. Combined central and peripheral precocious puberty i. Peripheral precious puberty can induce maturation of hypothalamic pituitary gonadal axis and trigger the onset of central precious puberty ii. Includes: 1. Treated CAH 2. McCune-Albright syndrome, late 3. Familial male precocious puberty, late 2. Classification a. Isosexual = sexual characteristics appropriate for child’s gender b. Contrasexual = inappropriate for child’s gender; virilisation of girls and feminization of boys 3. Investigations a. FSH and LH suppressed b. GnRH stimulation test shows NO increase in FSH or LH 4. Management a. Dependent on cause b. GnRH agonist therapy is ineffective

Answer 253

Girls • Ovarian cysts • Ovarian tumours Boys • Leydig cell tumours • hCG secreting tumours • Familial male-limited precocious puberty (LH receptor mutation) Girls and Boys • Exogenous estrogen/ testosterone • Adrenal tumours • CAH • Primary hypothyroidism (testicular enlargement only in boys • Pituitary gonadotrophin secreting tumours (rare) • McCune Albright (F > M)

Answer 254

1. Ovarian cyst a. Large functioning follicular cyst is the most common cause of peripheral precocity in girls b. Often present with breast development followed by an episode of vaginal bleeding which occurs due to estrogen withdrawal once the cyst has regressed c. Cyst may appear and regress spontaneously d. Associated with McCune-Albright syndrome 2. Ovarian tumour a. Ovarian tumours are a rare cause of peripheral precocity in girls b. Granulosa cell tumours typically present with isosexual precocity i. Produce estrogen independent of GnRH ii. Present with menstrual irregularities iii. Juvenile and adult subtypes – juvenile typically before puberty iv. Malignant potential c. Sertoli/Leydig cell tumours (arrhenoblastoma), pure Leydig cell tumours and gonadoblastoma may make androgens and cause contrasexual precocity Pigmented nipples = high levels oestrogen

Answer 255

1. Leydig cell tumours a. Consider in boys with asymmetric testicular enlargement even if no mass evident on palpation/ USS b. Testosterone secreting tumours almost always benign and cured by surgical removal 2. Chorionic gonadotropin-secreting tumours a. Rare tumours b. hCG stimulates LH receptors in the Leydig cells  elevation in plasma testosterone  increase in testicular size (usually only to early pubertal size) c. FH and LH remain low d. Tumours induce puberty in boys but NOT girls (ovarian production of estrogens cannot take place without FSH) e. Types of tumours i. Hepatoblastoma ii. Non-germinomatous or mixed germ cell tumours, choriocarcinoma, teratomas, teratocarcinomas iii. Tumours in other locations – mediastinum, gonads, adrenal glands 3. Familial male gonadotropin independent precocious puberty a. Rare b. Autosomal dominant inheritance of a missense mutation of LH receptor c. Results in Leydig cell activation INDEPENDENT of gonadotropin stimulation d. Clinical features i. Puberty at 2-3 years of age ii. Advanced osseous maturation iii. Associated with type 1a pseudohypoparathyroidism e. Investigations i. Elevated levels of testosterone ii. LH is low/ absent + not stimulated by GNRH g. Management i. Ketaconazole – inhibits testosterone synthesis (CYP17 – 17,20 lyase activity) ii. Other anti-androgens = spironolactone, flutamide and aromatase inhibitors (as estrogens are derived from androgen and stimulate bone maturation) iii. Slows down but does not halt pubertal progression and may not improve height prognosis iv. Medroxyprogesterone acetate – inhibits testicular steroidogenesis

Answer 256

* Isolated manifestations of precocity without development of other signs of puberty * Development of breasts in girls and sexual in hair in both sexes – most common Includes: - premature thelarche - premature adrenarche - premature menarche

Answer 257

1. Features a. Sporadic, transient condition of isolated breast development b. Most often occurs in first 2 years of life i. 2 peaks – one in the first 2 years of life, and the other in 6-8 years of age c. Occurrence in a child older than 3 years of age is most often caused by a condition OTHER than benign premature thelarche d. Benign condition but may be the first sign of true or peripheral precocious puberty, or may be associated with exogenous exposure to estrogen 2. Clinical manifestations a. Isolated breast development, either unilateral or bilateral i. Typically not developing beyond Tanner stage 3 ii. May be unilateral or asymmetric iii. Often fluctuates b. Absence of other secondary sexual characteristics i. Genitalia show NO evidence of estrogenic stimulation c. Normal height velocity for age (not accelerated) d. Normal or near-normal bone age i. May be slightly advanced 3. Natural history a. May develop after 2 years, often persists for 3-5 years, and is rarely progressive b. Menarche occurs at the expected age 4. Investigations a. Usually none required b. Indications for Ix i. Progressive secondary sexual development ii. Increasing height velocity iii. Accelerated bone maturation 6. Management a. Observation b. 10% have true central precocious puberty

Answer 258

1. Key points a. Appearance of sexual hair <8 years (girls) or <9 years (boys) – WITHOUT other evidence of maturation i. NO gender ambiguity b. Mild form of hyperandrogenism that is a variant of normal c. Slowly progressive incomplete form of premature puberty d. Diagnosis requires biochemical demonstration of serum steroid pattern e. More common in girls than boys f. NOTE: technically premature adrenarche and premature pubarche are NOT the same – adrenarche implies elevated adrenal hormones whereas hormones are normal in isolated premature pubarche 2. Clinical manifestations a. Physical findings i. Premature pubarche (sexual hair) – usually genital as opposed to axillary 1. Hair appears on the mons and labia majora in girls and perineal and scrotal area in boys 2. Axillary hair usually appears later ii. Increase in axillary body odour iii. Oily hair or skin (seborrhea) iv. Minor degree of microcomedonal acne v. NOTE: 1. NO other signs of puberty – breast development, testicular enlargement, frank virilisation 2. Check for systemic androgen effects (marked growth acceleration, clitoral/phallic enlargement, cystic acne, advanced bone age) c. Growth i. Tend to have linear growth rate and bone age that are above average, but still within normal range 4. Investigations a. Bone age = slightly advanced b. DHEA = best marker of adrenarche i. Adrenarche typically indicated by DHEAS level >40 ug/dL d. 17-hydroxyprogesterone (screening for non classic CAH - if elevated need ACTH stim to confirm) e. Response to ACTH stimulation i. ACTH stimulation test is the definitive test to diagnose or exclude congenital adrenal hyperplasia ii. Elevated 17-OHP = consistent with CAH iii. Indicated if clitoromegaly/ testicular enlargement f. USS = identify pelvic, scrotal or adrenal neoplasm 6. Treatment a. Slowly progressive condition that requires no therapy b. Monitor to assess height velocity and watch for signs of rapid progression or breast development indicating central precocious puberty c. 50% of girls with premature adrenarche are at risk for hyperandrogenism and PCOS i. Important to minimise other risks including obesity

Answer 259

a. Hypertrichosis i. Fine hair appearing in the genital area is often a manifestation of a generalised excess of body hair (hypertrichosis) ii. Cause = metabolic disorders (thyroid, anorexia, porphyria), medications (cyclosporine, phenytoin) b. Idiopathic premature pubarche i. Children with premature pubarche but no biochemical evidence of Adrenarche ii. Bone age + DEHAS and androgens = normal c. Gondadotropin-dependent precocious puberty i. Typically preceeded by the cardinal antecedent signs of precocious puberty (testicular enlargement in boys and breast development in girls) d. Virilising disorders i. Pubic hair may be the first manifestation of a virilising disorder ii. Rare – account for <5% of premature pubarche iii. Frank virilising disorders (eg. CAH) are suggested by rapid progression of sexual hair development, acne, growth spurt, musculature development, lowering of the voice, and clitoromegaly in girls iv. Includes 1. Virilising congenital adrenal hyperplasia a. Classical virilising CAH = most common and severe form presents in infancy i. Girls = always have gender ambiguity ii. Boys = premature pubarche in early childhood may be the first sign b. Non-classic CAH results from mutations that cause mild hyperandrogenism rather than frank virilisation; girls lack frank virilisation, may present with premature pubarche in mid-childhood i. Deficiency of 21-hydroxylase = most common ii. Deficiency of 11beta-hydroyxlase iii. Deficiency of 3beta-hydroysteroid dehydrogenase 2. Congenital ACTH-dependent forms of adrenal hyperandrogenism 3. Cushings syndrome 4. Virilising tumours 5. Exogenous androgen exposure 6. Peripheral androgen metabolic disorder

Answer 260

• Rare entity • MUCH less frequent than premature thelarche or premature adrenarche • Diagnosis of exclusion – need to exclude vulvovaginitis, FB, sexual abuse, urethral prolapse, sarcoma botryoides • Majority of girls with idiopathic premature menarche only have 1-3 episodes of bleeding • Puberty usually occurs at normal time, menstrual cycles are normal • Investigations o Gonadotropins – low o Estradiol – occasionally elevated due to ovarian estrogen secretion associated with ovarian follicular cysts

Answer 261

1. Key points a. Boys >14 years (usually 12-13 years) b. Girls > 12 years (usually 10-11 years) 2. Classification a. Primary hypogonadism i. Gonadal failure ii. High serum FSH and LH iii. Defect in gonad OR FSH/LH receptors b. Secondary hypogonadism i. Low FSH and LH ii. May be 1. Hypothalamic 2. Hypopituitarism 3. Hypothyroidism 4. Hyperprolactinaemia Concise aetiology - constitutional - primary hypogonadism (gonadal failure) - secondary hypogonadism (hypothalamic failure) - chronic disease - nutritional inadequacy

Answer 262

a. Primary hypogonadism = ↑ FSH and LH i. Congenital 1. Chromosomal abnormalities = Turner (most common in girls), Klinefelter 2. Anorchia (vanishing testes) ii. Acquired 1. Autoimmune 2. Post-infectious 3. Following trauma or surgery 4. Following chemotherapy or radiotherapy 5. Iron deposition – transfusions b. Secondary hypogonadism = ↓/normal FSH and LH i. Congenital 1. Isolated GnRH deficiency = idiopathic hypogonadotropic hypogonadism a. Without anosmia b. With anosmia (Kallman syndrome) c. Associated with adrenal hypoplasia congenital 2. GnRH deficiency associated with mental retardation/obesity a. Laurence-Moon-Biedl syndrome b. Prader-Willi syndrome 3. Idiopathic forms of multiple anterior pituitary hormone deficiencies 4. Congenital brain malformation causing GnRH or gonadotropin deficiencies (often associated with craniofacial abnormalities) ii. Acquired 1. Tumours = benign, craniopharyngioma, any other CNS tumour 2. ‘Functional’ gonadotropin deficiency a. Constitutional delay of growth and puberty b. Chronic systemic illness eg. celiac disease c. Acute illness d. Malnutrition e. Hypothyroidism, hyperprolactinaemia, diabetes mellitus, Cushing’s disease f. Anorexia nervosa 3. Infiltrative = haemochromatosis, granulomatous, histocytosis 4. Head trauma 5. Pituitary apoplexy 6. Drugs – Marijuana

Answer 263

a. Bone age b. Basic bloods – FBE, UEC, ESR, LFT, celiac disease c. Endocrine tests i. LH, FSH, estradiol and testosterone distinguishes between primary and secondary hypogonadism 2. ↑ LH + FSH indicates primary hypogonadism 3. ↓or normal serum Lh/FSH with low levels of testoerone or estradiol indicates constitutional delay or isolated GnRH deficiency ii. GnRH stimulation test – not recommended d. Prolactin – detect hyperprolactinaemia e. IGF-1 – excludes growth hormone deficiency as cause of delayed puberty f. TFTs – excludes hypothyroidism as cause of delayed puberty g. Ultrasound – to detect underlying structural abnormality h. Additional tests i. Primary hypogonadism 1. Karyotype to establish diagnosis of Klinefelter/Turner ii. Secondary hypogonadism 1. Head MRI – assess for hypothalamic or pituitary disease 2. Anosmia – olfactory function test 3. If GnRH deficiency strongly suspected – genetic testing 5. Evaluation for iron overload

Answer 264

a. When to intervene? i. When there may be no puberty ii. When there will be no puberty iii. Pubertal arrest iv. Late gonadal failure b. Key principles i. Mimic normal progress over 2.5-3 years ii. Aims 1. Maximize height achieved 2. Without premature epiphyseal closure 3. Allow breast development in girls 4. To allow for psychosocial adjustment iii. Remember 1. ‘menopausal symptoms’ can occur at any age in boys and girls 2. Bone loss occurs at any age 3. Increased lipids and reduced cardiovascular function c. Primary gonadal failure – sex hormone therapy i. Females = HRT 1. Treat at peer appropriate time ii. Males 1. Boy with growth potential and <16 years - testosterone, starting orally, increasing dose and then changing to IM/SC - do not use long acting until growth complete as fuses epiphyses 2. Boys > 16 years (first presentation) a. Start with IM testosterone b. Then transition for longer acting preparation d. Hypothalamic hypogonadism i. Males 1. Pubertal induction with hCG and FSH for boys with hypothalamic hypogonadism 2. Better mimics normal puberty – induces spermatogenesis 3. Subsequently change to testosterone e. Presumed constitutional delay i. Watchful waiting ii. Short-term hormone therapy

Answer 265

1. Key points a. Most common cause of pubertal delay but diagnosis of exclusion (accounts for >50% of cases of delayed puberty) b. Same frequency in boys and girls – boys present more often c. Physiological delay, bone age delayed >2SD below mean (<=12 years in girls, <=13 years in boys) d. Must exclude other causes of pubertal delay e. Hallmark is delayed skeletal age – can chart height based on skeletal age not chronological age and see how they are tracking 2. Pathogenesis a. Due to reduced secretion and/or action of hypothalamic GnRH b. Normal hypothalamic-pituitary-gonadal axis 3. Clinical manifestations a. Usually family history of the same (autosomal dominant) b. Bone age LESS than chronological age – helpful but not specific c. Shorter stature than genetic potential d. Prepubertal nadir in height velocity prolonged e. Spontaneous puberty at 11 years (girls) or 12 years (boys), bone age not beyond 12.5-13years as E/T required for epiphyseal closure 4. Natural history – further detail a. Growth usually slows at about 2 years of age – producing a fall in the height percentile b. Thereafter, growth is parallel to the 3rd centile, but the prepubertal decline in growth is exaggerated and the onset of the pubertal growth spurt is later than average c. Bone age is delayed; however, height for bone age is usually within the expected mid-parental range d. The final height is likely to be in keeping with that of other family members e. Childhood short stature but normal adult height – catch-up growth 5. Management a. If breast budding/testicular volume >4mL 95% chance spontaneous puberty b. Reassurance and monitoring for all c. Short term gonadal steroids (specific circumstances)

Answer 266

1. Ovarian function a. Spontaneous pubertal onset 30-40% i. Those within inhibin B are most likely to have spontaneous puberty ii. Continuing ovarian function most likely with AMH hormone levels b. Spontaneous menses 4% c. Fertile spontaneously 1% 2. Treatment a. Sex hormones i. Should NOT wait – start treatment with HRT around the age of 12 years iii. ALWAYS use continuous estrogen to prevent bone loss iv. Avoid use of contraceptive pill (as this induces hypertension – high lifetime risk in Turner syndrome) b. Growth hormone i. Most on growth hormone ii. Growth hormone + estrogen gives best height outcome c. Fertility i. Factors predictive of healthy follicles 1. Normal FSH, AMH 2. Spontaneous puberty 3. Spontaneous menarche Oocyte preservation not commonly done (most follicles are immature, not likely to be successful) iv. Note high risk of aortic dissection 1. 6x population risk – particularly age 20-40 2. Paediatric patients with dissection have known congenital heart disease in >90% of cases 3. 10 years: MRI of base of heart and great vessels, then every 5 years a. Size of aorta must be evaluated in relation to surface area d. Pregnancy i. Pre-pregnancy assessment 1. Height weight, BMI, resting BP, renal Doppler 2. If HTN – echo and mandatory MRI 3. TFT, HBA1c, lipids, TFTs 4. USS if 2 tests 6 months apart are abnormal/ portal hypertension 5. Pelvic USS – endometrial thickness, uterine size 6. Hysteroscopy if abnormal shape 7. Renal USS, UEC ii. Single embryo transfer only iii. Contraindications 1. History of aortic surgery or dissection 2. Largest aortic diameter >23 mm/m2 or 35mm 3. Coarctation 4. Uncontrolled HTN 5. Portal HTN, varices

Answer 267

• 1/500 • A chronically raised LH indicates inadequate androgen – increased risk for bone loss • Do NOT tell XXY patients they are infertile o Intratesticular sperm o 50-60% success rate for fertility • Give transition advice to adult colleagues • General risks = leukaemia, lymphoma, seminoma, teratoma, A-I disease

Answer 268

a. Multifactorial cause = chronic illness, poor nutrition, impaired growth, steroids, reduced mobility b. Crohn’s disease is WORSE than ulcerative colitis c. Low IGF-1 d. Consider i. Bone density ii. Nutritional status iii. Vitamin D iv. Puberty e. Management i. Induce puberty – x3 IM testosterone 125, 250, 350 mg – 3 weeks apart ii. ONLY when steroid dose low and in remission iii. Wait 6 months – take through puberty completely with testosterone (or estrogen for girl) f. NOTE i. Growth spurt may be poor ii. Final height may be less than mid-parental expectation

Answer 269

a. Consequences i. Growth hormone deficiency ii. Early puberty – due to disinhibition of hypothalamic-pituitary axis iii. Gonadal failure – if very early in life iv. Poor spinal growth v. Late pubertal failure b. Craniospinal irradiation i. The earlier the cranial irradiation for leukaemia or tumour the early puberty will occur – due to disinhibition c. Possible issues i. Growth hormone deficiency ii. TSH deficiency +/- primary hypothyroidism iii. FSH/LH deficiency evolving d. Investigations i. Bone age ii. GH testing, FSH, LH, TFT, cortisol, prolactin, calcium e. Treatment i. GH if indicated ii. Testosterone long-term iii. HRT with estrogen – note long term risk of CXRT on cerebral vasculature resulting in cerebral arteritis 1. Transdermal estrogen may be preferable

Answer 270

1. Anatomy a. C5-T1 b. 2 lobes connected in midline as the ismth (2nd and 3rd tracheal rings) – may have pyramidal lobe extending from this point superior into the remnant of the thyroglossal tract c. Relationships include (implications in thyroidectomy) i. Recurrent laryngeal nerve ii. Parathyroids 2. Embryology a. Arises from outpouching of the foregut at the base of the tongue b. Migrates to its normal location over the thyroid cartilage by 8-10 weeks c. Bilobed thyroid shape recognized by 10 weeks 3. Cells a. Follicles of epithelium – secrete thyroid hormone b. C (parafollicular/clear) cells – secrete calcitonin c. Colloid (not a cell) – storage of thyroid hormone

Answer 271

a. Key components i. Iodine (diet, only known use in the body) ii. Tyrosine (amino acid in body) derivative b. Overview i. Iodide is extracted from the diet (salt) ii. Iodide pumped actively in via Na-K ATPase linked I- pump (sodium-iodide symporter) iv. Thyroglobulin (produced by thyroid cells) contains 12 tyrosine residues and is located in the colloid I(-) -> I2 (oxidised) -> combined with thyroglobulin to make MIT/DIT (mono/di-iodothyronine) MIT+DIT = T3/T4 -> cleaved from thyroglobulin and secreted ix. NOTE = TSH controls uptake of iodine + endocytosis of thyroglobulin c. Thyroid hormones i. Enough is stored for = 2-3 months ii. 85% of thyroid hormone is released as T4 (4:1 ratio of T4:T3 release) iii. T4 is the most available form of thyroid hormone, T3 is the most metabolically active, half life 7 days iv. T3 is much more biologically active – more potent and greater affinity (x10) for receptor, half life 1 day v. Tetraiodothyronine (T4) = thyroxine (prohormone) > 90% [two tyrosine + 2 iodine] vi. Triiodothyronine (T3) = most potent > 10% [two tyrosine + 1 iodine] Selenium also required for deiodinase d. Protein binding i. Thyroxine binding globulin (TBG) = 95% 1. Low capacity, high specificity and affinity 2. Concentration of TBG is altered in many clinical circumstances – must be considered when interpreting total T4 and T3 levels Also bound to others eg albumin (5-10%), transthyretin (15-20%), others 99.98% T4 bound, 99.5% T3 bound

Answer 272

a. SUMMARY i. Hypothalamus  TRH  anterior pituitary  TSH  thyroid  T3/T4  bloodstream: T4  T3 ii. T3/T4  negative feedback to pituitary + hypothalamus iii. TSH  negative feedback to hypothalamus b. Thyrotropin-releasing hormone (TRH) i. Peptide secreted by hypothalamus ii. Pulsatile secretion iii. Physiological role is to determine set-point of TSH secretion iv. Factors affecting TRH secretion 1. Stimulation a. Cold 2. Inhibition a. T3/T4 b. Stress c. Thyrotropin/ TSH i. Synthesized and secreted by thyrotrophs of the anterior pituitary ii. Pulsatile secretion iii. Binds to TSH receptor in thyroid and simulates all steps in thyroid hormone synthesis iv. Factors affecting TSH secretion 1. Stimulation a. TRH 2. Inhibition a. T3/T4 b. Somatostatin c. Dopamine d. Glucocorticoids

Answer 273

a. Overview i. Target cells/tissues = most cells of the body ii. Target receptor = nuclear receptor iii. Action at the cellular level = increases activity of metabolic enzymes and Na+/K+ ATPase iv. Action at molecular level = production of new enzymes b. Specific i. METABOLIC 1. ↑ metabolic rate- increase activity of the Na-K ATPase to facilitate transport across the BM 2. ↑ heat production + ↑ oxygen consumption ii. CHO 1. ↑ insulin dependent entry glucose into cells (GLUT4) 2. ↑ gluconeogenesis 3. ↑ glycogenolysis- uptake and use are BOTH increased (unlike GH and cortisol) iii. FAT + PROTEIN 1. ↑ fatty acid oxidation + lipolysis 2. ↑ protein synthesis iv. OTHER 1. GIT = ↑ gut motility 2. CVS a. Effects via stimulation of B adrenergic receptors – increase response to catecholamines – Increase HR and CO 3. CNS development 4. Upregulation of GH 5. Fertility 6. Skeletal growth a. T4 stimulates GH release from pituitary b. Promotes chondrocyte hypertrophy (GH + IGF1 stimulates proliferation) c. Low T4 slows growth + epiphyseal ossification  thin growth plates d. High T4 accelerates epiphyseal fusion  advanced bone age

Answer 274

1. SUMMARY a. Fetal i. <20weeks – transplacental transfer of maternal T4 ii. >20weeks – fetal production of T3 increases progressively with hepatic thyroglobulin iii. Preterm infants – have lower TSH surge and greater fall over first week due to immature HPA - may have apparent transient hypothyroidism b. At birth i. Serum TSH increases – surges at 30mins of life due to cold/clamping cord; falls rapidly 1. By day 2 back to normal levels ii. T4/T3 increases – peak 24-36hours iii. TFTs fall rapidly in first 5 days, then slowly over 4 weeks, adult levels by 2 years c. Maternal effects of thyroid function = maternal thyroid antibodies, iodines, anti-thyroid medications (E.g. PTU) can cross placenta and cause fetal hypothyroidism 3. Maternal to fetal thyroid hormone a. 1/3 of maternal T4 crosses the placenta to the fetus b. Maternal T4 plays a role in fetal development, especially the brain, before synthesis of fetal thyroid hormone begins i. Fetus of a hypothyroid mother may be at risk for neurological injury ii. Hypothyroid fetus may be partially protected by maternal T4 until delivery iii. The amount of T4 which crosses to the fetus is not sufficient to interfere with the diagnosis of congenital hypothyroidism in the neonate 5. Thyroid function in preterm babies f. Preterm babies have higher incidence of ‘delayed’ TSH elevation and apparent transient hypothyroidism 6. Effect of maternal anti-thyroid drugs a. Thionamides (Carbimazole > PTU) cross the placenta b. Transient (<5/7) hypothyroidism due to maternal carbimazole (should NOT be treated with T4 due to risk of hyperthyroidism)

Answer 275

1. Serum thyroid hormones a. T3, free T3, T4, free T4 c. NON-thyroid conditions that affect level of thyroid hormones i. Acute illness, Chronic malnutrition, Fasting / anorexia, Certain medications v. These all act to reduce thyroxine-5’-de-iodinase \ reduce the conversion of T4 to T3 d. Thyroglobulin = small amounts escape into the circulation and are measurable in the serum i. Levels increase with TSH stimulation and decrease with TSH suppression e. TSH = most accurate/sensitive test of thyroid function 2. Newborn screen a. TSH only b. Only detects HIGH TSH (usually >15) d. Recall rates – 2 recall for every 1 true congenital hypothyroid e. Pitfalls i. 33% neonatal T4 from Mum therefore hypothyroidism may be missed on NST ii. Only TSH elevation therefore may not detect pathology when TSH low 1. Hyperthyroidism 2. Secondary/tertiary hypothyroidism Autoantibodies - TSH receptor antibody / stimulating immunoglobulin (85-90% Graves patients, 0% gen pop, 0% T1DM/pregnancy) - Anti-Tg (thyroglobulin) antibody (5-20% gen pop, 50-70% Graves, 80-90% autoimmune thyroiditis, 30-40% T1DM, 15% pregnancy) - anti-TPO (thyroid peroxidase) (10-25% gen pop, 50-80% Graves, 90-100% AI thyroiditis, 30-40% T1DM, 15% pregnancy) 5. Radionucleotide studies a. Iodine trapping or concentrating mechanism can be measured by uptake of radioactive isotope 6. USS studies a. Location, size, shape and assessing the solid or cystic nature of nodules

Answer 276

1. Key points a. Abnormalities of TBG are not associated with clinical disease and do not require treatment i. Levels of free thyroid hormones and TSH normal b. Usually identified when abnormally low or high levels of T4 identified 2. TBG deficiency a. Primary i. X-linked dominant disorder ii. Affected patients have low levels of T4 – but levels of FT4 and TSH are normal b. Acquired i. Androgens, Anabolic steroids, Glucocorticoids iv. Hepatocellular disease v. Severe illness vi. Protein losing nephropathy/enteropathy vii. Nicotinic acid viii. L-Asparaginase 3. TBG excess a. Primary i. X-linked dominant disorder ii. Affected patients have elevated T4 – but TSH and FT4 are normal b. Acquired i. Estrogens ii. SERM iii. Pregnancy iv. Hepatitis v. Porphyria vi. Heroin, methadone vii. Mitotane viii. 5-FU ix. Perphenazine 4. Note: a. Drugs (phenytoin, carbamazepine, frusemide, salicyclates, NSAIDs, heparin) inhibit binding of T3 and T4 to TBG b. CBZ and PHT – cause abnormalities of thyroid function by stimulating hepatic cytochrome P450 degradation of T4 and accelerate transport of T4 into tissues

Answer 277

1. Key points a. 85% of cases are sporadic (most caused by thyroid dysgenesis) b. 15% of cases hereditary (most caused by one of the inborn errors of thyroid hormone synthesis) c. Most infants are detected by newborn screening programs before symptoms occur d. If no elevated TSH NOT detected on newborn screening 2. Classification a. Primary hypothyroidism i. Dysgenesis = defects of fetal thyroid development 1. Aplasia, hypoplasia, ectopic ii. Dyshormogenesis = defect in thyroid hormone synthesis (dyshormogenesis) iii. TSH unresponsiveness 1. Mutation in TSH receptor; Defective TSH signaling G5alpha mutation (eg. type Ia pseudohypoparathyroidism) iv. Defect in thyroid hormone transport v. Resistance to thyroid hormone vi. Maternal antibodies – thyrotropin receptor blocking Ab (TRBAb) vii. Iodine deficiency (endemic goitre) viii. Maternal medications 1. Iodides, amiodarone 2. Propylthiouracil, methimazole 3. Radioiodine b. Secondary/Tertiary = Central (hypopituitary) hypothyroidism i. Isolated TSH deficiency ii. Isolated TRH deficiency – mutation in TRH gene iii. Multiple congenital pituitary hormone deficiencies (eg. septooptic dysplasia) iv. PIT-1 mutations – deficiency of TSH, growth hormone, prolactin v. PROP-1 mutations – deficiency of TSH, growth hormone, prolactin, LH, FSH +/- ACTH 3. Transient hypothyroidism a. Iodine i. Exposure to iodides ii. Severe iodine deficiency (most common cause WW) iii. Defective iodine transport (rare) b. TSH receptor antibodies – transplacental (3-6months resolves) c. Maternal ingestion – PTU, iodine etc. (G)

Answer 278

4. Clinical manifestations a. Newborn i. Most asymptomatic – partially due to maternal T4 transplacental passage (results in fetal levels which are 33% of normal at birth) ii. Birth weight and length normal iii. Anterior and posterior fontanelles open widely iv. Prolongation of physiological jaundice – caused by delayed maturation of glucuronide conjugation v. Feeding difficulties – sluggishness, lack of interest, somnolence, choking spells vi. Respiratory difficulties – large tongue, apnoea, noisy respiration, nasal respiration vii. Little crying, sleeping ++, poor appetites, generally sluggish viii. Constipation – not responsive to treatment ix. Umbilical hernia usually present x. Hypothermia – skin may be cold and mottled xi. Oedema of genitals and extremities xii. Slow HR, heart murmurs, cardiomegaly, asymptomatic effusions xiii. Macrocytic anaemia b. Older children i. Goitre ii. Decline in growth velocity, not associated with weight loss iii. Developmental delay iv. Constipation v. Delayed reflexes, cerebellar ataxia, paresthesias (carpal tunnel etc) vi. Menstrual irregularity, macrocytosis (anemia), hypercholesterolaemia, precocious puberty (severe - TSH cross reacts with FSH receptor) 5. Untreated a. Retardation of physical and mental development by 3-6 months of age i. Lethargic ii. Late to sit and stand b. Other physical features i. Poor growth – extremities short, head size normal or increased ii. Anterior fontanel large and posterior fontanel may remain open iii. Eyes appear far apart (hypertelorism), bridge of broad nose is depressed iv. Palpebral fissure are narrow and eyelids are swollen v. Mouth is kept open and thick broad tongue vi. Dentition delayed vii. Neck is short and thick viii. Hands are broad and fingers short ix. Skin is dry and scaly x. Myxedema manifested particular in eyelids xi. Skin shows general pallor xii. Carotinaemia can occur xiii. Scalp is thickened xiv. Hair coarse and brittle

Answer 279

a. Low serum T4 and elevated TSH – identified on newborn screening b. TFTs = low T4/FT4, T3 may be normal i. If defect primarily of the thyroid TSH elevated c. Thyroglobulin i. Usually low with thyroid agenesis or defects of thyroglobulin synthesis or secretions ii. Elevated with ectopic glands and other inborn errors of T4 synthesis d. Antibodies i. Antibodies in older children – thyroglobulin, thyroid peroxidase ii. Maternal antibodies in neonates e. X-ray i. Distal femoral and proximal tibial epiphyses (normally present at birth) are absent ii. Epiphyses often have multiple foci of ossification iii. Large fontanelles and wide sutures f. Scintigraphy + USS i. Ectopic thyroid tissue diagnostic of thyroid dysgenesis  requires lifelong T4 ii. Failure to demonstrate any thyroid tissue = thyroid aplasia (also occurs in infants with maternal TRAb and infants with iodide-trapping effect) iii. Normally situated thyroid gland with a normal or avid uptake indicates a defect in thyroid hormone synthesis g. ECG = low voltage P and T waves with diminished amplitude of QRS complexes suggestive of poor LV function and pericardial effusion h. Echo – confirm pericardial effusion i. Hearing test = in neonates with dyshormogenesis i. Newborn screening ii. Repeat at 4-8 weeks then 3 monthly in first year (Pendred) j. Screen for other anterior pituitary hormone deficiencies (eg. due to septo-optic dysplasia)

Answer 280

7. Treatment a. Levothyroxine (L-T4) – oral treatment of choice b. Start on 12.5 microgram per day in neonates, older children 3 microgram/kg c. Levels of T4/FT4TSH should be monitored 1-2 monthly  2-4 monthly d. Do not mix with soy formula or iron as they bind T4 e. Dose of T4 on a weight basis gradually decreases with age f. Monitoring i. TFTs 1. Half-life is 1 week – steady state takes 5 weeks 2. Goal is to maintain a. FT4 or total T4 in upper half of the reference range b. Serum TSH in the reference range 3. High TSH = inadequate treatment or non-compliance ii. Growth and development g. Those with transient conditions can be trialed off thyroxine at 2-3 years 8. Prognosis a. Early diagnosis and treatment <1month, excellent prognosis for normal intellectual development b. Severely affected infants or those with delayed Rx >6months at risk for neurodevelopment problems i. Reduced IQ, incoordination, hypotonia, speech problems ii. Associated with ADHD

Answer 281

1. Key points a. Includes = ectopia, hypoplasia, aplasia b. Most common cause of permanent congenital hypothyroidism worldwide - 80-85% of cases i. 2/3 of cases = rudimentary tissue found in ectopic locations (base of the tongue to normal position in the neck) ii. 1/3 no remnants c. 2:1 female to male ratio 2. Etiology a. Cause is usually unknown – familial cases reported but most are sporadic b. Monogenic causes: i. NXK2.1 (TTF1) mutations = congenital hypothyroidism, RS, ataxia, choreo-athetosis ii. NXK2.5 mutations = congenital hypothyroidism with congenital heart defects iii. PAX8 = congenital hypothyroidism, genitourinary anomalies (including renal agenesis) c. Other identified causes i. Genetic defects in TSH receptor Primary hypothyroidism -> elevated TSH Treat with levothyroxine

Answer 282

1. Key points a. AR defects b. Goitre almost always present c. Accounts for 15% of congenital hypothyroidism 2. Causes a. Defect of iodine transport i. Caused by mutation inn sodium-iodide symporter ii. Results in clinical hypothyroidism with or without goitre iii. Uptake of radioiodine is LOW (contrasting other forms of dyshormogenesis) v. Treatment with L-thyroxine b. Thyroid peroxidase defects of organification and coupling i. Most common form of T4 synthetic defects c. Defects of thyroglobulin synthesis i. Defects result in goitre, elevated TSH, low FT4, absent or low levels of TBG d. Defects in deiodination i. Deiodination usually occurs in the thyroid or peripheral tissue iii. Results in severe iodine loss from the constant urinary excretion of non-deiodinated tyrosine leading to hormone deficiency and goitre

Answer 283

1. Key points a. Broad definition = high serum TSH in the absence of a goitre (because TSH stimulates growth/hypertrophy/hyperplasia) b. Variable elevation in TSH – if severe will be elevated and detected on newborn screening 2. Genetics a. Incidence 1/40,000 M=F b. Autosomal recessive 3. Classification/ Clinical manifestations a. Differing degrees of resistance to TSH b. Fully compensated i. Impaired response to TSH is compensated by hypersecretion of TSH ii. Overcomes the resistance resulting in euthyroid hyperthyrotropinaemia iii. Usually stable over time – contrasts subclinical hypothyroidism due to autoimmune thyroiditis which tends to worsen over time c. Partially compensated i. High serum TSH cannot fully compensate for the defect ii. Results in mild hypothyroidism iii. May be initially euthythyroid (elevated TSH with normal FT4) but develop hypothyroidism over time d. Uncompensated i. Severe hypothyroidism ii. Most common with homozygous mutant TSH receptor with lack of function 4. Differential diagnosis a. Consider in infants with high serum TSH with normal or low T4/T and a normally located gland b. Differential diagnosis – conditions that impair thyroid secretion c. TSH has an important role in promoting growth therefore unlikely in those with a goitre

Answer 284

1. Key points a. Reduced responsiveness of target tissues to thyroid hormones b. Heterogenous depending on underlying mutation 2. Genetics a. 1/40,000 live births b. Autosomal dominant c. Highly heterogenous 3. Pathogenesis i. Resistance of pituitary thyrotrophs to thyroid hormone = ↑ TSH ↑ T4 and T3 production from the thyroid gland ii. The elevated levels of T3 and T4 do not downregulate TSH production as the pituitary gland is resistant b. Effect on metabolism i. ↑ thyroid hormone secretion compensates for resistance – most patients are clinically euthyroid 4. Clinical manifestations a. HIGHLY HETEROGENOUS b. Hallmark = paucity of symptoms and signs of thyroid dysfunction despite high T4 and T3 c. May have some signs of hypo or hyperthyroidism – variable and when present often inconsistent d. Most common clinical findings i. Goitre ii. Hyperactivity iii. Tachycardia iv. Hearing loss – may be due to recurrent ear infections (more common in RTH) 1. Sensorineural deafness is common among individuals with TR-beta gene deletion e. If hypothyroidism present i. Growth retardation ii. Delayed bone maturation iii. Learning disabilities + mental retardation iv. Sensorineural deafness v. Nystagmus f. Other features i. Higher prevalence of ADD and learning disabilities ii. Higher risk of autoimmune thyroid disease 5. Investigations a. Usually ↑ T3 and T4 b. Non-suppressed ↑ TSH = key to the diagnosis c. Often erroneously diagnosed as hyperthyroidism due to elevated T3 and T4 d. Diagnosis confirmed if supraphysiological doses of T4 or T3 are required to reduce TSH secretion or to induce appropriate responses in tissues (eg. increase in serum SHBG and reduction in cholesterol concentration) 6. Management a. Treatment usually not required as hyposensitivity to thyroid hormone adequately compensated by increased secretion of T4 and generation of T3

Answer 285

1. Key points a. Results in 2% of cases of congenital hypothyroidism b. Suspected when maternal history of autoimmune thyroid disease (Hashimoto thyroiditis or Grave’s disease), maternal hypothyroidism on replacement therapy, or recurrent congenital hypothyroidism of transient nature in previous siblings c. Note that can also have thyrotropin-stimulating antibody and thyroid peroxidase antibody 2. Pathogenesis a. Transplacental transfer of TSH-receptor blocking antibodies (TRB-Ab) can occur in infants of mothers with autoimmune thyroid disease b. Inhibits binding of TSH to receptor in neonate – therefore inhibits production of thyroid hormones 3. Investigations a. Maternal levels of TRBAb (thyrotropin binding inhibitor Ig) should be measured during pregnancy b. Detected by neonatal screening – endogenous TSH ↑ due to low FT4, however blocked by maternal antibody c. Iodine scan = may fail to detect any thyroid tissue mimicking thyroid agenesis d. USS = identifies normal thyroid 4. Natural history a. Half-life of the antibody is 21 days b. Remission of the hypothyroidism occurs in 6 months c. Infant grows out of T4 dose d. Correct diagnosis prevents unnecessary protracted treatment – if unsure usually trial off therapy 2-3 years (by this time majority of brain development is complete)

Answer 286

Radioiodine Administration • Hypothyroidism can result from inadvertent administration of radioiodine during pregnancy for the treatment of Grave’s disease or thyroid cancer • Fetal thyroid is capable of trapping iodide by 70-75 days of gestation Iodine Exposure • Congenital hypothyroidism can result from fetal exposure to excessive iodides • Can be caused by use of iodine antiseptic to prepare the skin for caesarian section • Also reported in mothers who consume large amounts of iodine as nutritional supplement • Usually transient

Answer 287

a. Autoimmune i. Hashimoto thyroiditis  most common ii. Autoimmune disease associated with T21, Turner syndrome, and possibly Klinefelter syndrome 1. Down syndrome = antithyroid Ab in 30%  hypothyroidism in 15-20% 2. Turner syndrome = antithyroid Ab in 40%  hypothyroidism in 15-30% 3. T1DM = antithyroid Ab in 20%  hypothyroidism in 5% iii. Autoimmune polyglandular syndromes types 1 and 2 b. Drug induced i. Excess iodide = amiodarone, nutritional supplements, expectorants ii. Anticonvulsants = PHT, phenobarbital, valproate iii. Anti-thyroid drugs = methimazole, Propylthiouracil iv. Miscellaneous = lithium, TK inhibitors, IFN alpha, stavudine, thalidomide, aminogltethimde c. Post-ablative = irradiation, radioiodine, thyroidectomy d. Infiltrative = cystinosis, Langerhans cell histiocytosis e. Haemangiomas (large) of the liver (type 3 iodothyronine deiodinase) f. Hypothalamic pituitary disease with pulmonary pituitary hormone deficiencies i. Tumours eg. craniopharyngioma ii. Meningoencephalitis iii. Cranial irradiation iv. Head trauma v. Langerhans cell histiocytosis g. Other i. DiGeorge syndrome ii. Williams syndrome iii. Haemangiomas

Answer 288

2. Clinical manifestations a. Goiter associated with Hashimoto thyroiditis b. Weight gain from fluid retention (myxedema) c. Constipation, cold intolerance, reduced energy, increased sleep d. Bradycardia, muscle weakness, cramps, nerve entrapment, ataxia e. Growth and puberty i. Deceleration of growth ii. Osseous maturation delayed iii. Adolescents have delayed puberty iv. Younger children may have galactorrhoea or pseudoprecocious puberty 1. Abnormally high TSH binds the FSH receptor with subsequent stimulation f. Other i. Headache and vision problems –associated with enlarged pituitary gland 1. Due to prolonged hypothyroidism 3. Investigations a. Hyponatreamia, macrocytic anaemia, hypercholesterolaemia, elevated b. FT4 and TSH = ↓FT4, ↑TSH c. Antibodies = elevated in autoimmune thyroiditis i. Anti-thyroglobulin + anti-peroxidase d. USS = if goitre present to identify nodular disease e. Radioactive iodine uptake scan = in children with a nodule and suppressed TSH – to determine whether hot or hyper functioning nodule f. Bone age X-ray = useful at diagnosis; degree of delay approximates duration and severity of hypothyroidism

Answer 289

a. L-T4 = treatment of choice i. FT4 and TSH – Monitor 4-6 monthly as well as 6 weeks after dose change b. During first year of treatment deterioration of schoolwork, poor sleep, restlessness, short attention span i. Transient and improve over time ii. Partially ameliorated by starting at sub replacement T4 doses c. Rare complication of LT4 = pseudotumour cerebri d. After catch up growth is complete the growth rate provides a good index of the adequacy of therapy e. Period bone age x-rays useful to monitor treatment and future growth potential f. In children with longstanding hypothyroidism catch up growth may not be complete g. During the first 18 months of treatment skeletal maturation often exceeds expected linear growth, resulting in a loss of approximately 7cm of predicated adult height

Answer 290

a. Transient hypothyroxinaemia i. Approximately 50% of premature infants (<30/40), due to immature HPA ii. Nadir occurs at age 10-14 days iii. Corrects spontaneously over 4-8 weeks iv. NO treatment required v. Key features 1. Normal TSH 2. ↓ FT4 b. Transient primary hypothyroidism i. Occurs in 20% prems ii. Develops 1-2 weeks following birth after transient hypothyroxinemia iii. May persist for 2-3 months iv. Worth treating v. Key features 1. ↑ TSH 2. ↓ FT4 3. Spontaneous resolution over time vi. Major causes 1. Iodine deficiency 2. Iodine excess 3. Passive transfer of maternal thyrotropin receptor blocking antibodies d. Low T3/T4 syndrome (sick euthyroid) i. Low T3 +/- T4 and normal TSH ii. Due to stressor on child iii. No treatment required • Non-thyroidal illness (prematurity, surgical stress, sepsis, malnutrition)

Answer 291

1. Key points a. Chronic lymphocytic thyroiditis b. Most common cause of thyroid disease in children and adolescents c. More common in girls than boys d. Starts to occur at age 6, peaks during adolescence e. Familial clusters common – incidence of siblings or parents of affected children as high as 25% f. Genetic syndromes i. APS-1 (10%) and APS-2 (70%) ii. IPEX syndrome iii. Turner syndrome and T21 iv. Klinefelter syndrome 2. Etiology a. Autoimmune disease c. Variety of thyroid antigens and antibodies involved i. Anti thyroid peroxidase antibodies (TPO-Abs) and antithyroglobulin antibodies (anti-TG Abs) = 90% of children with chronic lymphocytic thyroiditis and Grave’s disease 3. Clinical manifestations a. Goitre + growth retardation = most common clinical manifestation b. Compressive symptoms from goitre  dyspnoea, dysphagia c. Most children clinically euthyroid and asymptomatic  only laboratory evidence of hypothyroidism d. NO ophthalmopathy in autoimmune thyroiditis e. Triad = growth retardation + obesity + mental dullness 4. Natural history a. Variable b. Most children are euthyroid at presentation and remain euthyroid – some become hypothyroid 5. Investigations a. FT4 and TSH – often normal b. TSH – may be elevated in subclinical hypothyroidism c. Autoantibodies i. TPO-Abs and Anti-Tg Abs = 95% have one or both ii. Thyrotropin receptor blocking antibodies present in 10% d. Thyroid scans an USS usually not required 6. Treatment a. If overt hypothyroidism – treatment b. If euthyroid – treatment with suppressive doses of levothyroxine is unlikely to lead to significant decrease in size of the goitre c. Goitre usually shows some decrease in size but can persist for years d. Surveillance for hypothyroidism e. Prominent nodules (>1cm) should have FNA as thyroid carcinoma or lymphoma can occur in patients with Hashimoto’s thyroiditis

Answer 292

AKA Dequervain disease a. Rare in children b. Thought to have a viral cause and remits spontaneously c. Clinical manifestations i. Manifested by URTI with vague tenderness over the thyroid, low-grade fever  severe pain in region of the thyroid ii. Inflammation results in leakage of pre-formed thyroid hormone into the circulation iii. Mild symptoms of hyperthyroidism d. Natural history i. Acute phase = 2-6/52 1. Flu-like symptoms 2. Pain 90% 3. Mild hyperthyroidism ii. Hypothyroid phase = weeks-months 1. Transient hypothyroidism 50% 2. Permanent in 10% iii. Recovery phase = weeks-months 1. Normalisation – euthyroid e. Investigations i. T4 and triiodothyronine are elevated while TSH is suppressed ii. Radioiodine uptake depressed iii. Elevated inflammatory markers – particularly ESR f. DDx i. Early Grave’s disease = Ab +, increased radioiodine uptake, ESR usually normal ii. Hashimoto’s thyroiditis = can evolve from thyrotoxicosis to hypothyroidism, usually Ab +ve, ESR usually normal

Answer 293

a. Uncommon in children b. Usually preceded by respiratory tract infection with pharyngitis c. L) lower lobe is affected predominantly d. Most common organism is alpha-haemolytic streptococcus followed by Staphylococcus aureus e. Recurrent episodes or mixed bacterial flora suggests the infection arises from a piriform sinus fistula or thyroglossal duct remnant

Answer 294

* Enlargement of the thyroid gland * 4-5% of all children * Can be euthyroid, hypothyroid or hyperthyroid * Classification = congenital, acquired, endemic * Most often results from increased pituitary secretion of TSH in response to decreased circulating levels of hormones * Activation of TSH receptor from thyrotropin-receptor stimulating Ab (Grave’s disease), gain of function TSH receptor mutations, or inappropriate TSH secretion (from dominant negative thyroid hormone receptor mutation or TSH secreting adenoma) can also cause thyromegaly Congenital 1. Key points a. Usually sporadic 2. Etiology a. Fetal thyroxine (T4) synthetic defect (ie. congenital hypothyroidism) i. Defects usually caused by recessive mutations ii. Example = Pendred syndrome b. Maternal Grave’s disease – transplacental passage of thyroid-stimulating Ig i. Usually not large goitre c. Administration of anti-thyroid drugs or iodides during pregnancy for the treatment of maternal thyrotoxicosis i. Most severe if mother is hypothyroid iii. All infants born to women treated with anti-thyroid drugs in the third trimester should undergo thyroid studies at birth v. Temporary thyroid hormone supplementation required for 1-2 weeks d. Other drugs eg. amiodarone 3. Clinical manifestations a. Respiratory distress b. Difficulty feeding Acquired • Most acquired goitres are sporadic and develop from a variety of causes • Patients are usually euthyroid but may be hypothyroid or hyperthyroid • Most common cause is lymphocytic thyroiditis (Hashimoto’s) • Cause o Lymphocytic thyroiditis – most common o Sporadic thyroiditis – uncommon in children o Subacute painful thyroiditis – uncommon in children o Excess of iodide ingestion and certain drugs – amiodarone, lithium o Defects in synthesis of thyroid hormone Endemic - other note/card

Answer 295

1. Key points a. 2 billion people worldwide are at risk for iodine deficiency and iodine-deficiency goiter b. Dietary deficiency of iodine associated with goitre or cretinism (cretinism = severely stunted physical and mental growth due to hypothyroidism) c. Endemic cretinism = most serious consequence of iodine deficiency i. Occurs in geographic association with endemic goitre d. Iodine deficiency goiter can occur in neonates but is rare 2. Classification a. Includes 2 types of overlapping syndromes b. Neurologic syndrome i. Intellectual disability, deaf-mutism, disturbance in standing and gait, pyramidal signs ii. Affected individuals are goitrous but euthyroid, have normal pubertal development and adult stature, and have little or no impaired thyroid function c. Myxedematous syndrome i. Intellectually challenged and deaf, but in contrast to neurological type have delayed growth and sexual development, myxedema, and absence of goitre ii. T4 levels are low and TSH levels markedly elevated iii. Delayed skeletal maturation iv. Thyroid atrophy 3. Pathogenesis a. Iodine deficiency > increased efficiency of thyroid hormone synthesis > increased activity results in compensatory hypertrophy and hyperplasia > goitre b. Occurs in regions of the world where iodine deficiency is severe

Answer 296

4. Clinical manifestations a. If the deficiency in iodine is mild, thyroid enlargement does not become noticeable except when there is increased demand for the hormone during periods of rapid growth e.g. pregnancy, adolescence b. In regions of moderate iodine deficiency goitre is observed in school children, disappears with maturity and reappears with pregnancy or lactation c. Clinically most individuals are euthyroid 5. Investigations a. VARIABLE b. Endemic goitre = often low T4 levels with normal or moderately increased TSH 6. Treatment a. Single IM dose of iodinated poppy seed oil to women prevent iodine deficiency for 5 years b. Also given to children c. Universal salt iodization has reduced iodine deficiency

Answer 297

1. Key points a. Clinical manifestations in children and adolescents are similar to adults b. Grave’s disease is by far the most common cause of hyperthyroidism in children and adolescents Aetiology PRIMARY - Autoimmune: Graves (most common), Hashimotos (initial phase prior to hypothyroidism), subacute thyroiditis (self limiting viral infection) - Autonomy: McCune Albright, thyroid toxic adenoma (Plummer disease) or MNG, thyroid carcinoma (rare) - Exogenous: iodine induced, T4/T3 ingestion SECONDARY - pituitary adenoma (rare) - pituitary resistance to T4 (rare) TERTIARY - rare 4. Investigations a. ↑ FT4 and T3 b. ↓ TSH c. TSHR-Ab d. Radioactive iodine scan = indicated if TSHR-Ab not elevated

Answer 298

a. Growth i. Growth acceleration accompanied by epiphyseal maturation ii. More pronounced effect on growth if present in early childhood iii. With treatment HV and bone age approach a more normal bone pattern b. Puberty i. Age of puberty and attainment of pubertal stages not affected by hyperthyroidism ii. Girls who have undergone menarche may develop oligomenorrhoea or secondary amenorrhoea c. Eyes i. Stare and lid lag occur in many children – caused by sympathetic overactivity ii. Ophthalmopathy is characterised by inflammation of extra-ocular muscles and orbital fat and connective tissue resulting in proptosis, impairment of muscle function, and periorbital edema 1. Almost ALWAYS caused by Grave’s disease 2. 50-75% of children with Grave’s disease have some features of ophthalmopathy d. Goiter i. Most children with Grave’s have a diffuse goitre ii. May be associated with a bruit due to increased blood flow e. Cardiovascular i. ↑ CO caused by increased peripheral oxygen needs and increased cardiac contractility ii. ↑ HR, widened pulse pressure, decreased PVR iii. AF occurs in 10-20% of adults with hyperthyroidism – rare in children iv. MVP is 2-3x more prevalent in hyperthyroid patients f. Serum lipids i. ↓ total and HDL cholesterol g. Gastrointestinal i. Failure to gain weight or weight loss despite increased appetite – primarily mediated by increased caliorigenesis and secondarily by increased gut motility with associated diarrhoea and malabsorption ii. Children regain lost weight with treatment h. Musculoskeletal i. Proximal muscle weakness may be present ii. Hypokalaemic periodic paralysis (thyrotoxic periodic paralysis) – rare disorder associated with hyperthyroidism, especially in adolescent boys iii. Graves may be associated with myasthenia gravis and thymic enlargement iv. Effect on bone = osteoporosis 1. Thyroid hormone stimulates bone resorption resulting in increased porosity of cortical bone and reduced volume of trabecular bone i. Neuropsychiatric i. Tremulousness and tremor – best demonstrated on outstretched hands ii. Brisk tendon reflexes iii. Ataxia and chorea have been reported iv. Benign inctracranial hypertension v. Mood swings and disturbance of behaviour – particularly hyperactivity vi. Children <4 years can have neurodevelopmental delay j. Skin i. Skin is warm due to increased blood flow ii. Sweating increased due to increased calorigenesis iii. Onycholysis (loosening of nails from the nail bed) and softening of nail bed iv. Vitiligo and alopecia areata v. Dermopathy – rarely reported in children

Answer 299

1. Epidemiology a. Occurs in 0.02% of children b. Peak incidence 11-15 years c. Most children have positive autoimmune FHx d. Asian females highest risk 2. Aetiology a. Increased risk with HLA-B8 and DR3 b. Conditions associated with Grave’s disease = Addison’s disease, T1DM, myasthenia gravis, celiac disease, vitiligo, pernicious anaemia c. Risk increased with T21 and Turners 3. Pathogenesis a. Th cells become sensitive to TSH antigen > plasma cell production of thyrotropin receptor stimulating Ab (TRSAb) b. TRSAb binds to TSH receptor and stimulates overproduction of thyroid hormone c. Ophthalmopathy occurs as antigens shared by thyroid and eye muscle  orbital fibroblast stimulation  production of glycosaminoglycans by orbital fibroblasts

Answer 300

a. Highly variable clinical course b. Symptoms develop gradually; usually takes 6-12 months for diagnosis c. Thyroid crisis/thyroid storm = form of severe biochemical derangement, acute onset, hyperthermia, tachycardia, heart failure, and restlessness i. There may be rapid progression to delirium, coma and death ii. Precipitating events include trauma, infection, radioactive iodine treatment, or surgery d. Specific to Grave’s i. Eye signs (50-80%) – chemosis, ophthalmoplegia (diplopia, exophthalmos, lid lag) 1. Due to autoimmune reaction against retro-orbital muscles and connective tissue  lymphocytic infiltration 2. May not resolve when euthyroid – can worsen with treatment ii. Pretibial myxedema – very rare in children ``` General hyperthyroidism symptoms • Hyperactivity, irritability, altered mood, insomnia, anxiety, poor concentration • Heat intolerance, sweating • Palpitations • Fatigue, weakness • Dyspnoea • Weight loss with increased appetite • Pruritis • Increased stool frequency • Thirst and polyuria • Oligomenorrhoea and amenorrhoea ``` General hyperthyroidism signs • Sinus tachycardia, AF (rare in children), SVT • Fine tremor, hyperkinesis, hyperreflexia • Warm, moist skin • Palmar erythema, onycholysis • Hair loss or thinning • Osteoporosis • Muscle weakness and wasting (proximal) • High output cardiac failure • Chorea • Periodic (hypokalaemic) paralysis (primarily in Asian men) • Psychosis (rare) ``` Graves manifestations • Diffuse goitre • Ophthalmopathy • Feeling of grittiness and discomfort around the eye • Retrobulbar pressure or pain • Eyelid large or retraction • Periorbital edema, chemosis, scleral or conjunctival injection • Exophthalmos (proptosis) • Extraocular muscle dysfunction • Exposure keratitis • Optic neuropathy • Localised dermopathy (rare in children) • Lymphoid hyperplasia • Thyroid acropachy (rare in children) ```

Answer 301

a. ↓ TSH b. ↑ T4, T3, FT4, FT3 i. In some patients T3 may be more elevated than T4 c. Antithyroid Ab i. Thyroid peroxidase Ab – often present ii. TRSAb – frequently present in newly diagnosed d. Radiographic bone age – advanced skeletal maturation may be present e. Bone density – may be reduced at diagnosis, returns to normal with treatment

Answer 302

a. Summary i. Antithyroid drugs are the best-established treatment in children and provide a chance of permanent remission with euthyroidism (<20% chance of long-term remission) ii. Radioactive iodine cures hyperthyroidism replacing it with hypothyroidism requiring lifelong thyroid hormone replacement – no increased risk of cancer demonstrated iii. Surgery provides most rapid resolution of hyperthyroidism – however risk of surgery b. Medical therapy i. Anti-thyroid medication = carbimazole/methimazole (preferred in children), propylthiouracil (PTU) 1. Most studies report remission of 25% after 2 years 2. Can either add T4 or ↓ dose if become hypothyroid 3. Usually trial cessation of therapy after 1-2years 4. Mechanism of action a. Actively transported into the thyroid gland b. Inhibit the organification (blocks thyroid peroxidase) of iodine to tyrosine residues in thyroglobulin d. Reduces stores in 2-6 weeks 6. Monitoring a. Monitor TFT every 2-3 months - TSH levels suppressed for several months after starting treatment; hence T3 and T4 better initial markers of euthyroid state b. Recheck minimum 4 weeks after starting, long T1/2 TSH 7. Adverse effects a. Minor = 10-20% i. Transient granulocytopenia – not a reason to discontinue ii. Transient urticarial rashes b. Severe = 2-5% i. Agranulocytosis (0.1-0.5%) 1. Usually occurs in first 2-3 months – if febrile have FBE done ii. ANCA vasculitis = associated with PTU iii. Pancreatitis = associated with methimazole iv. Hepatotoxicity 1. PTU = fulminant hepatic necrosis, particularly in children 2. Methimazole = reversible cholestatic jaundice v. Teratogenicity vi. Lupus like polyarthritis syndrome vii. Glomerulonephritis 8. PTU a. Not used in children due to rare but significant risk of liver failure (1-2/4000) i. Days to years after initiation of treatment ii. Adjunctive 1. Beta blockers (propranolol or atenolol) – useful in severely toxic individuals c. Radioiodine i. Effective in children ii. In patients with severe thyrotoxicosis euthyroidism should be restored with methimazole prior to radioablation to deplete the gland of pre-formed hormone; preventing thyroid storm iii. Designed to completely ablate the thyroid gland iv. Require long-term T4 replacement d. Near total thyroidectomy i. Complications 1. Hypothyroidism (50%) 2. Recurrent thyrotoxicosis (10-20%) 3. Hypoparathyroidism (1-2%) 4. RLN palsy (1%), ELN palsy – husky voice (30%) 5. Post-operative bleeding → death due to airway obstruction 6. Thyroid storm – if not prepared for surgery adequately 7. Prognosis a. Remission – 20-50% after 2 years, 5-50% relapse (typically pregnancy), TSHR-Ab most predictive

Answer 303

Emergency Increase thyroid hormone - stress, infection, surgery, radio-iodine therapy Increase sympathetic drive - hyperthermia, tachycardia, CCF, irritability, sweating, coma Management - IV carbimazole/PTU - IV propranolol - rehydration - +/- iodine - +/- glucocorticoids (reduces T4 conversion, reduces autoantibody formation, protects from adrenal insufficiency)

Answer 304

Neonatal Graves disease (most common cause of neonatal hyperthyroidism) Thyrotropin receptor activating mutation McCune Albright syndrome TSHR Receptor Activating Mutation • Activating germline mutations of the TSH receptor are a rare cause of neonatal hyperthyroidism • Autosomal dominant • May be a family history of hyperthyroidism • Persists indefinitely – treatment with surgery or radioactive iodine (in children >10 years) is indicated McCune Albright • Activating mutation of alpha subunit of the G protein that stimulates adenylate cyclase • Typically occurs as part of the McCune-Albright syndrome • Somatic cell mutations – therefore sporadic disorder • Persists indefinitely – treatment with surgery or radioactive iodine (in children >10 years) is indicated (Neonatal Graves done separately)

Answer 305

1. Key points a. Occurs in 2% of infants born to mothers with a history of Graves’ disease i. Active Graves, Graves in remission, past history of Graves managed by radioactive iodine ablation or surgery, or rarely hypothyroidism and history of thyroiditis b. Usually self-limited – however can be severe, life-threatening and impact on neural development c. Most common cause of neonatal hyperthyroidism d. Active Grave’s disease in a pregnant women can result in hyper- or hypothyroidism depending on the balance of maternal stimulatory and inhibitory antibody and the drug i. The higher the maternal stimulatory thyrotropin receptor antibody (TSHR-Ab) during the third trimester the greater the likelihood of neonatal Grave’s disease ii. Most neonatal Grave’s disease occurs in the setting of active Grave’s hyperthyroidism (but has also been reported in a women with stimulatory TSHR-Ab associated with Hashimotos’) e. Babies destined to develop neonatal Grave’s disease are almost always hyperthyroid at or within 1 week of life 2. Pathogenesis + natural history a. Transplacental passage of stimulatory thyrotropin receptor antibody b. IgG half-life is 21 days c. Timing of symptoms i. Time and onset of symptoms varies – dependent upon whether mother taking anti-thyroid drug at the time of delivery 1. NO antithyroid drug – hyperthyroid at the time of birth 2. Antithyroid drug – become hyperthyroid at the time the drug is metabolised and excreted; usually 7-10 days after delivery ii. If thyrotropin receptor blocking Ab present – presentation delayed by several weeks d. Resolution i. Resolves spontaneously in 3-12 weeks as the maternal TSHR-Ab is metabolized and disappears from the infants circulation ii. Rarely persist for longer; these patients often have a significant family history of hyperthyroidism 3. Diagnosis a. May be in utero in the presence of fetal tachycardia and goitre b. Surveillance of TRSAb

Answer 306

4. Clinical manifestations a. Low birth weight for gestational age (intrauterine growth restriction) b. Premature birth c. Diffuse goiter in most - usually small, but occasionally large enough to cause compression of the airway d. Microcephaly (may be a manifestation of accelerated brain development with premature completion of neuronal morphogenesis) e. Frontal bossing and triangular facies, cranial synostosis f. Warm, moist skin g. Irritability, hyperactivity, restlessness, and poor sleep h. Tachycardia with a bounding pulse, and sometimes cardiomegaly, cardiac arrhythmias, or heart failure i. Persistent pulmonary hypertension (rare) j. Fetal hydrops (uncommon) k. Hyperphagia, but poor weight gain, and increased frequency of bowel movements l. Hepatosplenomegaly m. Stare and occasionally exophthalmos (presumably true Graves' ophthalmopathy) n. Hyperthermia o. Weight loss, hepatosplenomegaly and jaundice may occur p. Advanced bone age 5. Evaluation a. Measurement of TSHR-Ab during third trimester b. Testing of cord blood TSHR-Ab – can help predict risk of neonatal Grave’s disease c. Investigation of neonate i. Thyroid function should be assessed at delivery/soon after - as per bettersafercare, depends on high risk or not (antenatal evidence of thyrotoxicosis, elevated TSH receptor antibody in 3rd trimester, clinical thyrotoxicosis in 3rdT, PTU/carbimazole in 3T) - if high risk: cord blood, TFTs with NST 48-72hrs life, repeat day 7-10 - if low risk, no cord bloods 6. Investigations a. ↑ FT4 and T3 b. ↓ TSH c. Antibodies

Answer 307

7. Treatment a. Pre-natal i. If detected in utero  can treat fetus with PTU or carbimazole (carbimazole crosses placenta more readily but  risk of cutis aplasia) b. Post-natal i. Mild disease = β-blocker ii. Moderate to severe disease = carbimazole, PTU second line 1. Monitor TFT closely - if becoming hypothyroid ↓ dose +/- add T4 2. Takes several days to have an effect on T4 levels iii. Very severe 1. Iodide (Lugol’s solution/ K+ iodine) 2. +/- Glucocorticoids  reduce conversion T4→T3 (if use steroids then beware adrenal suppression) iv. If CHF = add digoxin (care if given glucocorticoids  since K+    digoxin toxicity) v. Can try to withdraw at 3 months c. Breast feeding / pregnancy not contraindicated in women with autoimmune thyroid disease – use PTU rather than carbimazole, less transfer into breast milk 8. Prognosis a. With adequate therapy initiated promptly most neonates improve rapidly – some patients have low IQs even if treated adequately b. Mortality as high as 15-20% if untreated c. Advanced osseous maturation (craniosynostosis), microcephaly and cognitive impairment occur when treatment delayed d. Intellectual development usually normal e. NOTE: likely to occur in subsequent pregnancies

Answer 308

1. Key points a. Frequency increases with age b. Single or multiple c. <2% of children have nodules d. 2% malignant – increased risk 30-40% if single nodule 2. DDx a. Lymphoid follicle – as part of chronic lymphocytic thyroiditis b. Thyroid developmental anomalies – intrathyroidal thyroglossal duct cyst c. Thyroid abscess d. Simple cyst i. Neoplasm 1. Benign 2. Colloid (adenomatous) nodule 3. Follicular adenoma 4. Non-thyroidal (eg. lymphohaemangioma) ii. Malignant 1. Papillary carcinoma 2. Follicular carcinoma 3. Mixed carcinoma 4. Undifferentiated (anaplastic) 5. Medullary e. Non-thyroidal i. Lymphoma ii. Teratoma 3. Investigations a. TFTs – determine need for further investigation i. If patient presents with suppressed TSH 1. Radionucleotide scan – to identify benign hyper functioning nodule ii. If euthymic 1. Thyroid USS 2. USS-guided FNA b. Other Ix – antibodies, TBG, calcitonin

Answer 309

1. Key points a. Rare in childhood b. Peaks in adolescence; girls > boys c. Childhood thyroid cancers characterised by very high rate of metastasis and recurrence, but usually have indolent course and most patients have a favourable outcome e. Increased risk with radiation iv. Risk begins 3-5 years after radiation and peaks 15-25 years 2. Risk factors a. RET proto-oncogene rearrangement (papillary carcinoma) b. Radiation c. Inactivating point mutation of p53 – anaplastic 3. Classification a. Differentiated i. Papillary 88% - most common, key risk factor ionising radiation ii. Follicular 10% b. Medullary 2% i. Very rare; 2% ii. Almost always in the context of MEN2A or MEN2B 4. Clinical manifestations a. Painless nodule in thyroid or in the neck b. Rapid growth, firmness, fixation to adjacent tissues c. Signs of invasion – hoarseness, dysphagia, neck lymphadenopathy d. RARELY functional 5. Diagnosis a. FNA b. Evaluation for metastasis – lungs, mediastinum, axilla, bone, skull and brain c. Almost all children euthyroid, rarely functional and produces hyperthyroidism 6. Treatment a. Surgical resection b. Adjunctive TSH suppression (dosing levothyroxine to lower TSH and deprive residual cancer cells of growth factor) for DCT only (not MTC) c. Adjunctive radiotherapy (to ablate remaining thyroid cancer) ii. PTC: only those who would benefit; MTC do not require 7. Prognosis a. Good outcome in most b. Cancer markers i. Serum thyroglobulin is a sensitive and specific cancer marker (in the ABSENCE of anti-thyroglobulin autoantibodies) – DTC ii. Calcitonin/CEA – MTC

Answer 310

1. Key points a. Arise from parafollicular (c cells) of thyroid b. Accounts for 2% of thyroid malignancies in children 2. Etiology a. Majority are sporadic b. 25% familial, autosomal dominant disorders c. Hereditary MTC divided into 3 distinct syndromes i. MEN2A 1. Autosomal dominant 2. Mutation in RET proto-oncogene 3. Features = MTC, phaeochromocytoma, parathyroid hyperplasia ii. MEN2B 1. Autosomal dominant 2. Missense mutation in RET 3. Features = MTC, phaeochromocytoma 4. Distinguishing features = mucosal neuroma syndrome  multiple neuromas 5. Also have Marfan like features iii. Familial MTC 3. Clinical presentation a. Asymptomatic palpable thyroid nodule 4. Investigations a. FNA b. High calcitonin in serum or FNA washing c. Testing for RET mutation d. Screening for MEN2 associated phaeochromocytoma and hyperparathyroidism prior to surgery 5. Treatment a. Total thyroidectomy – indicated for children with RET mutation b. Monitoring serum calcitonin and CEA useful for detecting metastatic lesions c. Periodic screening for phaeochromocytoma and hyperparathyroidism