Endocrinology Flashcards

1
Q

What is adrenal insufficiency?

A

Adrenal glands don’t produce enough hormones (cortisol +/- aldosterone)

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2
Q

What hormones control the release of cortisol and aldosterone from the adrenal glands?

A

Hypothalamus secretes CRH -> pituitary gland secretes ACTH -> release of cortisol from adrenal glands

Renin produced by kidneys -> RAAS system -> end product is aldosterone production from adrenal gland

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3
Q

Primary adrenal insufficiency

Labs (cortisol, aldosterone, renin, ACTH, CRH, Na, K)

Causes

Presentation

Tx

A

Problem with ADRENAL GLAND itself

  • > low in cortisol and aldosterone
  • high plasma renin activity
  • > high ACTH and CRH
  • > hyponatraeamia, hyperkalaemia

Causes

  • Most common cause in developed world is autoimmune destruction (incr levels of serum anti-adrenal Ab (anti 21 hydroxylase) = Addisons disease
  • Infection [Tb (most common cause worldwide), HIV, fungal]
  • Bilateral adrenal metastases
  • Bilateral adrenal infarction, haemmhorage (caused by meningococcaemia = waterhouse-friedrichson syndrome)
  • Congenital adrenal hyperplasia (most common cause in infancy)
  • Drugs
  • Adrenoleukodystrophy - peroxisomal disorder; incr serum VLCFA

Presentation

  • Hyperpigmentation of skin creases, oral mucosa due to excess ACTH
  • Salt craving due to low aldosterone
  • Signs of hypopituitarism

Tx - long term replacement of cortisol (hydrocort) and aldosterone (fludrocort)

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4
Q

Secondary adrenal insufficiency

Labs (cortisol, aldosterone, renin, ACTH, CRH)

Causes

Presentation

A

Results from insufficient production of ACTH from pituitary

  • Low ACTH and cortisol
  • Normal aldosterone (no problem w adrenals)
  • High CRH (positive feedback)

Causes

  • Panhypopituitarism (trauma or tumour within pituitary or compression by another tumour in vicinity)
  • OR isolated ACTH deficiency (autoimmune, genetic disorders, medications)

Presentation

  • headaches
  • visual abnormalities
  • signs of hypopituitarism
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5
Q

Tertiary adrenal insufficiency

What is it

Causes

Presentation

A

Insufficiency of CRH secretion from hypothalamus

  • Low CRH, ACTH
  • Low cortisol
  • Normal aldosterone

Causes

  1. Sudden withdrawal of chronic GC therapy
  2. Removal of ACTH secreting tumour
    - -> 1 and 2 are caused by sudden removal of high levels of EXOGENOUS circulating GC where neg feedback loop was suppressing CRH release from hypothalamus - takes a while for this neg feedback to resolve and for the hypothalamus to begin eleasing CRH again.

Other causes directly impacting hypothalamus:

  1. Head trauma
  2. Intracranial tumours

Presentation
- headaches
- visual abnormalities
- hypoglycaemia
+/- signs of panhypopituitarism

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6
Q

Adrenal crisis presentation

A

Triggered by some sort of stressor (infx/illness, surgery, trauma) in setting of adrenal insufficiency

Acute:
Hypotension, shock
Vomiting
Abdo pain
Fever
Drowsiness, Coma

Chronic:

  • fatigue
  • anorexia
  • nausea and vomiting
  • LOW/FTT
  • postural hypotension and salt craving
  • abdo, muscle, joint pain

IX

  • metabolic acidosis
  • hyperkalaemia and hyponatraemia
  • hypoglycaemia

Tx
- Immediately give IV fluids (20ml/kg) and stat dose IV hydrocort followed by q6-8hrly dosing hydrocort until no longer acutely unwell
+/- IV dextrose if hypoglycaemic
Note- hyperkalaemia normally resolves with fluid and steroid tx

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7
Q

Investigation/diagnosis of adrenal insufficiency - what investigations would you order?

A
  1. Morning serum cortisol level to confirm diagnosis of adrenal insufficiency
    a) LOW: confirms diagnosis -> proceed to measure serum ACTH levels (high: primary AI vs low: secondary/tertiary AI)
    b) HIGH: excludes
    c) Intermediate: proceed to ACTH stimulation test
  2. ACTH stimulation test (involves administering synthetic ACTH ‘cosyntropin’ and measuring serum cortisol levels before and after)
    - > if cortisol levels are normal before and after = AI excluded
    - > If levels are low before and low after = primary AI
    - > if levels are low before but increase after = secondary/tertiary
  3. To distinguish between sec and tertiary
    - CRH stimulation test (inject CRH then measure ACTH)
    - > no rise in ACTH: secondary
    - > Rise in ACTH: tertiary
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8
Q

Signs of panhypopituitarism

A

Presentation:

TSH: fatigue, lassitude, cold intolerance, constipation

GH: short stature, hypoglycaemia

ACTH : hypoglycaemia, vomiting, malaise

Aldosterone: Diabetes insipidus (polyuria, polydipsia, dehydration)

GH: Growth failure/short stature/FTT

LH, FSH: delayed puberty, Decr libido, Amenorrhoea

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9
Q

Adrenoleukodystrophy

A

Neurometabolic condition
Predominantly affects males age 4-8yo
VLCFA accumulate in CNS -> neurodev regression and adrenal cortex -> adrenal insufficiency

Presentation:

  • Initially resembles ADHD
  • Progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms
  • often have impaired adrenal function at the time of neurological sx onset
  • Lead to total disability within six months to two years

Female carriers
- 20% develop mild-to-moderate spastic paraparesis in middle age or later usually w normal adrenal function

Ix

  • incr serum levels VLCFA
  • MRI: T2 enhancement in Pareto-occipital regions
  • adrenal tests
  • genetic testing (mutation in ABCD1 gene)

Mx

  • Life long hydrocort tx
  • HSCT is an option for boys and adolescents in early stages of sx who have evidence of brain involvement on MRI
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10
Q

Congenital adrenal hyperplasia

What is it
What is the most common cause
Classical presentation
Ix/diagnosis

A

Congenital cause of primary adrenal insufficiency
Deficiency in enzymes involved in adrenal steroid synthesis pathways
-> 21-hydroxylase deficiency is most common cause (X-linked); salt wasting form
-> 11 beta hydroxylase deficiency is more rare
-> normal converts progresterone to aldosterone and cortisol precursor (get deficiency of these)
-> instead shunts it down androgen pathway so end up with EXCESSIVE androgen production)

Ix

  • Decr cortisol and aldosterone
  • Incr ACTH
  • -> Cells in adrenal gland proliferate in compensatory response, resulting in adrenal gland hyperplasia and excess androgen precursors (testosterone +/- DHEA)

Sx -
21 hydroxylase deficiency: Presents in neonatal period
Signs of adrenal crisis (often in first 1-2 weeks)
- Salt wasting (hyponatraemia, hyperkalaemia, dehydration)
- GC deficiency (adrenal crisis; shock, hypoglycaemia)
- ACTH excess (hyperpigmentation)

Note: 11beta hydroxylase deficiency is characterised by incr levels of MC so get HTN and hyperNa and hypoK and adrenal crisis is much rarer

  • Sx of androgen excess (both forms)
  • -> Females: genital ambiguity (external masculinisation)
  • Ambiguous genitalia (b/l undescended testes)
  • Enlarged clitoris
  • Early puberty
  • Advanced bone age, tall stature
  • Acne
  • Hirsutism
  • -> Males: *more likely to be diagnosed late *as appear normal at birth (may have hyper pigmented scrotum or enlarged phallus)
  • dx often not made until signs of adrenal insufficiency in first 1-2 weeks (shock, dehydration, hypoNa, hyperK) or much later with precocious puberty/tall stature/adv bone age, skin pigmentation, HTN, hirsutism, acne

Ix

  • NST
  • Reduced levels of 21 hydroxylase, aldosterone, cortisol
  • Increased levels of testosterone, androstenedione, ACTH, renin
  • Elevated serum levels 17 hydroxyprogresterone (progest -> 17 hydroxyprogesterone -> 21 hydroxylase -> cortisol)
  • HypoNa, HyperK, hypoglycaemia

Mx
- Hydrocortisone (synthetic cortisol) and fludrocortisone (synthetic aldosterone) daily

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11
Q

Cushing syndrome

Causes

Presentation

A

Endocrine disorder characterised by increased serum cortisol levels

Causes 
#1a Exogenous GC (medication) - most common 
#1b Pituitary adenoma ('cushings disease') secreting ACTH - most common -\> b/l adrenal hyperplasia 
#2 Adrenal adenoma/carcinoma producing excess cortisol 
#3 ectopic tissue excreting excess ACTH (neuroblastoma, Wilms) - v rare 

Presentation

  • Round, full moon shaped face
  • Truncal obesity
  • Skin thinning, striae, easy bruising
  • Osteoporosis -> fractures
  • Impaired growth -> short stature
  • Muscle wasting, thin extremities
  • Buffalo hump
  • HTN
  • Hyperglycaemia -> DM
  • Decr immunity (incr infections particularly fungal)
  • Menstrual irregularity
  • Psychiatric disturbances
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12
Q

Investigation of cushing’s syndrome
- diagnosis and investigative pathway for aetiology

A

Step 1: Diagnosis
- Exclude iatrogenic (excess GC medication)
Need 2x neg results:
a) Late night (midnight) salivary cortisol test (should be low at midnight and high in morning; in cushings will be high at midnight)
Or
b) 24hr urinary free cortisol level (anything >3x ULN)
c) Overnight dex suppression test (low dose)

Step 2: underlying cause
Serum ACTH levels
a) If low = ACTH independent (ie cushings not due to excess ACTH, likely adrenal source)
b) If high = ACTH dependent (either pituitary adenoma=cushing disease or ectopic ACTH secretion ie not from pituitary)
Distinguish with HIGH DOSE dex suppression test (giving high dose dex should suppress ACTH release if coming from pituitary, but will not if coming from elsewhere)
–> If low = pituitary/cushing disease
–> if high (not suppressed) = ectopic ACTH secretion (not from pituitary)
OR can distinguish with the CRH stimulation test
- Administer IV CRH
- Measure serum ACTH and cortisol levels 45min post infection
–> Incr ACTH and cortisol = Cushing’s disease
–> No rise = ectopic ACTH secretion

If cushing’s disease confirmed:
-> MRI head to confirm location of pituitary adenoma
If ectopic ACTH secretion:
-> CT or MRI of CAP to determine tumour location, stage

If ACTH independent

  • > Exclude iatrogenic GC
  • > Abdo CT to identify ?adrenal mass
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13
Q

Features of benign vs malignant adrenal masses

A

More often benign adrenal adenoma
RF for malignant adrenal carcinoma:
- Age <10, >50
- Androgen excess in females (acne, deep voice, hirsutism)

CT: malignant more likely to have areas of haemorrhage, necrosis, calcification

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14
Q

Type 1 DM

  • pathophys
  • sx/presentation
  • Ix
A

Pathophys:
Autoimmune pancreatic destruction (beta islet of langerhans cells)
- Often Ab against glutamic acid decarboxylase and Ab against islet cells (80% have ICA)
- Results in low insulin production -> glucose can’t be taken up into cells (‘starving in a sea of glucose’)

Sx appear when 90% of pancreatic islet cells have been destroyed:

  • 2 peaks: 3-6yo; 10-14yo
  • Presents with DKA
  • Acute onset polyuria, polydipsia, polyphagia, glycosuria
  • LOW
  • Severe dehydration
  • Abdo pain, N&V
  • Ketotic (fruity) breath and kaussmal breathing

Ix

  • Elevated GAD Ab
  • Elevated IA2 Ab
  • Decr C-peptide levels (reflects insulin deficiency)
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15
Q

Type 2 DM

  • pathophys
  • sx/presentation
  • Ix
A

Insulin RESISTANCE

  • Tissues aren’t taking up glucose despite normal insulin levels
  • Beta cells of pancreas begin by producing more insulin to compensate -> eventually get ‘tired’ and beta cells die off -> then get decreased insulin production

RF
>45
Family hx
BMI > 25
Sedentary lifestyle
CV risk factors (HTN)

Presentation

  • Polydipsia (secondary to dehydration)
  • Polyuria (water follows excess glucose in urine)
  • Polyphagia
  • Unexplained LOW

Ix -

  1. Fasting glucose test
  2. OGTT
  3. Random glucose test
  4. HBA1c (% of glycated Hb in blood ie fraction of RBCs that have glucose stuck to them) > 6.5%
  5. incr c peptide levels (reflects high insulin leve;s_

Mx - basal bolus insulin

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16
Q

Chronic problems of DM

A

Persistent hyperglycaemia can damage

  • vessels (arteriolosclerosis)
  • nerves
  1. Diabetic retinopathy
  2. Diabetic nephropathy
  3. Peripheral and autonomic neuropathy
  4. Peripheral vascular disease
    - > foot ulcers
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17
Q

Metformin

  • Class
  • MOA
  • CI and S/E
A

Is a biguanide

Actions

  • Increases insulin sensitivity and thus incr glucose uptake into tissues
  • Promotes weight loss
  • Doesn’t cause hypos

SE: nausea, diarrhoea, lactic acidosis
B12 deficiency -> macrocytic anaemia

CI: Chronic renal failure and heart failure (due to SE of lactic acidosis)

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18
Q

DKA
Causes
Presentation
Complications

A

Definition
1) Hyperglycaemia (and glycosuria)
-> BSL >11 (or fasting >7)
2) Metabolic Acidosis
-> pH <7.3 or bicarb <15
3) Ketonaemia (and ketonuria)
+/- high anion gap

Other ix

  • HyperK initially -> risk of hypoK with insulin tx as K is pushed back into cells
  • HypoNa

Causes

  • First presentation T1DM
  • Inadequate insulin
  • Illness (incr insulin requirements)

Presentation:

  • Dehydration
  • Kussmaul respiration (deep, rapid breathing)
  • Ketotic breathing (sweet and fuirty smelling)
  • Abdo pain
  • N&V
  • Polyuria, polydipsia
  • Mental status changes (delirium, psychosis, decr GCS) if cerebral oedema develops (hypoNa)

On first presentation do hypoglycaemia screen

Mgmt
Mild, tolerating oral intake:
- Give novorapid S/C (1unit/kg/day)
- Oral rehydration
- Recheck BSc, ketones 1 hr
Mod-severe:
- IV insulin infusion
- IV fluids (corrects dehydration)
- IV K if <5.5 (as insulin causes K uptake from blood into cells and can cause further hypokalaemia)
+/- IV bicarb if ph <7 or evidence of poor cardiac contractility
- regular monitoring of fluid balance, vitals, neuro obs, VBG/ketones, UEC (Na and K derangement), CMP (phosphate can drop)

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19
Q

Hypoglycaemia

Definition

Causes

  • In DM-
  • Non DM: transient vs persistent
A

BGL < 3.3 (<2.6 in infant)

Causes
In DM:
- Insulin (too much or not eating enough)
- Sulfonylureas
- Infection
- Too much exercise

Others:
Transient
- Prem, IUGR (decr liver glycogen and muscle protein and fat to use as substrate)
- Infant of diabetic mother (hyperinsulinism)

Persistent:

  1. Hyperinsulinism
    - Insulinomas (insulin secreting tumours)
    - Beckwith Wiedmann syndrome
    - Persistent hyperinsulinaemic hypoglycaemia of infancy
  2. Endocrine
    - GH deficiency
    - Hypopituitarism
    - Adrenal insufficiency (ACTH, adrenaline deficiency, addison disease)
  3. Substrate deficiency
    - Eating disorder
    - Ketotic hypoglycaemia (now ‘accelerated starvation’; essentially substrate decency)
  4. METABOLIC
    - Glycogen storage disorder
    - Fatty acid oxidation defect
    - Organic academia
    - Carb metabolism disorder (galactosaemia, hereditary fructose intolerance, fructosaemia)

Sx (autonomic system activation)

  • palpitations
  • sweating
  • shaking
  • nausea
  • hunger
  • At extreme - confusion, seizure, coma

Mx
Give rapid oral glucose or soft drink/juice/milk feed followed by carb (bread or banana)
if comatose - give IV 10% dextrose 2ml/kg or IM glucagon

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20
Q

Features of diabetic retinopathy on fundoscopy

A

Cotton wool spots
Flare haemorrhages
Microaneurysms

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21
Q

Diabetic Nephropathy

Histological features

what is the earliest sign?

A

Nodular glomerulosclerosis

Histology:
Kimmelstiel-wilson nodules (clumps of hyaline material in arterioles)

Microalbuminaenuria is earliest sign -> can progress to CKD

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22
Q

Insulin tx in diabetes

A
  1. Long-acting insulin first, nocte (detemir or glargine)
    -> adjust dose depending on morning fasting BSL
  2. Add doses of rapid insulin throughout day, building to ‘basal bolus scheme’
    = administer short-acting insulin 3 x day, before breakfast, lunch, dinner with nocte long-acting insulin
    = measure BSL before each meal and before administering insulin

OR can give 2x doses pre-mix insulin/day (before breakfast and before dinner)

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23
Q

What do you give if cerebral oedema suspected in child w DKA

A

Mannitol (no NOT wait for CNS imaging, give immediately)

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24
Q

Causes of hypoglycaemia in the adolescent (non DM related)

A

Insulinoma
Adrenal insufficiency
eating disorder

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25
Causes of hypoglycaemia in the child
``` Accelerated starvation (previously known as “ketotic hypoglycaemia”) hypopituitarism growth hormone deficiency ```
26
Causes of hypoglycaemia in neonate to 2 yo age group
``` Congenital hyperinsulinism (most common cause of persistent hypoglycaemia \<2 yrs) Inborn errors of metabolism Congenital hormone deficiencies (eg growth hormone deficiency) ```
27
Causes of hypoglycaemia in neonates
Causes of incr metabolic rate - Prematurity - IUGR - Perinatal asphyxia - Hypothermia - Sepsis - Resp distress GDM Macrosomia Syndrome (eg Beckwith-Wiedemann) Pancreatic dysfunction
28
Sx of hypoglycaemia in newborns (\<48 hrs)
Apnoea, hypotonia, jitteriness, poor feeding, high pitched cry
29
1st presentation hypoglycaemia workup investigations
Take bloods whilst patient is hypoglycaemic (before giving tx) 1. Plasma glucose 2. Ketones (beta hydroxybutyrate) 3. FFA - FA oxidation defect 4. Insulin and C-peptide 5. Lactate - metabolic, sepsis 6. Ammonia - metabolic 7. Cortisol (deficiency) 8. Carnitine/acylcarnitine - FA oxidation defect 9. Amino acids - metabolic 10. Electrolytes 11. LFTs 12. GH (deficiency)
30
What cofactors are essential for the krebs cycle?
NAD+ (niacin) Thiamine
31
Rickets What is it? Causes Presentation Ix Tx
Soft bones/failure in mineralisation of growing bone Can be caused by deficiency of Ca, Phosphate or vitamin D (most common) which leads to bone... - softening - impaired growth - malformations Causes 1. Inadequate vit D intake - Prem - BF infants (esp to mothers w low vit D) - Malnutrition - Malabsorption - Inadequate sunlight exposure (esp dark skinned) 2. Impaired metabolism of vit D to active form - liver or renal disease - phenytoin (metabolises vit D) 3. Incr excretion of Phosphate - Familial hypoPh Rickes - Fanconi syndrome (RTA) Presentation - bone, joint pain - prox muscle weakness - bone fragility and incr risk fractures - genu varum (bowing of legs w knock knees) - prominent frontal bone/frontal bossing - rachitic rosary (bumps along chest from bulbous enlargement of costochondral jxn) - harrison groove or sulcus, pigeon chest - protruding abdomen - craniotabes (demineralized area or softening of the skull) - large fontanelle w delayed closure fontanelle Ix - Ca, Ph - High PTH - High ALP - 25 OH D3 and 1,25 OH D3 depend on cause - Xray L wrist (or L knee if \<2yo) Tx - Vitamin D supplementation (calceriferol if nutritional; calcitriol if renal disease) - Treat underlying cause
32
Bone mineralisation
Osteoblasts Build bones - secrete osteoid which is made of type 1 collagen (framework) Then have deposition of ca and Ph within the framework Requires enzyme ALP to carry out this process
33
Vitamin D formation
Vitamin D - ingested in food (cholecalciferol = vitamin D3 and Vitamin D2) - created in skin in response to UV exposure (7 dehydrocholesterol to vitamin D3) Liver - via 25 hydroxylase -\> 25-hydroxy-vitamin D Kidneys via 1 alpha hydroxylase -\> 1,25 hydroxy-vitamin D (=active form = Calcitriol)
34
Role of calcitriol (Active vitamin D)
Increases serum Ca, Ph levels Incr renal tubular reabsorption Ca2+ Incr intestinal absorption Ca2+ and Phosphate Stimulates bone mineralisation Suppresses PTH release from parathyroid gland
35
PTH - role of
Released from parathyroid in response to low Ca levels Results in: incr plasma Ca and decr plasma Ph 1. Stimulates resorption of Ca and Ph from bone into blood (Incr Ca, decr serum Ph) 2. Boosts 1 alpha hydroxylase activity -\> formation of more active vitamin D in kidneys 3. Incr gut absorption of Ca 4. Incr reabsorption of Ca from kidneys but incr urinary excretion of Ph
36
Causes of vitamin D deficiency
Intestinal malabsorption - celiac, chrons disease Decr sunlite/UV light exposure Medications - Phenytoin (competes for liver hydroxylase enzymes so reduces formation of active vit D) Liver and Kidney disease (can't form active vitamin D)
37
Xray findings of rickets
Widened epiphyseal plate Incr joint space Metaphyseal cupping and fraying Metaphyseal fraying Bowing of legs Subperiosteal haemhorrages +/- subperiosteal erosions, cysts, fractures, osteopenia if severe
38
Sx of hypothyroidism
Lethargy LOA, weight gain (reduced metabolic weight) Proximal muscle weakness (myopathy) Constipation (reduced GI motility) Dry skin(reduced secretion from sweat, sebacious glands) Cool skin (vasoconstriction) Brittle nails Cold intolerance Myxedema ('puffy' appearance due to water retention) Goitre Menorrhagia, low libido, infertility Bradycardia, low CO, dyspnoea Low mood
39
TFTs of hypothyroidism
Low T3 and T4 TSH levels vary - High w primary cause - Low/N w secondary cause
40
Production of thyroid hormones
Hypothalamus detects low levels of Thyroid hormones and releases TRH - \> Anterior pituitary thyrotropes produce TSH - \> stimulates thyroid gland follicles to convert thyroglobulin to iodine-containing T3 and T4 (T4 is ultimately converted to T3 which is the active form)
41
Role of thyroid hormones
T3 (active form) does the following: - Incr cardiac output - Stimulates bone resorption - Activates SNS - Sweat and sebacious gland secretions - Hair follicle growth - Skin fibroblasts
42
3 types of hypothyroidism
Primary - thyroid gland isn't making enough thyroid hormone - pituitary incr TSH production Secondary - damage to pituitary -\> decr TSH release Tertiary - damage to hypothalamus -\> decr CRH -\> decr TSH release
43
What is the most common cause of hypothyroid in developed countries?
Hashimoto thyroiditis
44
Hashimoto thyroiditis
Autoimmune condition - Antibodies against thyroglobulin and thyroid peroxidase (anti-TG and anti-TPO) = Type 4 T cell mediated HS reaction Genetics: - HLA-DR3,4,5 positive Thyroid responds to autoimmune damage by undergoing hypertrophy and hyperplasia -\> GOITRE formation Thyroid scan: patchy uptake On histology: Hurthle cells and lymphoid aggregates with germinal centre (Due to lymphoid infiltration) Tx - thyroxine
45
De Quervain thyroiditis
Inflammatory condition following flu-like illness Self-limiting 3 phases 1. hyperthyroidism 2. hypothyroidism 3. return to normal function Histology 1. neutrophils, destruction of thyriod follicles 2. granulomas surrounding follicles OE - jaw pain and tender thyroid. Ix - high ESR
46
What is cretinism
This is congenital hypothyroidism
47
Causes of congenital hypothyroidism
80% Thyroid dysgenesis (abnormally formed) - \> Aplasia 1/3 - \> Ectopic 2/3 20% Dyshormonogenic goitre - inborn error of thyroid hormone production -\> ex: Pendred syndrome: goitre, SNHL, hypothyroidism 2% Transient disease = Ab-mediated maternal hypothyroidism (placental transfer of maternal anti-TRab antibodies due to maternal autoimmune disease, or due to antithyroid drugs) ``` Other Iodine deficiency (in countries without iron fortification of foods) ``` Transient hypothyroixinaemia - 50% of prom infants due to immature HPA - corrects over 4-8 weeks - no tx required - normal TSH, low FT4
48
Presentation of congenital hypothyroidism
6 Ps: Pot-bellied Pale Prolongued jaundice (unconjugated; may be first sx) Puffy-faced Protruding umbilicus (umbi hernia) Protuberant tongue (macroglossia) Poor brain development (ID by 3-6mo) Other - Hypotonia FTT, feeding difficulty Constipation LARGE FONTANELLES Dry skin Apnoeas Bradycardia
49
Causes of central hypothyroidism
Ie Secondary - - \> anterior pituitary tumour - \> infarction that damages pituitary gland - \> leads to decr TSH production Tertiary (damage to hypothalamus) - trauma - tumour - \> decreased TRH production
50
Treatment of hypothyroidism
Replacement of thyroid hormone (levothyroxine)
51
Types of hyperthyroidism
Primary - thyroid gland is secreting too many thyroid hormones Secondary (pituitary gland secreting too much TSH)
52
Primary hyperthyroidism - causes - ix
Causes - graves disease most common (95%) - toxic multinodular goitre - thyroiditis - triggered by iodine- IV contrast TSH low T3, T4 high Radioactive iodine uptake test and thyroid scan can distinguish between causes
53
Graves disease Pathophy Related genes Features Histology
Autoimmune - Anti-TRAb antibodies (anti-TSH receptor Ab) -\> - Type II HS reaction: antibodies bind to the TSH receptor and result in production of thyroid hormones - In neonatal form it is due to maternal transfer of Ab and this is only transient, lasts 6-12 weeks Genes: - HLA DW3 - HLA B8 Features: Diffuse toxic goitre Exopthalmous Pretibial myxedema Sx of hyperthyroidism Hisitology - Tall and crowded follicular epithelial cells with scallopped colloid (consumption of colloid) Thyroid scan - Diffuse b/l symmetrical increased uptake
54
Toxic multinodular goitre
Cuase of hyperthyroidism BENIGN One or more throid follicles starts to grow bigger and produces lots of Thyroid hormone independent of TSH regulation Focal patches of hyperfunctioing cells with lots of colloid inside 'hot nodules' - incr activity on radioactive iodine uptake tests
55
Sx of hyperthyroidism
Metabolic: Heat intolerance Incr sweating Tremor GI Increased appetite LOW Diarrhoea Skin/hair: Warm, moist skin Fine, fibriable hair Nail bed separation MSK: Graves opthalmopathy Osteoporosis Thyrotoxic myopathy (prox muscle weakness) Reproductive: Oligomenorrhoea, amenorrhea, low libido, infertility Gynaecomastia in males Cardiac: Tachycardia, HTN, chest pain, dyspnoea Cardiomegaly Arrhythmias (AF-rare) Restlessness, anxiety, insomnia
56
Thyroid storm cause features tx
Can worsen during acute stress (infx, trauma, surgery) Fever Tachyarrhythmia, HTN Restlesness, delirium, agitation, coma, death if not rapidly treated Tx - IV PTU - IV propanolol
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Tx of hyperthyroidism
Beta blockers (propanolol) Methimazole or Propothiouracil = 'PTU' (inhibits thyroid peroxidase, thus decr thyroid hormone synthesis) Prednisolone (inhibits T4 to T3 conversion) Potassium Iodide (lugol solution) decr thyroid hormone synthesis and decr vascularisation in thyroid May need thyroidectomy
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Secondary causes of hyperthyroidism
Often pituitary adenoma secreting excess TSH High levels HCG (structurally similar to TSH so bind to the TSH receptor and stimulate it) - \> IE in first trimester of pregnancy - \> HSG-secreting germ cell tumours of testicles or ovaries T3, T4 high TSH high or normal
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Effect of dopamine on HPA axis
Dopamine inhibits prolactin release
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What hormones does the posterior pituitary release and what triggers their release
Hormones produced in herring bodies - ADH/vasopressin - Oxytocin Release triggered by neuronal signals from hypothalamus Hormones released into systemic circulation
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Ectopic thytoid
Thyroid in wrong location
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Panhypopituitarism as a cause for hypothyroidism, is this detected on the NST?
Due to a central or secondary cause -\> LOW TSH -\> Low T4 \*not picked up on NST as low TSH (NST detects elevated TSH)
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Thyroid agenesis
Total lack of thyroid tissue -\> low T3/T4, high TSH
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LH and FSH
Triggered by GnRH from hypothal FSH - M: binds to Sertoli cells -\> sperm development - F: binds to Glomerulosa cells -\> testosterone to oestrogen conversion LH - M: binds to Leydig cells -\> testosterone product - F: binds to Ovarian cells -\> steroidogenesis
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TSH what triggers vs inhibits its release What is its action
Triggered by TRH from hypothal Inhibited by somtatostatin, dopamine and GC Bind to receptor on thyroid follicular cells to cause release of T3, T4 (via activation of adenylyl cyclase)
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Prolactin
Triggered by serotonin, ACh, opiates, estrogens from hypothalamus Inhibited by dopamine Acts on 1. breast -\> lactation (high levels during neonatal period) 2. uterus -\> cessation of menses during puerperium
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Glycogenolysis
Breakdown glycogen (liver and muscle) to glucose
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Glycogenesis
Formation of glycogen (stored form of glucose in liver, muscles)
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What forms is vitamin D given as a supplement
Cholecalciferol (vitamin D3) -\> goes to liver -\> kidney Calcitriol (1,25 dihydroxy vitamin D) given to kids with CKD as this is the active form (doesn't require metabolism by kidneys)
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What do TSH and gonadotropins have in common?
Contains same alpha subunit as LH and FSH and HCG (differentiated based on beta subunit)
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GH release pathway HPA axis Effects Stimulation Inhibition
Hypothalamus -\> release of GHRH -\> acts on pituitary to stimulate GH release from anterior pituitary Pulsitile release, small peaks with big gaps in between during day and larger peaks with smaller gaps between during sleep * *Effects** - increase bsl - incr uptake of aa into muscle -\> cell proliferation - Diabetogenic (more glucose produced in liver -\> IGF production -\> incr growth and inhibits further GH release from pituitary) - Growth stimulated via GH binding to receptors -\> IGF1 release -\> long bone growth * *Stimulation** - stress/illness/trauma - exercise - hypoglycaemia - starvation - adrenaline/NA - sleep - protein intake (incr muscle mass) - sex steroids * *Inhibition** - hyperglycaemia - obesity
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Features of hypogonadotrophic hypogonadism
Low testosterone and low FSH, LH, sex steroids Microphallus, cryptorchidism (undesc testes)
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What is the main cause of persistent hypoglycaemia in infancy/neonatal period? causes (2) Ix features
Hyperinsulinaemia hypoglycaemia of infancy 2 main genetic causes - K ATP channel defect - glucokinase defect Hypoglycaemia \<2.2 Detectable insulin (\>14) Absence of ketones Inappropriately low FFA
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Functions of ADH What inhibits release
Osmolality maintenance Insertion of aquaporin 2 into collecting ducts of kidneys to cause water reabsorption and concentration of urine Release inhibited by NA
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hyponatraemia in dka what causes this and how do you correct for this?
depressed level due to the dilution effect of the hyperglycaemia Need to 'corrected sodium' = measured Na + 0.3 (glucose - 5.5)
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Metformin MOI SE
Biguanide Increases insulin sensitivity SE - GI upset Weight loss
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Where does the pituitary gland sit anatomically?
Inferior to hypothalamus, in the sella turnica below optic chiasm - \> anterior pituitary arises from Rathke's pouch (dorsal outpouching from roof of oral cavity), signals from hypothalamus via portal vessels - \> posterior pituitary arises from neural ectoderm, signals frmo hypothalamus via neuronal axons
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Diabetes Insipidus Ix and tx how to distinguish between central vs peripheral cause?
Ix 1) Urine osmolality and specific gravity (low) -\> lots and lots of very dilute urine as unable to concentrate urine properly 2. High serum osmolality, often w hyperNa 3a) Water deprivation test: DI (urine osmolality will remain low) vs other cause of polydipsia (urine will concentrate) 3b) Desmopression/ADH analogue: if central cause, urine will concentrate/osmolality will increase; if nephrogenic, urine osmolality will stay low/only incr slightly. Tx - Neonates: primarily fluid tx due to incr volume requirement - Treat underlying cause if reversible - If central cause: desmopressin infusion - If nephrogenic: thiazides, carbamazepine and cloramphenicol to sensitise tubules
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What hormones does the anterior pituitary release and what triggers their release?
1. ACTH and MSH 2. GH 3. LH, FSH 4. TSH 5. Prolactin
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What is the most common cause of permanent congenital hypothyroidism?
Thyroid dysgenesis (includes ectopia, hypoplasia, aplasia) Sporadic aetiology Sometimes associated with cardiac and renal anomalies
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What is the Wolff Chaikoff effect?
Autoregulatory phenomenon, whereby a large amount of ingested iodine acutely INHIBITS thyroid hormone synthesis within the follicular cells, irrespective of the serum level of thyroid-stimulating hormone (TSH) Results in - HIGH TSH - Low T3, T4
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Dyshormonogenesis as cause for congenital hypothyroidism How common Technician scan Causes
- Defects of synthesis of thyroid hormones - 15% of congenital hypothyroidism (2nd most common cause) - GOITRE most always present - incr uptake on technician scan (except is low w/ iodine transport defects) Caused by defects in: - most common is thyroid peroxidase 'organification' (required to incorperate iodine to tyrosine) - iodine transport - thyroglobulin - Deiodination
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Technetium 99 scan - causes of... 1. absent or reduced thyroid uptake 2. ectopic thyroid tissue 3. increased uptake
1. absent/reduced uptake: - agenesis - maternal thyroid blocking Ab - Infants with iodine trapping/iodine transport defects - maternal lithium use in pregnancy (lithium competes for uptake) 2. ectopic thyoid tissue (form of dysgenesis) 3. Incr uptake - dyshormogenesis - excessive iodine exposure
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Prolactin
Prolactin triggered by serotonin, ACh, opiates, estrogens from hypothalamus Inhibited by dopamine
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Growth hormone deficiency causes presentation ix
Congenital or acquired causes of low GH Presents w growth failure and delayed bone age Ix - Low IGF-1 - Low IGFBP-3 - Confirmed with GH provocation test - MRI to exclude central causes (hypothal/pituitary tumours such as craniopharyngioma)
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Layers of adrenal cortex and what they secrete
Capsule (outer most) -\> 'G F R' SALTY 1. Zona Glomerulosa -\> mineralocorticoids (aldosterone - salty) - regulated by RAAS SWEET 2. Zona Fasciculata -\> glucocorticoids (cortisol - sweet) - regulated by CRH -\> ACTH SEX 3. Zona Reticularis -\> androgens (DHEA, androstenodione - sex) - regulated by CRH -\> ACTH 4. Medulla -\> catecholamines (adrenaline)
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How can the pigmentation in Addison's disease be explained?
ACTH is cleaved from POMC MSH (melanocyte stimulating hormone) is also cleaved from POMC In Addisons you have decr cortisol, but increased levels of ACTH as compensation. Hyperpigmentation is caused by overproduction of POMC, resulting in incr levels of ACTH and MSH. High levels of circulating ACTH also cross-react with the melanocortin 1 receptor on the surface of dermal melanocytes.
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What are genetic syndromes causing shortness?
Turners (45XO) Achondroplasia (dominant) Down's Prader Willi Noonan Russel-Silver
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Features of hypogonadotrophic hypogonadism
Low FSH, LH, sex steroids (testosterone etc) Microphallus, cryptorchidism (undesc testes)
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Arm span and upper: lower segment ratios and impact on assessment of growth
Arm span: height should be 1: 1 at all ages - \> Abnormal in Marfans/Klinefelters/dwarfism - \> Arm span \< height = skeletal abnormalities Upper (crown to pubic symphysis) Lower (pubic symphysis to ground) RATIO CHANGES W AGE - \> 1.7:1 as a neonate - \> 1.4:1 4-5 years - \> 1:1 at 10-12 years - \> Proportionate = familial short stature
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Functions of ADH What inhibits release
Osmolality maintenance Insertion of aquaporin 2 into colleceting ducts of kidneys to cause water reabsorption and concentration of urine Release inhibited by NA
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Short stature: Definition Causes - Most common causes 1. Equal reduction in height/HC/weight 2. Height more affected 3. Weight more affected 4. GENDER - \> Most common cause in boys vs girls - \> Most common cause in girls vs boys
Height \< 2 SD below the mean OR \< 2nd centile Growth velocity \<25th centile - Most common cause is familial short stature (short parents) - Constitutional growth delay (delayed bone age and delayed puberty w family history) - common in boys 1. Equal reduction in height/HC/weight = - \> TORCH - \> Chromosomal (Turners, Downs, Noonans, Prader-Wili, Bloom, Russel-Silver syndromes) - \> Chronic illness (any form of chronic illness = Coeliac, CF, renal failure etc) 2. Height more affected = - \> Endocrine (Hypothyroid, GH deficiency, Cushing syndrome) - \> Skeletal dysplasia (achondroplasia, hypochondroplasia) 3. Weight more affected = malnutrition/psychosocial deprivation (think of tall skinny child with big head) GENDER Girls with short stature = turners XO until proven otherwise Boys with short stature = commonly physiological
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Pituitary adenoma presentation
Secretory and no secretory forms 1. Secretory (65-70% tumours) - excess hormone secretion (prolactin, GH, cortisol; tends to be only one hormone depending on cell of origin) 2. Non secretory can present w sx due to mass effect (headaches, bitempral hemianopia)
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Craniopharyngoma presentation Where does it arise from? What does it look like on MRI?
Most common supratentorial tumour (5-10% childhood brain tumours; 50% occur under 20yo) Arises from rathkes pouch Often large, cystic and CALCIFIED Presents w - Mean age 8yo - Headache - Bitemporal hemianopia (compression optic chiasm) - Hydrocephalus (bulging fontanelle, nausea/morning headache w vomiting, sun set eyes, seizures) - Deficiency in hormone production can lead to endocrine abnormalities - -\> Growth slowing (hypothyroidism, GH deficiency) - -\> Pubertal delay - -\> Diabetes insipidus due to low aldosterone - -\> Addisonian crisis
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Central vs nephrogenic diabetes Insipidus
Central: Insufficient ADH production from posterior pituitary gland Nephrogenic: Renal insensitivity to ADH (less common, more severe) -\> polyuria and polydipsia -\> dehydration, weight loss/FTT, collapse (particularly in babies) Central causes - Idiopathic - Tumours (craniopharyngioma, optic glioma, germinoma, LCH) - infiltrative (LCH, sarcoid, haem malignancy) - Infective (listeria in newborns; TB meningitis) - Trauma (surgery, rdiotx, asphyxia, IVH) OR peripheral/nephrogenic causes - Resistance to ADH - Genetic (mutation V2 receptor; defective Aquaporin 2 gene) - RTA - HyperCa -\> nephrocalcinosis - Hypokalaemia if severe and prolonged
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What thyroid conditions does NST detect?
Detects HIGH TSH (and therefore low T4) = Primary thyroid conditions Examples - Thyroid dysgenesis (85% cases) - Dyshormonogenesis (errors in thyroxine synthesis -15% cases) - TSH resistance (v rare) - Iodine deficiency and excess - Maternal Ab-mediated hypothyroidism (very rare) Does NOT detect central hypothyridism (as TSH is normal/low)
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What is the most common cause of permanent congenital hypothyroidism?
Thyroid dysgenesis (includes ectopia, hypoplasia, aplasia) Sporadic aetiology Sometimes associated with cardiac and renal anomalies
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Dyshormonogenesis as cause for congenital hypothyroidism How common Technician scan Causes
- Defects of synthesis of thyroid hormones - 15% of congenital hypothyroidism (2nd most common cause) - GOITRE most always present - incr uptake on technician scan (except is low w/ iodine transport defects) Caused by defects in: - most common is thyroid peroxidase 'organification' (required to incorperate iodine to tyrosine) - iodine transport - thyroglobulin - Deiodination
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Main factors driving growth at each of the following phases of life 1. Fetal 2. Infancy 3. Childhood 4. Puberty
1. Fetal - placental nutrient supply - mother's size 2. Infancy (first 3 yrs) - Nutrition (GH **independent**) 3. Childhood - **GH-dependent** - Nutrition - Thyroid hormone - Vitamin D - Steroids 4. Puberty - Sex hormones and GH
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Age range of growth spurts in girls and boys and how does this relate to timing of puberty and menarche
Growth spurts age range - Girls: 9-15 (peak 11-13); preceded by breast bud development (first sign of puberty in girls) - Boys: 11-17 (peak 13-15); preceded by testicular enlargement (first sign of puberty in boys) In girls menarche occurs AFTER the pubertal growth spurt ie menarche onset occurs once they've reached their final height Once patient has reached puberty, they have reached their max height and in girls always precedes menarche
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Effect of craniospinal irradiation on growth and mechanism for this
Short stature -\> reduction in spinal growth mediated by reduced levels of GH Endocrine abnormalities common after radiotx to pituitary hypothalamic axis -\> can get GH, TSH, ACTH, GnRH deficiencies (in that order) Can also get central precocious puberty as well as ACTH deficiency and GH deficiency
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What are genetic syndromes that cause tallness?
Fragile X Kleinfelters 47XXY marfans\* homocysteinuria\* ehlos danlos syndrome\* \*Also cause primary osteoporosis
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What are genetic syndromes causing shortness?
Turners (45XO) Achondroplasia (dominant)
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Normal weight loss/gain after birth
- Weight loss in first few days 5-10% of birth weight - Return to birth weight 7-10 days of age (or 10-14 d if preterm); ~3.5kg - Double birth weight by 4-5mo (7kg) - Triple BW at 1yr (~10kg)
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Arm span and upper: lower segment ratios and impact on assessment of growth
Arm span: height should be 1: 1 at all ages - \> Abnormal in Marfans/Klinefelters/dwarfism - \> Arm span \< height = skeletal abnormalities Upper (crown to pubic symphysis) Lower (pubic symphysis to ground) RATIO CHANGES W AGE - \> 1.7:1 as a neonate - \> 1.4:1 4-5 years - \> 1:1 at 10-12 years - \> Proportionate = familial short stature
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Fragile X syndrome inheritance/gene presenting features
X-linked dominant, **FMR1** gene mutation Intellectual disability Autism 'Elven appearance' - long narrow face, large ears, prominent forehead/jaw Joint laxity Large testes after puberty Chronic otitis media Seizures Tremor/ataxia (late onset, \>50yo)
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Short stature definition Causes 1. Equal reduction in height/HC/weight 2. Height more affected 3. Weight more affected GENDER -\> Most common cause in boys vs girls
\< 2 SD below the mean IE below 2.3rd centile Equal reduction in height/HC/weight = TORCH/chromosomal Height more affected = endocrine/skeletal dysplasia Weight more affected = malnutrition GENDER Girls = turners XO until proven otherwise Boys = commonly physiological
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Physiological causes of short stature
constitutional delay of growth adn puberty Familial short stature
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Carpenter syndrome DDx for this
Obesity o ID o Craniosynostosis almost always present - abnormal head shape o Brachycephaly, polydactyly, syndactyly of feet o Cryptorchidism, hypogonadism in males o Umbilical hernia ddx - bardot biedel syndrome (also has retinal dystrophy/early night blindness, renal abnormalities, DI or DM etc; doesnt have umbni herni or craniosynostosis)
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Endocrine causes of short stature
Things you need to grow: vit D, Ca/Ph, GH/IGF1, Thyroid hormone, steroid/sex hormones * Cushing’s syndrome * Hypothyroidism * Pseudohypoparathyroidism * Rickets * IGF1 (GH) deficiency * Sexual precocity
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Precocious puberty i a boy - what age is abnormal and think what until proven otherwise?
Sec sexual characteristics \<9yo is abnormal ``` Brain tumour (hypothalamic hamartoma) until proven otherwise (ix: hCG and alpha-FP); could also be testicular tumour - choriocarcinoma etc Other - CAH, dysgerminomas ```
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Genetics assoc w t1dm
HLADR3/DR4 + DQ2/8
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Precocious puberty in a girl - who age and think what?
Sec sex characteristics \<8yo or menarche \<10yo is abnormal Unlikely to be pathological Mostly familial causes
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Delayed puberty in a boy - what age and think what?
Failure of puberty onset by 14yo Unlikely to be pathological Most common cause is constitutional delay (short child with delayed bone age and family history)
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Cause of short stature in renal failure
IGF-1 deficiency (renal failure distorts the GH/IGF-1 axis leading to high GH and inappropriately normal/slightly low IGF-1
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Cause of short stature in Turners
Short Stature Homeobox (SHOX) insufficiency
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Features of constitutional delay of growth and puberty
Normal height for bone age but NOT for chronological age (delayed bone age for chronological age) Family history of delayed growth and/or puberty
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Effect of craniospinal irradiation on growth and mechanism for this
Short stature -\> reduction in spinal growth mediated by reduced levels of GH Endocrine abnormalities common after radiotx to pituitary hypothalamic axis - \> can get GH, ACTH and TSH deficiencies Can also get central precocious puberty as well as ACTH deficiency and GH deficiency
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BSL targets (fasting/random) Normal Impaired Diabetes
Fasting: Normal \< 6 Diabetes \> 7 Random or OGTT Normal \< 7.7 Diabetes \> 11.1
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Target BSLs for children w diabetes
Aim BSL 4-8 before meals
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What does HBA1c reflect and what is target for children w diabetes? What conditions can affect the HBA1c level ?
Reflects BSL control over past 2-3 months Is a measure of glycated haemoglobin (sugar bound to RBCs) Aim HBA1C \< 7.5 Any condition that reduces RBC lifespan and increases turnover may falsely lower HbA1c. Examples include: - red cell aplasia - blood transfusion - haemorrhage - renal disease treated with erythropoietin
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Bardet-Biedl syndrome FEatures
Obesity onset age 2 Deafness Retinitis pigmentosa Polydactyly Hypogonadism Intelectual deficit Hypotonia Renal disease
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Fragile X syndrome
X-linked dominant, FMR1 gene mutation Intellectual disability Autism 'Elven appearance' - long narrow face, large ears, prominent forehead/jaw Joint laxity Large testes after puberty Chronic otitis media
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Prader WIlli SYndrome Mutation
``` loss of function of genes on chromosome 15 Imprinting defect (loss of paternal contribution) ``` Initial FTT the onset obesity age 2-3 with hyperphagia Microcephaly Short stature Hypotonia Learning difficulties High-arched palate Almond shaped eyes Narrow hands and feet Delayed puberty
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Beckwith Widemann syndrome
Deregulation of imprinting genes on chromosome 15 (11q15.5) incl IGF2 Features • Hemihypertrophy • Organomegaly • Abdo wall defects: omphalocoele, umbilical hernia • fetal macrosomia, polyhydramnios • Hyperinsulinemia -\> Hypoglycemia and Intolerance of fasting • Macroglossia • Macrocephaly • Eat pits/creases • Tumour predisposition (Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) • Renal disease
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Cohen syndrome
o Obesity onset mid childhood o ID o Microcephaly o Small hands and feet with long, thin fingers and toes o Prominent central incisors o FTT in infancy w hypotonia
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Alstrom syndrome
o Obesity onset age 2-5 o Blindness, deafness o Chronic neuropathy o Acanthosis nigricans o Normal IQ o Chronic nephropathy
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Auto-antibodies in T1DM
o Anti-insulin antibodies – appears first, disappears w tx o Anti-glutamid acid decarboxylase (GAD) – most common (70-80% at diagnosis) o Anti insulinoma protein 2 o Islet cell antibodies o Anti-zinc transporter
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Autoimmune disease assoc w T1DM
Autoimmune thyroid disease - Anti-TPO, Anti-thyroglobulin Coeliac disease - Anti-tTg - Anti-IgA (endomysial antibodies) - Anti-gliadin - Diaminated gliadine peptide (DPG) IgA or IgG Adrenal disease - Anti 21-hydroxylase
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Synthesis pathway of androgens Where are they made?
Made in zona Reticularis (inner most layer of Adrenal cortex) Cholesterol -\> Pregnenolone - \> Progesterone or 17-hydroxypregnenolone - \> 17-hydroxyporgesterone - \> Dehydroepiandrosterone (DHEA) - \> Androgen - \> Testosterone - \> DHT (formation of ext male genitalia and prostate) via 5 alpha-reductase -\>OR to Estrogen via aromatase)
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Synthesis of cortisol Where is it made?
Made in zona fasciculata in adrenal cortex Cholesterol -\> Pregnenolone - \> 17-hydroxypregnenolone + 17-hydroxyprogesterone - \> 11-deoxycortisol - \> cortisol
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Synthesis of aldosterone Where is it made?
Made in zona glomerulosa (outer most layer of adrenal cortex) Pregnenolone - \> progesterone - \> 11-deoxycorticosterone - \> aldosterone
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What is the diurnal rhythm of glucocorticoids?
Highest at waking in hte morning, low in late afternoon + evening, lowest whilst asleep
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What products are made in the adrenal medulla?
Dopamine NA Adrenaline
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Non classic CAH presentation
Present AFTER the neonatal period with signs of hyperandrogenism and WITHOUT adrenal insufficiency Premature pubarche Advanced bone age Medication resistant cystic acne Accelerated growth w tall stature In females - hirsutism, menstrual irregularity, low fertility DDx - PCOS
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What is Conn's syndrome? Presentation Ix Causes Tx
Primary aldosteronism - exessive aldosterone secretion independent of RAAS Rare in children but 5-10% of HTN in adults Presentation - HTN w headache, dizziness, visual disturbance - Proximal muscle weakness (due to hypoK) - Polyuria * *Ix** - High serum Na - _Low serum K_ - Metabolic alkalosis - **High plasma aldosterone:renin ratio** - Reduced urine Na:K ratio - High 24 hr urine aldosterone - Decr renin activity * *Causes** - Idiopathic adrenal hyperplasia 66% - Adrenal adenoma of zone glomerulosa secreting aldosterone 33% - Adrenal carcinoma secreting aldosterone - Familial Hyperaldosteronism * *Tx** - Pred (suppresses aldosterone release) - Spironolactone (aldosterone antagonist, incr K and lowers BP) - Surgery
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Phaeochromocytoma - what is it - sx - ix - tx - What genes/syndromes are associated with this tumour?
Catecholamine secreting tumour arising from chromaffin cells in adrenal medulla or along sympathetic chain -\> Secretes NA \> adrenaline, dopamine Sx are INTERMITTENT: headache, sweating, tremor, tachycardia, HTN, postural hypotension ,anxiety/panick attacks, abdo pain, dizziness, cachexia Ix - 24 hr urinary catecholamines (VMA and metanephrins) - Serum catecholaemines - MIBG (special chromatin tissue isotope scan) - Imaging (ct/MRI, MIBG/PET) - Genetics (**NF1, MEN2, VHL** or von Hippel-Lindau) Tx - Surgical excision - BP control - Tachycardia control (alpha blocker followed by beta blocker)
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Gluconeogenesis
Production of glucose from breakdown of non-CHO substrates (lipids, protein)
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Glycogenolysis
breakdown of glycogen to glucose (glycogen in liver broken down into glucose)
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Glycogenesis
formation of glycogen (glucose taken up into liver and stored here)
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Glucagon role
Increases blood glucose via: - glycogenolysis (main action) - gluconeogenesis - lipolysis (minor)
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Insulin effect
Decr blood glucose (aa and FFAs) via incr glucose uptake into muslce, adipose tissue -\> lipogenesis, protein production, glycogen synthesis Incr glucose uptake into liver -\> glycogen synthesis
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What cells produce glucagon
Alpha cells in pancreas
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What cells produce insulin
Beta cells in pancreas
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What is the role of somatostatin and where is it produced
Inhibits GH, insulin and glucagon secretion Produced by hypothalamus and gamma cells in pancreas in response to hyperglycaemia, hypothyroidism
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What organ doesn't require insulin for glucose uptake and what channel does it involve
Brain Glucose taken up by GLUT1 transporters, insulin independent
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Screening for diabetic microvascular complications
Retinopathy - dilated eye exam Neuropathy (peripheral and autonomic) - vibration - monofilament for pressure sensation - proprioception Nephropathy - Albumin: creatinine ratio (first sign in albuminuria) Thyroid - Serology at diagnosis - TFTs Celiac disease - serology at diagnosis then annually
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Hypoglycaemia in DM
Definition - BSL \<4 Causes Missed meal/snack Exercise alchohol Too much insulin Mx - treat regardless of sx 1. 5-10g of quick acting carb - -\> or if decr GCS, seizure or unable to tolerate oral intake, give glucagon or IV 10% dextrose 2. WAIT 15 MIN -\> repeat BSL 3. if \<4, repeat step 1. of \>5, give 10-15g of long-acting carb
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Ketosis Causes When to test for ketones? When to treat?
Treat if ketones \>1 (in serum OR urine) Causes - Missing insulin - Illness Check if - BSL \>15 - Diabetic child unwell Treat with extra insulin
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Sick day management principles for children w T1DM
Treat underlying illness - note bacterial and viral illnesses can cause high BSLs, use sugar-free fluids for hydration - illnesses with vomiting, diarrhoea and decr appetite can cause low BSLs -\> use fluids containing sugar Facilitate regular oral intake Monitor BSLs every 2-4 hrs Check ketones if BSL \>15 Do NOT omit insulin, may have to reduce dose Give extra insulin if BSL \>15 + ketones (short acting only, 5-20% more)
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Complications of DKA
- Acute cerebral oedema - Cardiac arryhmias due to K imbalance - Mucormycosis (fungal infection that starts in sinuses but can spread to brain)
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Potassium changes in DKA and how does this change with treatment
1. Often elevated to begin with in serum (BUT total body deficit) 2. Correction of acidosis results in hypokalaemia (K+ moves into cells) 3. Therefore generally K replacement therapy required
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What is the corrected sodium and how do you calculate this?
Measured serum sodium is depressed by the dilutional effect of the hyperglycaemia (water moves with glucose) -\> So the actual/corrected Na will be HIGHER Corrected (i.e. actual) Na = measured Na + 0.3 (glucose - 5.5) mmol/l
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What clinical feature is a marker of insulin resistance?
- Acanthosis nigricans – marker of insulin resistance found in 50-90% of youth with T1DM - skin tags - alopecia - amenorrhoea - hirsutism - infertility in women
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MAnagement of T2DM
Aim HBA1C \<6.5% Lifestyle - Diet, low GI foods - Exercise 60min/day - Screen time \<2hrs/day Medication - Metformin is treatment of choice both in BSL mgmt and aids in weight loss - Insulin if HBA1c \>9%, BSLs \>15 or ketosis Screen for/manage complications
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Hyperosmolar non-ketotic acidosis
Development of severe hyperglycaemia WITHOUT ketosis, usually in setting of T2DM Triggered by sepsis most often Clinical presentation - polyuria, polydipsia - extreme dehydration - shock - hypercoagulable state Tx - Fluid resus - Treat underlying causes - Similar to DKA except use less insulin
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Risk factors for CF related DM
Due to pancreatic insufficiency - deficient insulin RF a. Increasing age b. Pancreatic insufficient c. Delta F508 homozygous d. Female
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Development of gonads - differentiation (males vs females)
All embryos start with bipotential gonads - \> Mullerian (ultimately become female organs) - \> Wolffian ducts (become male organs) Testicular development requires Y chromosome (sex determining region 'SRY') Differentiation between sexes begins at 6 WEEKS of gestation following secretion of hormones by fetal testes (ovary is silent) - Anti-mullerian hormone (AMH) from Sertoli cells -\> regression of mullerian structures - Testosterone from Leydig cells -\> formation of Wolffian duct structures - Dihydrotestosterone -\> development of prostate and external genitalia Female ovarian development occurs around week 10, requires ABSENCE of SRY, testosterone and AMH. - Mullerian duct becomes uterus, uterine tubes - Wolffian duct degenerates
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Absent or partial puberty with anosmia and cleft palate in MALE Diagnosis Inheritance Cause Other features of the condition
Kallman syndrome - Cause of ISOLATED hypogonatropic hypogonadism (due to _GnRH deficiency)_ 85% AD, 15% X linked Genetic mutation in KAL1 (now called ANOS1) or KAL2 gene that leads to failure of olfactory and GnRH expressing neurons to migrate from their common origin to the brain - \> males: gynaecomastia, not much facial/chest hair, small gonads/penis - \> females: delay in breast and pubic hair development and no menstruation Other features: - Short stature - Colour blindness - Ichthyosis (dry thick scaly skin) - Renal abnormalities (agenesis)
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Features of Klinefelter syndrome - specifically what cardiac defect is associated?
47 XXY - most common sex chromosome disorder (1/500) Features o Primary hypogonadism – small, firm testes, decreased virilisation, small phallus, hypospadias, cryptorchidism , gynaecomastia o Growth – tall, legs \> trunk 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
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Investigation of suspected hypogonadism in MALES
1. Test morning total testosterone levels 2a. if T normal/high, measure LH - \> if LH high, consider androgen insensitivity - \> if LH low, excludes hypogonadism 2b. if T low, repeat. if low again, measure LH/FSH - \> if LH high= primary hypergonadotrophic hypogonadism -\> karyotype (could be turner or kleinfelters) - \> if LH, FSH low = hypogonadotropic hypogonadism
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Causes of primary or 'peripheral' hypogonadism (or hypergonadotropic hypogonadism due to elevated FSH, LH with low testosterone) in MALES
Congenital - Klinfelter syndrome - Noonan syndrome - Cystic fibrosis - Mutations in steroid synthesis pathway - FSH, LH resistance Acquired - Chemo - Radiation - Infarction (testic torsion) - Infection (mumps) - Trauma
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Primary vs secondary hypogonadism in MALES
Both have decr total testosterone levels measured at 8am Primary (eg anorchia) - hypergonadotropic hypogonadism (defect at the gonads) - elevated FSH, LH (from pituitary) - low AMH (indicates no functional sertoli cells/anorchia) and low inhibin B (released from leydid cells) useful in first 2 yrs of life to determine whether there is functional testicular tissue presence (?anorchia) - **Small or no rise in testost w _hCG stimulation test_** Secondary/central - hypogonadotropic hypogonadism (defect at the anterior pituitary or hypothalamus) - low FSH, LH
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Causes of hypogonadotroic hypogonadism (Secondary) in MALES
Congenital - Kallman syndrome - Prada Willi synd - Bardet-Biedl synd - Alstrom synd - Isolated HH at pituitary - idiopathic Acquired - Anorexia - Drug use - Malnutrition - Chronic illness (crohns) - Hyperprolactinaemia - Pituitary tumours - Pituitary infarction - Infiltrative disorders - Haemochromatosis, haemosiderosis - Radiation
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Primary hypergonadotropc hYpergonadism in women Definition Sx Causes
Ovarian failure (loss of oocytes, folliculogenesis and ovarian estrogen production, infertility) accompanied by high FSH before age 40 Hard to diagnose before puberty except in cases of turner's syndrome (most common cause) Sx include - irreg menses - infertility - hot flushes, dry vagina, bone loss, osteoporosis Causes - Genetic (turners, FSH/LH resistance, steroid synthesis pathway mutations, noonan, galactosaemia, fragile X, bloom, fanconi, ataxia telangiectasia) - Acquired (**chemo, radiation**, cmv/mumps) Tx - puberty induction with transdermal estradot (oestrogen/progestone supplementation)
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Galactosaemia - what is this caused by and what endocrine effect does it have?
* Inherited inborn error of metabolism affecting galactose pathway * Most commonly due to deficiency in galactose1-phosphate uridyl transferase (GALT) * Results in progressive ovarian fibrosis; testis spared (=\> primary hypergonadotropic hypogonadism)
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Definition of micropenis
Length \<2.5cm Width \<0.9cm
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Turners Syndrome
45XO (sporadic inheritance) Symptoms can include ... - short stature - recurrent otitis media - pubertal delay/virilisation - a wide, webbed neck - a low or indistinct hairline in the back of the head - swelling (lymphedema) of the hands and feet - broad chest and widely spaced nipples - shortened 5th metacarpal - arms that turn out slightly at the elbow - congenital heart defects or heart murmur - scoliosis (curving of the spine) or other skeletal abnormalities - kidney problems - an underactive thyroid gland a slightly increased risk to develop diabetes, especially if older or overweight osteoporosis due to a lack of estrogen, (usually prevented by hormone replacement therapy)
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define virilisation
the development of male physical characteristics (such as muscle bulk, body hair, and deep voice) in a female or precociously in a boy, typically as a result of excess androgen production.
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Benign premature adrenarche
* Typically refers to appearance of sexual hair \<8 years (girls) or \<9 years (boys) – WITHOUT other evidence of maturation * Mild form of hyperandrogenism that is a variant of normal * Slowly progressive incomplete form of premature puberty * Diagnosis requires biochemical demonstration of serum steroid pattern (hormones within normal range, andrenal angrogens ie DHEAS ULN/high) * More common in girls than boys * normal bone age
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thelarche - what is this, what does it indicate and when does it typically occur?
onset of breast development (first sign of puberty onset in girls, generally 8-13yo)
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Idiopathic premature thelarche
* Isolated breast development (sporadic, transient) most often appears in the first 2-3 years of life * BENIGN condition, but may be the first sign of true or peripheral precocious puberty, or it may be caused by exogenous exposure to estrogens * Normal growth/bone age * Normal menarche and bone age * Normal genitalia * Normal ix (serum hormone concentrations, bone age, ultrasound)
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How do you calculate BMI
BMI = (weightkg)/(heightcm)^2
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What hormone is responsible for secondary sexual characteristics?
DHEA
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Management of hypercalcaemia What is the threshold for treatment?
Treat if \> 3.5 (severe) 1. Increase urinary excretion - \> Rehydration with N saline + 5% glucose (incr filtration) - \> Loop diuretics (inhibit Ca reabsorption) 2. Increase GI excretion with glucocorticoids 3. Prevent bone resorption by inhibiting osteoclasts - \> Bisphosphonates (longer-term effects) - \> Calcitonin (acute effect) - \> Oral phosphates bind w Ca
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Mcunin Albright syndrome
Triad of
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Causes of tall stature
Idiopathic - Familial (normal GV and bone age) = most common cause - Precocious puberty (start out tall, end up short) - Obesity Endocrine - Hyperthyroid - Pituitary gigantism (GH excess) - CAH (similar to precocious puberty - start out taller, end up short) Syndromes - Marfan syndrome - Kleinfelter (XXY; low IQ) - Triple X (low IQ) - XYY (low IQ) - Homocystinuria (low IQ) Large babies/infants - Gestational diabetes - Beckwith Wiedemann - Cerebral gigantism of sotos (Sotos Syndrome)
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Features of Marfan Syndrome
- Arachnodactyly (long thin fingers) - Increased arm span compared to height - Ligament laxity chest deformity (pacts excavatum, scoliosis) - Cardiac AR/dissection - UPwards Subluxation lens - High arched palate - Osteoporosis
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Definition of tall stature What is normal growth velocity
Tall stature \> 97.7th centile or velocity \> 75th centile Growth velocity - Sensitive marker of normal vs abnormal growth progression (gold standard) - Calculation: height difference in cm (2 measurements at least 4 months apart divided by time difference in years between the 2 measurements (eg 0.3yrs) - Normal growth velocity: - Crossing \<2 centiles in height - Or between 25-75th velocity centiles - 2-6 years: ~9cm/year - 6 years - puberty: ~6cm/year
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Precocious puberty: How does bone age compare with chronological age? Central vs peripheral Causes Mx
Bone age \> chronological age = Advanced bone age (from oestrodiol) Causes - **_CENTRAL_** (driven by HPA axis with **elevated LH and FSH**) - -\> Familial (more commonly in girls) - -\> Hypothyroid - -\> Brain tumours (hypothalamic haemartomas the most common) - -\> Acquired (post sepsis, surgery, DXT, radiation) ***--\> Treatment with GnRH agonist 'Lucrin/Leuprolide'*** *(suppresses LH, FSH release)* aims to *maximise max adult height* (biggest benefit when started \<6yo) - **_PERIPHERAL_** (not central/HPA axis driven; **low FSH and LH**; driven by **elevated oestrogen or testosterone** **or adrenal androgens**) - -\> Andrenal: CAH (virilising), adrenal tumour (feminising) - -\> Gonadal: ovarian or testicular tumour (oestrogen of HCG producing) - -\> McCune-Albright syndrome (coast of maine lesion, bony fibrous dysplasia) - -\> Hypothyroid Tx: Removal of any cysts/tumours excreting hormones; Tamoxifen (partial estrogen receptor antagonist) or Ketaconazole in boys (androgen antagnoist)
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Indications for treatment with growth hormone CI
GH deficiency Intracranial lesion or cranial irradiation - at 12 months in remission Turner syndrome Prader-Willi infants \<2years old (improves body composition) Chronic renal disease Short and slow growth (\<1st centile) CI - Diabetes mellitus - Risk of malignancy (downs syndrome, bloom syndrome) - Active malignancy
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What is the absorbance of Ca in the gut and what factor improves this?
20-30% absorbed via GIT Vitamin D improves absorption
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Phosphate - roles
Makes up CaPh in bone matrix Buffer for H+ Component of DNA, RNA, aa etc Reabsorbed in PCT Na/Ph cotrasnporter Regulated by PTH (increases excretion)
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Ca: Where is it reabsorbed What is it regulated by?
Roles - Ca-phosphate bone matrix (99%) - muscle contraction - enzyme activity - blood coagulation - releasing NT Reabsorption - Ca reabsorbed mostly in PCT, along with Na - Thick ascending limb via paracellular pathway - Intestine Regulation - PTH -\> incr reabsorption in gut and kidneys, incr Ca bone resorption, incr vit D synthesis in kidneys - Vit D -\> incr calcium reabsorption in gut - Calcitonin -\> inhibits Ca reabsorption
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Magnesium Roles Sites of reabsorption
Roles - Strengthens bone matrix - Cofactor for glucose and fat breakdown, antioxidant production, enzymes/proteins, DNA/RNA synthesis, regulation of cholesterol production Reabsorption 30% reabsorbed in PCT 60% reabsorbed in TAL via paracellular pathway
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What things can falsely elevated Ca levels?
``` Low pH (acidosis) Albumin ``` These things free Ca from being bound to protein (ie increase free ionised calcium levels which are measured)
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Causes of TRUE hypercalcaemia
``` HIGH PTH, high Ca, low Ph: Primary hyperparathyroidism (hypoplasia or adenoma; men 1 and II) ``` Ectopic PTH from tumour Low PTH, high Ca, high Ph: Malignancy (leuk/lymph, solid tumours w mets, renal tumours, adenomas) -\> releases parathyroid hormone which stimulates osteoclasts to release Ca into blood -\> lytic bone lesions Excess vitamin D -\> excess Ca absorption in GIT Medications - thiazide diuretics: incr Ca reabsorption in distal tubule Genetic - Familial hypocalciuric hypercalcaemia (PTH inappropriately normal, AD, asymptomatic) - Williams syndrome (sensitive to vitamin D) In neonates - fat necrosis (w birth trauma) - Transient neonatal hyperparathyroidism (mo who are hypoparathyroid) - Neonatal hyperparathyroidism 13q13 (inactivation of PTH receptor so hard to detect Ca levels)
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Hypercaemia - clinical signs/sx
'Stones (renal), bones (pain), abdominal moans (peptic ulcers) and psychiatric groans (confusion, delirium, seizures) Slows neuronal transmission: - Sluggish reflexes - Constipation - Generalised muscle weakness - Confusion, hallucination - Seizures Cardiac: Tachycardia, HTN, AV block, shortening of QTc, cardiac arrest Causes hypercalciuria -\> loss of fluid -\> dehydration -\> Ca oxalate kidney STONES Can also cause nephrogenic DI from nephrocalcinosis Bones: chonedrocalcinosis, subperiosteal bone erosions
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Causes of true hypocalcaemia
Low PTH (hypoparathyroidism) - -\> autoimmune destruction of parathyroid gland - -\> surgical removal of parathyroid gland - -\>- DiGeorge Syndrome (hypoplastic/absent parathyroid gland) - -\> Mg deficiency (required for PTH production) - High PTH - -\> Pseudohypoparathyroidism - -\> Rickets: Low vitamin D levels (required for GIT reabsorption), excessive urinary Ca excretion - Kidney failure - poor reabsorption so Ca is excreted in urine - Excess Phosphate intake (binds to Ca, precipitates in urine) - Tissue injury (burns, rabdo, TLS) - Acute pancreatitis (FFA bind to Ca, causing precipitation in urine) - Too many blood transfusions (chelation of blood products binds to Ca, compound is inactive) In neonate - prematurity - growth restricted - infant of diabetic mother - mo who is vitamin D and/or Mg deficient - Mo who is hyperparathyroid - Transient PTH resistance - Transient hypoparathyroidism - Primary hypoparathyroidism
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Clinical effects of Hypocalcaemia
- Tetany - Trousseau's sign [tetanic spasm of hands and wrist from inflated BP cuff for 3-5mins \>15mmHg above SBP; sensitive and specific (1% false positive)] - Chovstek's sign (facial spasm from tapping facial nerve in front of ear) - Muscle cramps - Parasthesias - Abdo pain - Periorbital tingling - Seizures - CV: prolonger QT, arrhythmia (torsades de pointes)
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Tx hypocalcaemia
1. Treat underlying cause 2. Vitamin D +/- Mg supplementation 3. Consider Ca supplementation - Oral Ca carbonate or Ca gluconate if mild-moderate - IV only if severe/sympomatic - \> IV ca gluconate or ca chloride - \> require telemetry to monitor for arrhythmias
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Pseudohypoparathyroidism Cause Ix Phenotype Vs pseudopseudohypoparathyroidism
PTH resistance due to genetic defect in hormone receptor adenylate cyclase system Is a cause of low Ca with elevated PTH and Phosphate, elevated ALP Several types 1A- Albrights hereditary osteodystrophy (most common) 1B 1C 2 Phenotype: - obesity, short stature, stocky with round face - shortening of 4/5th metacarpals - subcutaneous Ca deposits - skeletal deformities (bowed legs, short wide phalanges) - tetany, stridor, convulsions - IUGR - dev delay and ID VS pseudopseudohypoparathuroidism - same phenotype but NORMAL BIOCHEMICAL PARAMETERS (Ca, Ph, ALP, PTH)
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Albrights hereditary osteodystrophy What is its other name? Genetics, causes Ix Assoc
Pseudohypoparathyroidism type 1A - Most common type of pseudohypoparathyroidism Genetics - Autosomal dominant - Gene mutation of GNAS1, usually sporadic, imprinting condition Cause - Results in PTH resistance in renal tubules - \> Ca excretion -\> hypocalcaemia, high Ph Assoc - Also get resistance to other hormones (TSH -\> hypothyroid w goitre; LH/FSH -\> menstrual irregularity, reduced fertility, cryptorchidism; GnRH -\> GH deficiency)
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Causes of Rickets
Calcipenic: ca absorption \< Ca demand 1. Vitamin D deficiency (most commonly) or hereditary resistance 2. Calcium deficiency (in setting of normal vit D) Phosphopaenic: almost always caused by renal ph wasting - Presentation: short with PROFOUND skeletal bowing 1. Genetic familial hypohosphataemic rickets (x-linked dominant) - defective prox tubular reabsorption of Ph with reduced 1,25OHD3 synthesis 2. Inadequate intake (prep, antacids) 3. Renal losses - fanconi - distal RTA - dent disease (similar to fanconi)
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Renal fanconi
Waste Phosphate in urine -\> rickets Glycosuria Aminoaciduria Tubular proteinuria Proximal RTA Waste bicarb in urine -\> acidaemia Hypokalaemia (due to secondary hyperaldosteronism)
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Causes of undervirilised 46XY (male)
1. Disorders of testicular development - Gonadal agenesis/dysgenesis - Denys-drash syndrome (WT1 mutation) - WAGR syndrome - SRY gene mutation 2. Deficiency of testicular hormones - CAH - -\> 3 beta hydroxysteroid dehydrogenase deficiency - -\> - 17 hydroxylase deficiency - LH receptor mutation - Persistent mullerian duct system 3. Defect in androgen action - 5 alpha reductase mutations (normally converts testosterone to dihydrotestosterone so get DHT deficiency with excess estrogen) - Androgen R defects (androgen insensitivity)
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Causes of overvirilised 46XX (female)
1. Androgen excess - CAH - -\> 21-hydroxylase deficiency \*most common cause\* - -\> 11beta hydroxylase deficiency) - Aromatase deficiency (can't convert testosterone to oestrogen) - GC receptor gene mutation - Virilising ovarian or adrenal tumour - Androgenic drugs (progesterone, danazol) 2. Disorders of ovarian development (hermaphroditism) - Ovotesticular DSD (born with both ovaries and testes) - Testicular DSD (SRY region usually on Y chromosome translocated to X chromosome resulting in male phenotype w male internal and external genitalia in a 45XX individual)
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5 alpha reductase deficiency what is it inheritance presentation
Cause of undervirilised XY Dihydrotestosterone deficiency, elevated testosterone which is converted to estrogen instead of dihydrotestosterone Have elevated testosterone and low DHT autosomal recessive Presentation: 46XY, bilateral testes (and internal male urogenital tract leading into blind-ending vagina) Female external genitalia (may have clitoromegaly)
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What is ovotesticular DSD
'true hermaphroditism' presence of both functional ovary and testis
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What is testicular DSD, what causes it? Presentation features
**XX genotype** _SRY region_ usually on Y chromosome _translocated to X chromosome_ resulting in **male phenotype w male internal and external genitalia** in a 45XX individual Features * male external genitalia ranging from normal to ambiguous * two testicles * azoospermia * absence of müllerian structures * Approximately _85%_ of individuals with nonsyndromic 46,XX testicular DSD _present after puberty_ with normal pubic hair and normal penile size but **small testes**, **gynecomastia,** and **sterility** resulting from azoospermia. * Approximately _15%_ of individuals with nonsyndromic 46,XX testicular DSD _present at birth_ with **ambiguous genitalia**. Gender role and gender identity are reported as male. If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency
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Alopecia areata - what is it - pathophys - associations
- An autoimmune condition characterised by a rapid and complete loss of hair in round or oval patches on the scalp and on other body sites - Autoimmune lymphocytes react against hair follicles, all patients have autoantibodies to hair follicle antigens - Assoc w other autoimmune conditions, atopy, nail changes, cataracts
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what is a barr body?
Inactive ('silenced') x chromosome in a cell with more than 1 x chromosome (XX, YXX, XXX) Inactivation occurs early in embryonic life
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Idiopathic Precocious puberty What is it characterised by?
Premature but otherwise normal appearing pubertal development in GIRLS (is as a rule almost always pathological in boys) Girls develop breasts and have an early growth spurt (before age 8) with advanced bone age compared with chronologic age These children have pubertal levels of FSH, LH and sex hormones.
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Presentation of GH deficiency in neonates
FTT Hypoglycaemia Sparse hair Prominent forehead Delayed bone age Micropenis Small facies w hypo plastic nasal bridge Delayed eruption of dentition
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What is sick euthyroid syndrome What changes occur to TSH, T3, T4 Tx
Disturbance of thyroid function in the settling of non-thyroidal illness (usually severe illness). Can also occur in fasting, chronic malnutrition and with some drugs. Often presents with LOW T3 secondary to inhibition of thyroxine 5’ deiodinase +/- low or high T4 Low or high TSH Tx- treat underlying illness. No indication for Thyroxine replacement.
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APECED
Autoimmune polyendocrinopathy AIRE gene AR disorder Type 1 presents 1st decade of life 1. First presents with chronic mucocutaneous candidiasis before progressing to 2. hypoparathyroidism 3. Addison’s disease Type 2 presents 2nd-3rd decade of life 1. Addisons disease 2. Thyroid disease 3. Diabetes (T1DM)
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osteogenesis imperfecta
- 'brittle bone disease' - 90% AD genetic disorder - lack of type 1 collagen due to mutations in **COL1a1 or col1a2** genes - 10% rare AR mutations - Results in bones that break easily - Sx: brittle bones, short stature, blue sclerae, loose joints, hearing loss, aortic dissection -Tx: lifestyle changes, PT, braces, metal rods through long bones ? bisphophonates
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Mechanism of action of thiazolidinediones
Bind avidly to peroxisome proliferator-activated receptor gamma in adipocytes to promote adipogenesis and fatty acid uptake (in peripheral but not visceral fat) Increases insulin sensitivity (decr resistance)
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Fanconi syndrome What is it What serum changes does it cause What causes this
RTA type 2 (impaired proximal tubular function) Bicarb wasting in urine -\> serum acidosis Also waste: Ph, glucose, uric acid and aa in urine -\> low serum levels of these compounds Leads to rickets (phosphopenic) Causes - cystinosis - wilson's disease - hereditary fructose intolerance
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McCune-Albright syndrome ('MAS') Classic triad Pathophys/cause
Triad of 1. precocious puberty 2. patchy hyperpigmentaion (~irregularly outlined cafe au lait with 'coast-of Maine' border) 3. fibrous dysplasia of bone Other - arrhythmias - hepatitis - intestinal polyps Pathophys/cause: Patients with 'MAS' have a somatic mutation of the alpha subunit of the G3 protein that activates adenylate cyclase (cAMP). This mutation leads to continued stimulation of hormone RECEPTORS Ie have low levels of the actual hormones (ACTH, TSH, FSH, LH) but overstimulation of receptors leading to: - \> Precocious puberty - \> Gigantism - \> Cushing syndrome - \> Adrenal hyperplasia - \> Thyrotoxicosis
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Presentation of glycogen storage disease in neonate
- Profound neonatal hypoglycaemia, although more often presents at three-four months of age when feeding becomes less frequent. - Hepatomegaly is often massive - Ketosis is usually present - glucose requirement to maintain normoglycaemia is NOT usually elevated in these infants, with normal requirement being 4-6 mg/kg/min of glucose.
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Hyperinsulinaemia - causes - presentation
- suspected when neonates with hypoglycaemia have an elevated glucose requirement to maintain normoglycaemia, with a requirement \>8mg/kg/min being one of the diagnostic criteria - large for GA - mild hepatomegaly Causes - maternal GDM - inherited (1/50000) - arabic, jewish descent are high risk
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Fatty acid oxidation disorder - presentation
- symptomatic hypoglycameia after prolonged period of fasting, typically presenting in infants or toddlers. - Once glycogen is consumed, these children have an impaired ability to break down fatty acids to form ketone bodies, but no increased glucose requirement for correction.
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Diazoxide - Use - MOA
- Mgmt of neonatal hyperinsulinaemic hypoglycaemia - Acts to inhibit insulin release by opening ATP-dependent potassium channels on pancreatic beta cells in the presence of ATP and Mg2+, resulting in hyperpolarization of the cell
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Phases of puberty (in order) for female
1. Breast development (thelarche) is usually the first sign of puberty (10–11 years) 2. Appearance of pubic hair (adrenarche) 6–12 months later 3. Peak height velocity occurs early (at breast stage II–III, typically between 11 and 12 years of age) in girls and always precedes menarche The interval to menarche is usually 2–2.5 years but may be as long as 6 years The mean age of menarche is about 12.75 years
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Phases of puberty (in order) for male
1. Growth of the testes (\>3 mL in volume or 2.5 cm in longest diameter) and thinning of the scrotum are the first signs of puberty 2. Followed by pigmentation of the scrotum and growth of the penis 3. Pubic hair then appears, axillary hair usually occurs in midpuberty 4. Acceleration of growth maximal at genital stage IV–V (typically between 13 and 14 yr of age
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Androgen insensitivity syndrome
- 46XY with testes present - Normal to elevated testosterone levels - HIGH LH/FSH - X-linked inheritance Phenotype varies: 1. Complete androgen insensitivity syndrome (CAIS) - Typical female external genitalia 2. Partial androgen insensitivity syndrome (PAIS) - Predominantly female, predominantly male, or ambiguous external genitalia 3. Mild androgen insensitivity syndrome (MAIS) - Typical male external genitalia bur infertility
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Williams syndrome Features
Elfin facies Supravalvular aortic stenosis HTN intellectual disability Cocktail party manner Hypercalcaemia and hypercalciuria thought to be due to elevated vitamin D or incr vit D sensitivity May get nephrocalcinosis
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What medication used to treat hypothyroid has SE of liver failure (and thus is not often used in children)?
PTU
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Russel Silver Sydrome
Methylation defect chromosome 11 Overexpression of maternal genes Dx - clinical +/- genetics Prominent forehead Triangular face Downturned corners of mouth Short stature/IUGR: Small with relatively large head compared w rest of body Hemihypertrophy Hypoglycaemia Hypotonia Mild dev delay Tx - may respond to GH treatment Pneumonic S - small for GA I - imprinting defect L - triangLe shaped face F - feeding difficulties E - unEven (hemigypertrophy) R - relatively large forehead
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AMH deficiency in males
XY karyotype with normal male external genitalia Perseverance of female ovarian organs as Anti-mullerian hormone (secreted by sertoli cells) -\> regression of mullerian structures In other words... External virilization is complete but, due to AMH deficiency, müllerian ducts do not regress and coexist with testes and male excretory ducts.
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What is the main stimulus for secretion of PTH
Ionised calcium level
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Kleinfelter syndrome
XXY (can have XXXY) Non disjunction of sex chromosomes in male or female foetus Clinical features - Tall stature - Normal or low intelligence/learning difficulties - Cardiac: mitral valve prolapse - Incr risk of extragonadal germ cell tumours - gynaecomastia - primary hypogonadism so testicular origin (small testes/penis from puberty on, reduced virilisation) Mx - consider testosterone replacement when LH and FSH start to rise in puberty aromatase inhibitors to treat gynaecomastia
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11 beta hydroxylase deficiency
Type of CAH (rare) Also have decr cortisol and aldosterone Hypertension due to build up of DOC (precursor of aldosterone, more mild form of it) Also get hyperkalaemia Hypoglycaemia
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What is the most common cause of neonatal hyperthyroid disease? How do these babies present What is tx
Neonatal graves disease - Are classically premature, born to mothers who have hx of graves disease, on anti-thyroid medications - Due to transfer of maternal TRAb Ab across placental membrane (maternal hx graves disease) - targets TSH R (T2 HS reaction) Presentation - IUGR - Goitre - Exopthalmous - Microcephaly - Irritable, hyperalert - Tachycardia, tachypnoea - Hyperthermia/fever - Jaundice - HTN - Progression to cardiac decompensation Ix: Incr T3, T4; Decr TSH; anti-TRab antibodies Tx - Beta blocker - Carbimazole or PTU - Iodide +/- steroids (blocks conversion of T4 to T3)
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Albrights osteodystrophy
- Pseudohypoparathyroidism type 1a (PHP1a) - Short stature - Obesity - Round face - Subcutaneous ossifications (formation of bone under the skin) - Short fingers and toes (brachydactyly) - particularly the 4th and 5th MC
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What is pseudohypoparathyroidism
resistance to PTH high levels of PTH and Ph Low levels serum Ca and vitamin D (calcitriol)
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Hypothalamic-pituitary axis: hormones secreted
Hypothalmus -\> anterior pituitary -\> target tissue 1. GnRH -\> Lh + FSH -\> ovaries, testes 2. GHRH -\> GH -\> many tissues 3. Dopamine -\> breasts, gonads inhibits prolactin 4. TRH -\> TSH -\> thyroid T3, T4 5. CRF -\> ACTH -\> adrenals cortisol Hypothalmus -\> post pituitary 6. Vasopressin -\> ADH -\> kidneys (collecting duct) 7. Oxytocin -\> Oxytocin -\> breasts \*Note to remember hormones released from ant pituitary: FLAT PiG FSH LH ACTH TSH Prolactin GH
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Which tumour type is known to cause gigantism?
Pituitary MICROadenoma (ie very small, most skull X-rays are normal) - \> very rare - \> excessive GH secretion Presentation - \> if before growth plate closure (12 girls/14 boys) -\> gigantism/tall stature - \> if after growth plate closure -\> acromegaly (hands, feet, face) - deficiencies in other pituitary hormones leads to: - \> hypogonadism and delayed puberty - \> hyperprolactinaemia - \> Diabetes mellitus (GH is diabetogenic, leads to glucose production in liver)
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What analogue can be used to suppress GH secretion?
Octreotide (synthetic somatostatin analogue)
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Teenage girl presents with headache, nausea and vomiting and galatorrhorea. Also has not yet had her period. What is the diagnosis?
Prolactinoma - \> most common pituitary tumour occurring in adolescnece - \> Presents in teenage girls with headache, bitemporal hemianopia, nausea, vomiting, galactorrhoea, amenorrhoea, hypogonadism, delayed puberty and hypopituitarism Ix: prolactin level \> 2000 (extremely high) Also test for other pituitary hormones Mx: 1. Medical : - \> Bromocriptine and Cabergoline: DA agonist -\> can reduce tumor size by inhibiting the synthesis and secretion of prolactin, and inhibiting angiogenesis in the surrounding tissue 2. Surgical excision
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Order of hormone loss in hypopituitarism (ie with invasion or compression by lesion)
1. GH most commonly lost first 2. FSH/LH 3, TSH 4. ACTH
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Causes of hypopituitarism
Generally deficiency in anterior pituitary hormones over posterior pit. hormones (GH \> FSH/LH \> TSH \> ACTH) Congenital - Septo-optic dysplasia (HEX1 mutation/De Morsier's) - Kallman syndrome - Genetic GHRH or GH deficiency' - Holoprosencephaly, anencephaly - Empty sella syndrome Destructive: - Neoplastic infiltration or compression (Craniopharyngoma, adenoma, meningioma, glioma, secondary deposits) - Infective (Tb, meningitis, encephalitis, toxoplasmosis) - Traumatic (post radiotx, post-op, NAI, traumatic delivery) - Infiltrative (LCH, haemochromatosis, sarcoid) Functional: Neglect, AN, starvation
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Infant with visual impairment, nystagmus and GH deficiency Hex1 mutation What is this condition and what are the diagnostic features?
De Morsier's syndrome or septo-optic dysplasia Diagnosis requires 2/3 (req MRIB and hormone levels): 1. underdevelopment of the optic nerve (optic nerve hypoplasia) 2. hypopituitarism (GH 70%, severe cases may have panhypopituitarism) 3. absence of the septum pellucidum (a midline part of the brain)
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SiADH - What is it - Serum and urine ix findings - Causes - Cx if untreated - Tx
Excessive ADH secretion -\> Increased renal reabsorption of water Ix - \> Reduced serum osmolality - \> HYPONa - \> Normal-Increased urine concentration/osmolality - \> Inappropriately high urine Na Causes - CNS: meningitis, encephalitis, head trauma, brain abscess, asphyxia, IVH, subdural haematoma - Infx: rotavirus, HIV, Tb - Tumours: brain tumours, lymphoma, thymic cancers, ewing sarcoma - Lungs: pneumonia, abscess, CF - Metabolic: acute intermittent porphyria - Drugs: carbamazepine, vincristine, cyclophosphamide, morphine, TCAs Cx - Cerebral oedema -\> nausea, vomiting, irritability, seizures, coma Tx - Fluid restriction (2/3 maintenance)
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Differentials for hyponatraemia
1. Systemic dehydration (fluid loss -\> hyperNa -\> incr ADH secretion -\> hyponatraemi) 2. Salt losses - \> GIT (gastroenteritis), - \> kidneys (AIN, CRF, PCKD) - \> skin (CF) 3. SiADH (hypoNa, decr plasma osm, incr urine osm & Na) 4. Cerebral Na loss sec to CNS disorder/trauma (due to hyper secretion ANP -\> incr urine Na and output -\> hypovolaemia) 5. Primary polydipsia (incr water retention) 6. Hyperglycaemia (fluid shift out of cell -\> dilutional effect)
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Relative strength of steroids
``` Cortisol/hydrocort = 1 (IV hydrocort, most potent) Pred = 4 (tablet, mid-potency) Dex = 25 (cream for eczema, least potent) ```
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Roles of aldosterone
Production is stimulated by RAAS system -\> stimulates CRH release from hypothalamus -\> ACTH release from ant pit -\> aldosterone release from adrenal gland zona glomerulosa Function: - Increase Na+ and water retention -\> incr BP - Lower plasma K+ concentration - Secretion of H+ into tubules (incr serum pH)
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Role of ANP
Atrial natriuretic peptide - \> Released in response to incr stretch of atrial walls (indicating high BP) - \> Acts acutely to lower BP via 3 mechanisms: 1. Increased renal excretion of salt and water 2. Vasodilation 3. Increased vascular permeability
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What does the NST detect in regards to thyroid disease What false negatives are possible
Detects high TSH as a marker for primary hypothyroidism (thyroid gland dysfunction) DDX - Congenital hypothyroidism - Atrophic autoimmune thyroiditis - Hashimoto thyroiditis - Iodine deficiency False negatives with - sick euthyroid - prematurity - secondary or tertiary hypothyroidism (as TSH will be low)
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What causes a goitre
Increased pituitary secretion of TSH in response to decr circulating levels of thyroid hormone In Graves is due to Anti-TRAb stimulating the TSH receptor Also infiltrative disease, inflammation/infection adn neoplasms
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Role of calcitonin
Produced by C cells in thyroid gland in response to high serum Ca Acts to LOWER serum Ca and Ph via 1. Inhibits osteoclasts = incr bone mineralization 2. Renal Ca excretion 3. Renal Ph excretion
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ECG signs of HYPOCa
Prolonged QTc Arrhythmia (torsades de pointes)
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PCOS presentation ix mx
Presentation: Adolescent girl Acne Menstrual irregularities or secondary amenorrhoea Obesity Hirsutism Insulin resistance USS - large polycystic ovaries Increased circulating androgens (testosterone N/incr, LH incr, FSH decr or N) -\> High LH:FSH ratio Mild hyperprolactinaemia Mx - OCP or cyproterone (anti androgen) - Pred (pituitary ACTH suppression)
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Persistent hyperinsulinaemic hypoglycaemia of infancy - what is it? - tx?
Developmental disorder where there are hyper plastic abnormally dispersed pancreatic beta cells resulting in inappropriately HIGH levels of plasma insulin \*REQUIRE extremely high rates/doses of glucose infusions during periods of hypoglycaemia/fasting\* Tx- diazoxide and thiazide diuretic second line tx is w octreotide and/or glucagon
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What is ketotic hypoglycaemia?
Children between 18mo-5years presenting with hypoglycaemia (+/- difficult to rouse in morning, coma, seizure) in setting of a prolonged fast/illness/missed meal Essentially these children have low muscle mass and are unable to tolerate a fast due to low substrate availability Ix - hypoglycaemia with appropriate ketonaemia, ketonuria, low plasma insulin
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Addisons disease
Autoimmune primary adrenal insufficiency - most common cause for primary adrenal insufficiency in developed world FT - \> low cortisol and aldosterone - \> high plasma renin activity - \> high ACTH and CRH - \> hyponatraeamia, hyperkalaemia Causes - Most common cause in developed world is autoimmune destruction (incr levels of serum anti-adrenal Ab (anti 21 hydroxylase) = Addisons disease
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MEN gene - I vs II; inheritance
Multiple endocrine neoplasia AD gene - assoc w number of endocrine tumours I - not as nasty. parathyroid, pituitary (prolactin, GH, ACTH), pancreas IIa - nasty. pheochromocytoma, thyroid medullary carcinoma (nasty; prophylactic thyroidectomy if child is known to carry the gene) IIb - same as IIa but marfanoid features + multiple neuromas
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What does bone age tell you? How do you assess the bone age?
Bone age = skeletal maturity Tells you how far the skeleton has matured and gives you an idea of potential height and the cause of short stature Assess bone age via LEFT HAND/WRIST XR (L Knee X-ray if \<2yo) -\> Assess the number of epiphyseal centres (rate of ossification) Compare bone age with chronological age -\> Bone age \> chronological age = Advanced bone age -\> Bone age \< chronological age = Delayed bone age Delayed bone age in the ABSENCE OF PATHOLOGY = slow maturation = more potential growth
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Causes of Advanced bone age
Bone age \> chronological age = Advanced bone age Causes of advanced bone age - Growth advance - Precocious puberty - Excessive androgen production - Hyperthyroid
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Causes of Delayed bone age
Bone age \< chronological age = Delayed bone age Causes of Delayed bone age - Familial delayed maturation - Delayed puberty - Severe illness - Hypothyroid - GH deficiency
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Causes of delayed puberty
Failure of onset of any signs of puberty by 13 yrs (F) or 14 yrs (M) \*Most common in boys\* - cause usually constitutional delay (short stature, delayed puberty, fhx) CAUSES of Secondary (central) hypOgonadotrophic (Low LH, FSH and low testosterone) - Constitutional/familial or sporadic - HPA - -\> Panhypopituitarism - -\> GnRH deficiency - -\> Kallman syndrome - -\> Intracranial tumour (prolactinoma) - Hypothyroidism - Systemic disease - -\> Chronic disease eg: renal failure - -\> Malnutrition - -\> AN, psychosocial etc CAUSES of Primary (peripheral) hypERgonadotrophic (High LH, FSH and low testosterone) - Chromosomal - -\> Kleinfelter's 47XYY (most common cause of delay and infertility in males) - Steroid hormone enzyme deficiency - -\> CAH (3beta hydroxysteroid dehydrogenase deficiency) - Gonadal dysgenesis - -\> Turner syndrome 45XO - -\> CF - -\> Noonan syndrome - -\> Congenital anarchia (absence of testes in phenotypic male) - Gonadal disease - -\> Chemo/radiotherapay - -\> Trauma - -\> Torsion - -\> DXT
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What is the role of Mg in Ca homeostasis
Magnesium is required for secretion as well as action of PTH Therefore, hypomagnesaemia causes hypocalcemia refractory to correction unless magnesium is normalized.
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What blood test results would indicate infertility vs pubertal failure in a child with kleinfelters?
**Inertility = Sertoli cell failure:** High FSH Due to loss of sertoli cell negative feedback Also would have LOW inhibin B (released from sertoli cells) Vs delayed puberty = leydid cell failure would be represented by high LH. At this stage would start testosterone supplements (monitor LH ~yearly)
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How do you investigate for 1. GH excess 2. GH deficiency
?GH excess 1. OGTT - GH should be suppressed after administration of OGTT. If it isn't, indicates GH excess ?GH deficiency 1. Look at heigh velocity as screening test - if \>/= 25th centile, you can r/o growth failure 2. If low, go on to do GH stimulation test (adminsiter arginine, clonidine, glucagon or insulin). If you have 2x GH peaks \<5=, confirms GH deficiency
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Which sex hormone is predominantly responsible for growth cessation?
Estrogen - responsible for skeletal maturation and closure of growth plates. Deficiency of estrogen leads to prolongued growth, tall stature due to delayed closure of growth plate.
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Effect of hypothyroidism on growth
Delayed bone age due to delayed maturation of bone and growth Leads to cessation of growth and short stature Thyroixine supplementation enables catch up growth and ability to reach predicted/target height
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When should you suspect an endocrine problem in an obese child? Differentials
Suspect endocrine when weight/obesity increasing but _height static_ (as generally obesity drives vertical height growth as well) DDX * Hypothyroidism * GH deficiency * Cortisol excess (Cushings)
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Mid parental height calculation Significance of this
Boys: Dad height + (mums height +13cm) /2 Girls: (Dad height - 13cm) + mum's height / 2 Child's height should be within 8cm either side of mid parental height (if familial short stature)
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Calculation and clinical significance of height velocity
Height velocity differentiates normal variant short stature from pathological short stature (slow HV) HV = (difference in height between 2 measurements/time between measurements in months)\*12 Should be calculated over 6-12mo interval of time NORMAL HV lives within 25-75th centile Pathological short stature has HV \< 25th centile Normal variant short stature has 2 main causes, both with NORMAL HV 1. Familial short stature has normal bone age (\<1 yr of CA) - final height short 2. Constitutional delay of growth and developemnt has delayed bone age - final height is normal. also delayed puberty.
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What fracture types raise suspicion for pathological fracture?
Vertebral fractures - common presentation of ALL Tibial fracutres
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Osteoporosis in children: reduced bone mineral content for height and weight \<2 SD below mean **Causes** * CF * IBD * Asthma * CP * Epilepsy * Coeliac disease * Organ transplant * Hypogonadism