Endocrinology Flashcards
1
Q
46XX disorders of sexual development
A
masculinisation external genotypic female from androgen exposure wk 8-13 gestation
1. P450 def (21 hydroxylase)
2. 3b-hydroxysteroid dehydrogenase def
3. P450 def (11 hydroxylase)
4. Mixed gonadal dysgenesis 46XY/45X
2
Q
46XY disorders of sexual development
A
Inadequate masculinisation in male
- P450 def
- 3b hydroxysteroid dehydrogenase def
- Dysgenetic tests
- Complete/partial androgen insensitivity
- 5a reductase deficiency
3
Q
5 alpha reductase deficiency
A
46XY DSD
Converts testosterone to DHT
DHT 20X potency
Clinical: ambiguous genitalia, external feminization, internal male, virilization at puberty, minimal pubic hair
Investigations: high testosterone, no DHT
Diagnosis: HCG stimulation test
4
Q
Acquired goitre
A
Usually sporadic
Usually euthyroid
Causes: subacute thyroiditis, iodide goiter, amiodarone, lithium
5
Q
ACTH Synacthen test
A
use: to check adrenal insufficiency
method: administer ACTH and check cortisol response
diagnostic:
- primary (Adrenal) cause: no change in cortisol after ACTH
- secondary (Pituitary) cause: cortisol will increase after ACTH
2 types: short and long synacthen tests
- short: inject IM ACTH and measure cortisol at 0, 30mins and 60mins post
- long: uncommonly used. ACTH IV over 8hrs
6
Q
Addison’s Disease
A
pathogenesis: AI destruction adrenal cortex
primary adrenal insufficiency: absent mineralocorticoid/glucocorticoid
- hyperpigmentation, high potassium/renin
- low BP/glucose/sodium
- anorexia, weakness, shock, amenorrhoea, arthralgia, poor mood, vitiligo
secondary adrenal insuff: no hyperpigmentation/hydration, hypoglycaemia more common
hyperpigmentation: due to pro-hormone cleaved into ACTH and melanocyte stimulating hormone (MSH)
investigations: low cortisol
associations: Autoimmune Polyglandular Syndromes APS I and APS II
treatment: hydrocortisone/fludrocortisone
7
Q
Anatomy
A
8
Q
Adrenal deficiency
- aldosterone
A
symptoms: salt craving, vomiting, hypotension, shock, FTT, diarrhoea, weakness
electrolyes: hyponatraemia (salt wasting), hyperkalaemia, acidosis
9
Q
Congenital adrenal hypoplasia/adrenal haemorrhage
A
all adrenal steroids LOW
10
Q
Adrenal insufficiency
- Cortisol
A
clinical:
- hypoglycaemia
- poor stress response
- vasomotor collapse
- hyperpigmentation
- apneic episodes
- muscle weakness/fatigue
11
Q
Adrenocortical tumours
A
Most benign and secrete nothing
1. Adenomas
- most commonly cortisol but also aldosterone
- androgen secreting adrenal tumours secrete testosterone usually malignant
2. Carcinomas
- rare, usually malignant
- 50% present with Cushing’s, 25% Cushing’s and virilization
12
Q
Aldosterone
A
class: mineralocorticoid hormone
source: secreted zona glomerulosa
action: Na/Cl reabsorption in DT/CD and excretion K/H
control: via RAS, ACTH enhances production, Plasma K/H
increase: High K/Low Na, Loss of ECF, anxiety, primary hyperaldosterone (Conn’s syndrome), secondary hyperaldosterone, RAS, constriction of IVC
decrease: Elevated Na, adrenalectomy
investigations:
- ?HIGH: 24hr urine collection
- ?LOW: early AM cortisol
13
Q
Androgen insensitivity
A
46 XY
normal feminization, absense of pubic hair, primary amenorrhoea
all mullerian structures lacking and intraabdominal testes
14
Q
Androgen insensitivity syndrome
A
incidence: 1:20,000 (most common form of male DSD)
karyotype: 46XY
mechanism: X linked mutation androgen receptor gene
clinical: female external genitalia, blind ended vagina, no uterua
- no pubic hair, no menarche, male height
investigations: high LH/FSH/oestradiol
15
Q
Autoimmune Polyendocrine Syndrome Type 1
A
TRIAD
1. polyendocrinopathy
- 90% hypoPTH before 3 yrs
- 90% AI adrenal insufficiency by 6 yrs
2. chronic candidiasis
3. ectodermal dystrophy
(30% have all 3 symptoms)
other: immune def (Ecoli sepsis), DM1, hypogonadism, pernicious anaemia, vitiligo
clinical: 1st candidiasis, 2nd hypoparathyroidism, 3rd addison’s disease
16
Q
Insulin therapy goal BGLs
A
<5yrs: 4.5-10mmol/L
5-10yrs: 4.5-8.5mmol/L
>10yr: 4-7mmol/L
17
Q
Biguanide
A
drug: metformin
mechanism:
- reduced hepatic glucose production
- increased peripheral glucose utilisation
risks: NO risk hypoglycaemia, lactic acidosis (0.03/1000)
18
Q
Bound hormones
A
thyroid: albumin, TBG (most), thyretin
aldosterone: weak binding to albumin (1/2 life 20 mins)
testosterone/oestrogen: SHBG (44%), albumin (54%)
- SHBG binding: strongest dihydrotestosterone>testosterone>oestrogen
cortisol: transcortin
19
Q
CAH
11-hydroxylase deficiency
A
incidence: 1/100,000, 2nd commonest CAH (5%)
genetics: CYP11B1 gene Ch 8
pathogenesis: deficieny 11-hydroxylase enzyme prevents degradation 11-deoxycortisol/11-deoxycorticosterone
- normal aldosterone
clinical: virilization with salt retention, hypokalaemia, HTN (65%)
diagnosis: high 11-deoxycortisol/deoxycorticosterone, low renin
treatment: glucocorticoids
20
Q
CAH
21- hydroxylase deficiency
A
incidence: 1/15,000, 90% CAH
- non classical 1/1000 (normal aldosterone/cortisol)
genetics: ch 6, genes CYP21P/CYP21
pathophysiology: 21-hydroxylase deficiency impairs conversion 17-hydroxyprogesterone to 11-deoxycortisol causing aldosterone/cortisol deficiency
- salt losing 75% form also progesterone to deoxycorticosterone
- decreased cortisol causes increased ACTH and increased androgen production
clinical:
- onset 10-14 days
- virilization female genitalia/male no external
- salt wasting assoc shock/dehydration: hyponatraemia, hyperkalaemia, met acidosis, hypoglycaemia
diagnosis: ACTH stimulation test
- high 17-OHP/ACTH/renin/testosterone, low cortisol/aldosterone
treatment: hydrocortisone/fludrocortisone
21
Q
CAH
3 beta hydroxysteroid deficiency
A
incidence: 2% CAH
pathogenesis: impaired gonadal and steroid hormone synthesis and excess DHEA
clinical: salt wasting crisis, males hypogonadism, girls mildy virilised, precocious adrenarche
investigations: low cortisol/aldosterone/androstenedione, high DHEA
treatment: glucocorticoids/mineralocorticoids
22
Q
DKA cerebral oedema
A
incidence: 1-5% 6-12hr post commencing tx
mortality: 20-80%
cause: osmolar shift
risk factors: higher BUN conc, low pCO2, Na not increasing with tx, treatment with bicarb
treatment: IV mannitol
23
Q
Constitutional growth delay
A
variation of normal growth
pubertal delay 1.5-2yrs
delayed bone age
growth rate at lower limit of normal
history of family member
24
Q
Chronic mucocutaneous candidiasis
A
definition: chronic candida nails, mucosa, skin
cause: primary defect lymphocytes to candida
causes:
Autoimmune regulator deficiency (AIRE)
- gene: AR Ch21q22.3
- onset: 2 months-18 years
TRIAD
- mucocutaneous candidiasis
- hypoparathyroidism (most common assoc endocrinopathy)
- adrenal insufficiency (2nd most common endocrinopathy)
Autosomal dominant chronic mucocutaneous candidiasis
gene: defect STAT 1
1. mucocutaenous candidiasis
2. ONLY endocrinopathy is HYPOTHYROIDISM
25
Microvasc complications DM
**Microvascular complications**
- 98% retinopathy by 15yrs
- 20-30% nephropathy by 15yrs
**Strict glycaemic control (HbA1c\<7)**
- decreased microvascular complications by 40%
- increased hypoglycaemic events x3
- increased weight gain
26
Congenital goitre
**cause:** sporadic
**clinical:**
_hypothyroid:_ antithyroid drugs in pregnancy (iodides, amiodarone)
_hyperthyroid_: neonatal Grave's disease
_Pendred's syndrome:_ familial goitre, SNHL
27
Congenital hypothyroidism
1:2,000
Dysgenesis (85%): agenesis (1/3), aplasia or ectopic (2/3)
Dyshormonogenesis (15%) (disorder of intrathyroid metabolism) with goiter (1:30,000) indicates IEM in iodine or thyroid hormone biosynthesis or maternal antithyroid drugs
- defective thyroid iodination (10%): AR inheritance
Maternal autoantibodies (5%)
- 1:50,000
- passage maternal TRBAb inhibits TSH binding receptor
Clinical: normal weight/length, increased HC, hypotonia, increased fontanelles, lethargic, poor feeding, resp issues, prolong jaundice, constipation, oedema, hypothermia
Investigations: radioisoptope scanes
Treatment: oral thyroxine
Prognosis: late dx associated MR/growth retardation
28
Cortisol
**production:** zona fasciculata/reticularis of adrenal cortex
**stimulation:** triggered by ACTH, depression, stress, hypoglycaemia
**effect:**
- antagonises insulin: increased BGL
- increased gastric acid secretion
- decreased T cell proliferation
- reduced calcium absorption from gut
- inhibits loss of Na from intestine
- potassium excretion
- increased BP: increased sensitivity to adrenaline/noradrenaline
- antiinflammatory: decreased histamine secretion
29
Cushing's Syndrome
**definition:** elevated glucocorticoids
**causes**:
**_1. ACTH dependent_**
- cushing's disease
- pituitary hypersection ACTH by pituitary adenoma
- bilateral adrenal hyperplasia
- ectopic ACTH/CRH from non pit/hypo tumours
- exogenous ACTH
**_2. ACTH independent_**
- exogenous steroid
- adrenocorticol adenomas/carcinomas
- primary pigmented nordular adrenocortical disease
**clinical**: central obesity, failure growth, hirsutism, weakness, nuchal fat pad, acne, striae, HTN, hyperpigmentation, hyperglycaemia, osteoporosis
**investigations**: 24hr urinary cortisol, dexamethasone suppression test
**treatment:** resection pit adenoma (60-80% success), inhibitors of adrenal steroidogenesis, adrenalectomy
30
Defective bone mineralization
**Rickets:**
- nutritional, congenital, prematurity, Vit D resistance (type I, II), neoplastic rickets, hypophosphataemic rickets, drug induced
**Renal causes:**
- renal osteodystrophy, Fanconi's syndrom
**Tumour** induced osteomalacia
**Other:** hypophosphataemia, McCune- Albright syndrome, osteogenesis imperfecta
31
Delayed puberty
Constitutional delay 53%
Delayed but spontaneous 19%
Hypogonadrotrophic hypogonadism 12%
Hypergonadotropic hypogonadism 13%
32
Genetics DM1
**genes:** HLA on chromosome 6
- 90% HLA-DR3 or HLA-DR4
**inheritance:**
- no family hx 0.4%
- affected mother 2-4%
- affected father 5-8%
- both parents 30%
- sibling of affected patient 5%
- dizygotic twin 8%
- monozygotic twin 50%
**antibodies:**
- islet cell ab 80%
- ZnT8 ab 70%
- insulinoma-assoc protein 2 ab (IA-2) 58%
- glutamic acid decarboxylase (GAD) ab 20%
33
Diagnosis DM1
**One of the following:**
1. Fasting glucose\> 7mmol/l
2. Random glucose\>11mmol/l
3. 2hr glucose\> 11mol/l
4. HgbA1c\>6.5%
34
Diazoxide
**class**: K channel activator
**mechanism:** hyperpolarisations insulin producing cells beta islets
**use:** hyperinsulinaemia hypoglycaemia or resistant HTN
35
Diabetic ketoacidosis (DKA) criteria
**1.** ph \<7.3
**2.** bicarbonate \<15mEq/L
**3.** elevated ketones
36
DM1 associated autoimmune
More common DM expressing HLA-DR3
Thyroid disease (no 1 association)
- 20% anti-thyroid Ab
- 2-5% hypothyroid
Coeliac disease (no 2)
- 5% develop CD/gluten- sensitive enteropathy of SB
- 7-10% antiendomysial Ab or tissue transglutaminase Ab
Adrenal disease
- \<1% autoimmune adrenalitis
Polyglandular autoimmune syndrome type 2
37
DM2
Cause: increasing peripheral resistance to insulin mediated glucose uptake
RFs: obesity, positive family hx, female (1.3:1.7), LBW, GDM, puberty, PCOS
Clinical: DKA or ketonuria, hyperosmolar hyperglycaemia state
Diagnosis: fasting BGL\>7, random BGL\>11, HbA1c\>6.5
Treatment:
- metformin (biguanide): suppresses liver glucose output and increases insulin sensitivity muscle/fat
- thiazolidinediones: increase glucose utilization and decrease production
Comorbidities: HTN, dyslipidemia, Non alcoholic fatty liver disease
38
Endemic Goiter
Thyroid hypertrophy secondary to iodine deficiency
Mild deficiency: goiter during periods rapid growth
Moderate deficiency: goiter at school age
Severe deficiency: ~50% population goiters and endemic cretinism common
Endemic cretinism:
1) Neurologic type (ID, deaf-mutism, poor standing/gait, pyramidal sugns)
- due iodine/thyroid deficiency in utero affecting foetal brain development in the 1st trimester
Rx: iodine after birth causes normal thyroid function
2) Myxoedematous type (ID, deaf, neuro Sx, ALSO delayed growth and sexual development, myxedema, NO goiter).
- thyroid atrophy unclear why hypothyroidism persists post iodine administration ? selenium deficiency
Rx: IM iodinated poppy seed to women – adequate iodine for 5yrs of pregnancies, Iodination of water
39
Fetal thyroid
First 20 weeks: transplacental
Second 20 weeks: increased fetal T4 and hepatic thyroglobulin, dependent on maternal iodine intake (250-300mcg/day)
Birth: rapid increase TSH/T4/T3, TSH surge 30mins, T4/T3 at 24-36hrs
Postnatal: TFTs fall after first 5 days
Premature: levels lower due to immature HPA
RDS/IUGR: lower levels TFTs
40
Foetal development reproductive tract
5-6 weeks: gonads
- Wolfian: SRY in males codes TDF and testes secrete testosterone/anti-mullerian hormone
- Mullerian duct: absensce of test/AMH
9 weeks: sexual differentiation
6-10 weeks: testicular descent (complete 28 weeks)
12 weeks: genitalia distinctly formed
41
Genetics DM2
Offspring of parents with T2DM – 40% chance
Offspring of both parents with T2DM – 60%
Monozygotic twins – 90% chance
42
Growth hormone
pulsatile secretion binds GH-BP
**effect:** protein/glucose sparing and fat utilising
-induces production/secretion IGF-1 in liver
**stimulated:** GRF, ghrelin, exercise, fasting
**inhibited:** somatostatin, SRIF, leptin
**IGF-1 ↓:** malnutrition, CRF, CLD, hypothyroidism, obesity
43
Idiopathic growth hormone deficiency
1:10,000
pituitary aplasia or midline defect
defects GH, GRF or GH receptor
degrees of pituitary deficiency
slow growth post birth (short + chubby), high voice, microphallus (\<2cm), fasting hypoglycaemia
_Test GH stimulation:_
- agents: L-Dopa, clonidine, arginine
- measure: IGF-1/IGFBP3
44
Autoimmune polyendocrine syndrome type 1
Whitaker syndrome
Autoimmune
Auto recessive
AIRE gene
Multiple endocrine gland dysfunction
hypothyroidism
hypogonadism and infertility
vitiligo (depigmentation of the skin)
alopecia (baldness)
malabsorption
pernicious anemia
chronic active (autoimmune) hepatitis
45
Goiter
4-5% all children
May be euthyroid/hypothyroid/hyperthyroid
46
Gonadal dysgenesis
**mosaic mixed gonadal dysgenesis:**
_karyotype:_ mosaicism 45X/45XY
_phenotype:_ ambiguous genitalia and 1 gonad (1 streak and 1 ova/testis)
- 95% male phenotype, 5% ambiguous
**XY mixed gonadal dysgenesis**
_phenotype:_ asymmetrical external dysgenesis, some have uterus
- streak ovary does not produce AMH
- eg Turner's
**XY pure gonadal dysgenesis (Swyer syndrome)**
_genetics:_ SRY gene mutation
_phenotype:_ female phenotype, normal stature, gonads: bilateral undiff streaks not functioning
_clinical:_ no thelarche/menarche, hypergonadotrophic primary amenorhoea
associations: high risk of cancer, WAGR syndrome, Denys Drash syndrome
47
Grave's disease
**incidence:** 1:100 11-15yrs, F\>\>M
**risk factors:** family history, HLADR3/HLAB8 gene
**pathogenesis:** increased thyroid function by autoantibodies (TSI)
**diagnosis:** high T3/T4, low TSH
**clinical:** irritability, muscle weakness, insomnia, tachycardia, heat intolerance, diarrhoea, weight loss, diffuse goiter, exopthalmos and lagging of upper eye lid
**investigations:** high T3/T4, TSH suppression
**treatment:** radioiodine therapy, medications (carbimazole, methimazole), and thyroid surgery
48
Growth Hormone
**secretion:** peptide hormone from somatotroph cells in anterior pituitary
**stimulation:** GnRH, ghrelin, sleep, exercise, hypoglycaemia, fasting
**inhibition:** somatostatin, GH/IGF-1, hyperglycaemia, glucocorticoids
**effects:**
- anabolism: stimulation osteoblasts, chrondrocytes
- calcium retention
- increased muscle mass
- increased lipolysis
- increased protein stimulus/gluconeogenesis
- growth intestinal organs/brain/immune system
49
GROWTH TERMS
Short stature
Growth failure
short stature: \<3rd percentile
growth failure: height velocity \<5th percentile for age
Investigation IF
- height \<3.5 SDs below the mean
- height velocity\<5th percentile
-
50
Hashimoto thyroiditis (lymphocytic thyroiditis)
most common acquired hypothyroidism
autoimmune: lymphocytic inflitration
assoc goiter with pebble-like surface
1:1,000
peak adolescence F\>\>\>M
family history 25-35%
decline in height velocity but not weight
fatigue, weight gain, pale or puffy face, feeling cold, joint and muscle pain, constipation, dry and thinning hair, heavy menstrual flow or irregular periods, depression, panic disorder, a slowed heart rate, and problems getting pregnant
elevated anti thyroid peroxidase ab
assoc AI diseases
51
HbA1c aims
\<6yrs: 7.5-8.5%
6-13yrs: \<8%
\>13: \<7%
52
Hormone response hypoglycaemia
**plasma glucose**: low normal (3.5-8.0)
**insulin:** low (15-120)
**betaOHbutyrate** (ketones): high (0.1-0.3)
**lactate**: normal (0.3-2.0)
**cortisol**: high (150-450)
53
Hyperinsulinaemia Hypoglycaemia
**genetics:** genes SUR1/Kir6.2 on chromosome 11 involved in ATP dependent potassium channel of beta cells
**pathogenesis:**
- _glucokinase activating mutations:_ closure of K channels and hyperinsulinaemia
- _glutamate dehydrogenase_: hyperinsulinaemia and hyperammonaemia
**clinical:** hypoglycaemia within days
- non-ketotic hypoglycaemia
- inappropriately high insulin
- increased glucose requirements
54
Persistent hyperinsulinemic hypoglycaemia of the newborn
1:30,000
inherited and sporadic
genetic cause: 50% with K channel defect on ch 11
- K channels regulate insulin secretion
cause: elevated insulin during hypoglycaemia with absent ketones
- hyperplasia of the pancreatic beta islet cells
Symptoms: LGA, severe hypoglycaemia 1-3 hours feeding, glucose requirement 3x normal
Investigation: PET scan
Treatment: diazoxide, octreotide, ca channel blocker, surgery
55
Congenital hyperthyroidism
transplacental transfer TSIs
masked until effect of transplacental antithyroid meds wear off
irritability, tachycardia, polycythaemia, craniosynostosis, poor feeding FTT
tx: methimazole, beta blocker
56
Hypogonadotropic hypogonadism
(low gonadrotropins/gonadal steroids)
Isolated gonadtropin deficiency
Kallmann syndrome
Idiopathic mulitiple pituitary deficiencies
Hypothalamic pituitary tumours
57
Idiopathic ketotic hypoglycaemia
age 18m-5 yrs
definition: hypoglycaemia post prolonged fasting with illness
cause: defective mobilisation of alanine for gluconeogenesis
symptoms: thin
investigations: low insulin, normal lactate/pyruvate, elevated GH/cortisoll/FFA/ketones
diagnosis: diagnosis of exclusion
treatment: high protein/carb meals
58
Hypophosphatasia
1:100,000
Low activity tissue specific ALP: unable to break down ph precursor
clinical: rickets and osteomalacia
investigations: decreased ALP, increased Ca/PO4
management: diuretics, calcitonin
59
Hypopituitarism
1:4000-1:10,000
Growth failure:
Causes
- generic: PROP1: AR panhypopituitarism, ACTH def 30%
- congenital: M\>F, ant pit hypoplasia, absent stalk, ectopic post bright spot and associ anencephaly/holoprosencephaly
- acquired: craniopharyngioma, germinoma, eosiophilic granuloma, trauma, infarct, HIE etc
60
Hypothalamic deficiency
**diagnosis:** ↑ prolactin ↓ all other pituitary hormones
**causes:** craniopharyngioma, acquired hypopituitarism, congenital hypopituitarism (assoc cleft palate, holoprosencephaly, septic-optic dysplasia)
**clinical:** growth failure, hypothyroidism, micropenis, pubertal delay, polyuria/polydispsia
61
Insulin treatment
30-50% long acting, 50% short
Very short acting: lispro, aspart (30-90mins)
Short acting: (2-3hrs)
Intermediate: isophane (4-10hrs)
Long acting: glargine (6-14hrs)
Require 0.5-1.0 units/kg/24 hours
62
Leptin
Protein hormone
Regulates energy intake/expendicture/appetite/metabolism
Produced adipose tissue
Acts on hypothalamus: appetite inhibition by counterating effect of neuropeptide Y
Influence on timing puberty
Leptin resistance: homozygous receptor defect in small no. obese adults
63
Leydig cell aplasia
No production testosterone
Female phenotype
64
Medullary thyroid carcinoma
Parafollicular cells of thyroid
25% familial with mutation RET oncogene
1) MEN2A
- AD somatic mutation
- triad: medullary thyroid carcinoma (\>90%), phaeochromocytoma (50%), parathyroid hyperplasia (20%)
2) MEN2B
- missense mutation
- triad: medullary thyroid carcinoma (\>90%), phaeochromocytoma (50%), no PT, neuromas
3) Familial MTX
- medullary thyroid carcinoma \>90%
Treatment: total thyroidectomy
65
Methimazole
Mechanism: inhibits enzyme thyroperoxidase
- prevents oxidization if iodine
Side effects: atopic rash, agranulocytosis
66
Multiple endocrine neoplasia
***MEN 1*** **= Werner syndrome =** ***the P adenomas***
* pancreatic islet cell adenomas (produce insulin and gastrin)
* pituitary gland adenoma (produce prolactin)
* parathyroid hyperplasia or adenoma
***MEN 2*** **–** ***PhAT*** **– Phaeo, adenoma (parathyroid), Thyroid ca**
* Medullary thyroid carcinoma
* Parathyroid adenomas
* Phaeochromocytoma
* Also – GIT neuromas, pit tumours, adrenocortical tumours, marfanoid (Type IIB)
**MEN 3 = Sipple syndrome**
* MEN 2 plus multiple mucosal neuromas and Marfanoid habitus
67
Nodules
2% children develop solitary nodules
most benign
carcinoma 1% paed cancers
papillary and follicular 90% thyroid tumours paeds
medullary carcinoma thyroid associ MEN
68
Obesity
1/3 all children
obese parents: 2-3x risk
Overweight or obese: 27% preschool (2-5yrs), 33% school aged (6-11yrs), 33% adolescents (12-19yrs)
Obese: 12% preschool, 18% school aged, 18% adolescents. Severe obesity: 10% preschool, 13% school aged, 13% adolescents.
Peristence in adulthood: related to age, girls\>boys
Endocrine issues\<1%
Obesity increases FFA increases glucose increases insulin with C peptide
69
Osteogenesis Imperfecta
**incidence:** 1:20,000 autosomal dominant
**definition:** structural defect in alpha chain of type 1 collagen
**clinical:** blue sclera, deafness, fragile bones
_Type 1:_ mild, most common, recurrent fractures after birth, improves after puberty
_Type 2:_ lethal perinatal form, babies commonly LBW, multiple intrauterine fractures
_Type 3:_ most severe non-lethal form, intrauterine fractures common, short stature, scoliosis, vertebral fractures, decreased lifespan
_Type 4:_ moderately severe, post birth or after recurrent fractures, normal life span
70
46XX or 46XY Ovotesticular DSD
75% XX, 10% XY, 20% mosaic
Sporadic
Clinical: amibiguous external genitalia, both ovarian and testicular tissue present, most common bilateral ovotestis
71
Parathyroid hormone
72
Persistent Mullerian Duct
46XY
Cause: 50% AMH gene defect, 50% AMG receptor defect
Clinical: external male phenotype, internal female
73
Placental aromatase deficiency
46XX
Cause: aromatase deficiency prevents transfer of fetal androgen to maternal oestriol
Clinical: virilization mother and child, hypergonadotropic hypogonadism: ovaries lack oestrogen, no puberty
74
Precocious puberty
sexual development: \<9 boys, \<8 girls
Central: gonadarche from premature activation HPA (GnRH dependent)
- any CNS disorder (germinomas, gliomas, astrocytomas, ependymomas, hamartomas)
Peripheral: no HPA (GnRH independent)
- eg McAlbright syndrome: precocious gonadarche, fibrous dysplasia, hyperpigmented lesions from G protein defect
- adrenal adenomas/carcinomas
- familial GnRH indep sexual precocity with premature leydig cell maturation via X-limited dominant defect with continuous production testosterone
- hCG secreting tumours (pineal dysgerminomas/hepatoblastoma)
- CAH
75
Precocious puberty
CENTRAL :
- cause: 80% idiopathic, CNS lesions, genetics, primary hypothyroidism
- Gonadotropin dependent precocious puberty
- early maturation of hypothalamic-pituitary axis
- early thelarche/pubarche in girls, and testes growth/pubarche in boys.
PERIPHERAL :
- cause: ovarian cysts/tumours, leydig cell tumours, HCG secreting tumours, adrenal tumours, pituitary tumours
- gonadotropin independent precocious puberty
- excess sex hormones (androgen/oestrogen) from the gonads/adrenals/exogenous/germ cell tumour
INCOMPLETE: isolated thelarche/adrenarche/pubarche in boys or girls
Management: aromatase inhibitor, SERM, flutamide, testolactone
76
Premature adrenarche
10-25% minimal disorder adrenal steroid enzyme biosynthesis
Spectrum of normal
F\>M, black\>white, obese\>thin
Odour first then axillary hair
Due to adrenal production 17-hydroxypregnenolone and DHEA
Slightly advanced height/bone age
77
Premature thelarche
Usually idiopathic/sporadic
Onset 2 years
Isolated breast development
Slightly elevated FSH/LG normal oestradiol
Ovaries may have few small cysts
78
Primary adrenal insufficiency
**CAUSES**
**Inherited**
_1. inborn error of steroidogenesis_
- CAH (most common), lipoid adrenal hyperplasia,
_2. Adrenal hypoplasia congenita_
- males, mutations DAX1 gene Xp21, presents neonate period
_3. SF-1 deficiency_
- transcription SF-1 required for adrenal/gonadal development
_4. ALD (adrenocortical deficiency)_
- associated demyelination CNS, neonatal onset rare
**type I Polyendocrinopathy:**
- AR, autoimmune polyendocrinopathy/ candidiasis/ ectodermal dystrophy syndrome
- candidiasis first, then hypoparathyroidism, then Addisons in early adolescence
**acquired etiologies:** AI Addisons, infections, drugs, haemorrhage adrenal gland
79
Primary hypogonadism
syndrome of gonadal dysgenesis (XO)
klinefelter syndrome and variants (XXY)
famial XX or XY gonadal dysgenesis (XX or XY)
80
Propylthiouracil
Mechanism: inhibits thyroperoxidase
Side effect: liver failure, agranulocytosis
81
Pseudohyponatraemia
**definition:** reading of Na that is falsely low
**cause:** equipment that reads Na assumes that blood is 97% water and 3% solids
- is there is an increase in solids (protein/lipids) then the reading fo Na can be inaccurately low
**correction for hyperglycaemia:** corrected Na= measured Na + (BGL mmol/l/4)
82
Pseudohypoparathyroidism
**definition:** elevated PTH with hypocalcaemia due to PTH resistance
**_Type 1_**
- decreased urinary cAMP response PTH
- Ch 20 GNAS1 mutation encoding G protein surface receptor
**_Type 1a (most common):_** Albright's hereditary osteodystrophy
- AD maternally transmitted
- round face, short stature, short 4th MC, obesity, DD, subcut calcification
- assoc resistance TSH/LH/FSH/GrRH
**_Type 1b_**
- hypocalcaemia but without physical abnormalities
- PTH deficiency confined to kidney
**investigations:** low Ca, high PO4/PTH
83
Primary hypoparathyroidism
Hypocalcaemia but NOT rickets
1. Congenital malformations from dev abnormalities 3rd/4th brachial arches eg DiGeorge
2. Surgical procedures
3. Autoimmune destruction PT gland
↓calcium, ↓PTH, ↑phosphate, normal Vit D
84
Pseudohypoparathyroidism
autosomal dominant
assoc G protein/adenylate cyclase
↓calcium, ↑phosphate, ↑PTH, normal Vit D
Tx: calcium and vit D supplementation
85
Familial hypophosphatemic rickets
X-linked
diagnosed first few years
failure kidney to reabsorb phsophate
low serum phosphate
86
Rickets
decreased/defective bone mineralisation
bone soft and metaphyses widen
bowing of legs on WB, thickening wrists/knees/ribs
nutritional (poor intake, poor absorption, vit D metabolic defects)
- Vit D deficiency calcium not absorbed from intestine
Normal calcium, ↓phosphate, ↓Vit D, ↑PTH,
87
Puberty in females
Age: mean 10.5 yrs (precocious \<8yr, delayed \>12yrs)
1st stage: thelarche (drive by Oe/Prog/Prol)
2nd stage: pubarche (driven by androgens)
3rd stage: peak heigh
4th stage: menarche (need 17% body fat)
88
Puberty in males
Mean age: 11.5 (precocious\<9yrs, delayed\>14yrs)
1st stage: increased testicular volume (10-12 yrs 5ml, adult 15-35ml)
2nd stage: increased penile length (5cm to 9.5cm)
3rd stage: pubarche
4th stage: peak height velocity
5th stage: sperm in urine/nocturnal sperm
89
Rickets
causes
- vitamin D deficiency
- calcium deficiency
- vitamin D dependent type 1: AR defective conversion 25OHD to 1,25OH2H
- vitamin D dependent type 2: end organ resistance vitamin D
- X linked hypophosphatemic rickets: 1:20,000 AR/AD
- Hereditary hypophosphatemic rickets with hypercalcuria: AR, high Ca excretion in urine
definition: failure of mineralization of growing bones/cartilage
clinical: asymptomatic, pain, irritability, DD, poor growth, infections, delayed closure fontanelles, craniotables, frontal bossing, costochondral junctions, wide wrists, bow/knock knees
XR: low bone density, wide growth plates
NB. Osteomalacia: impaired mineralisation post growth plate closure
Investigations: decreased Ca/PO4, increased PTH
90
Sulfonylureas
**drugs:** gliclazide, glimepride, glipizide
**mechanism:** increases pancreatic insulin secretion
**risks:** weight gain, hypoglycaemia
91
Congenital thyroxine-binding globulin deficiency
1:10,000
Low serum T4 normal free T4
Normal TSH
euthyroid
92
Terms of puberty
Adrenarche: activation of adrenal cortex for production of androgens
Gonadarche : activation of gonads by LH and FSH
Thelarche : appearance of breast tissue
Pubarche: appearance of pubic hair
Menarche: first menstrual period
Spermarche : age at first ejaculation
93
Testicular DSD
46XX
Cause: Yp translocation onto X, +/- SRY
Clinical: klinefelter phenotype but not as tall, infertile
94
Thiazolidinediones
**drugs:** rosiglitazone, pioglitazone
**mechanism:** increases sensitivity of peripheral tissues to insulin
95
upper:lower ratio
infant 1.7:1
1yr 1.4:1
10yr 1:1
decreased: hypogonadism, marfans, klinefelters
increased: hypothyroidism, dwarfism
96
WAGR syndrome
46XY DSD
Missing copy 11p13
W- Wilm's tumour
A- aniridia
G- genitourinary anomalies
R- mental retardation
97
Pendred's syndrome
**gene:** AR SLC26A4 gene
**pathogenesis:** anion transporter known as pendrin which transports iodide across apical membrane of the thyrocte into the colloid space
**diagnosis:** partial discharge of iodide
**clinical:** euthyroid, goitre worsens with deficiency
98
MODY
| (Mature Onset Diabetes of the Young)
**definition:** monogenic non insulin dependent DM
**incidence:** 2-5%
**gene defects (6 major)**
**1.** hepatocyte nuclear factor 4a (HNF4a) \<10%
- tx: sulfonylurea
**2.** glucokinase gene 15-30%
- tx: diet
**3.** HNF1A 60%
- tx: sulfonylurea
**diagnosis:**
- gene sequencing
- auto Ab negative
99
Menstrual cycle
