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Paediatrics > Endocrine > Flashcards

Endocrine Flashcards

1
Q

Diagnosis of diabetes

A
  1. Fasting BSL >7mmol/L (no caloric intake for 8hrs)
  2. 2hr plasma glucose >11.1 during OGTT (glucose load of 1.75g/kg, max 75g)
  3. Random BSL >11.1 in a pt with Sx of hyperglycemia or DKA
  4. HbA1c >6.5% (paediatric patients = 6.35%)
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2
Q

Premature thelarche

A
  1. Isolated breast development - slow progression
  2. Absence of other secondary sexual features
  3. Normal linear growth
  4. Normal bone age - important
  5. Peaks at around 2yo and again at 6-8yo
  6. Soy based formulas, lavender oil and tea tree oil - ??increased risk of premature thelarche
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3
Q

When to investigate “premature thelarche”

A
  1. Progressive secondary sexual development
  2. Increasing height velocity
  3. Accelerated bone maturation
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4
Q

GnRH dependent (central) precocious puberty

A
  • Early maturation of hypothalamic-pituitary-gonadal axis
  • Characterised by evidence of sustained sex steroid exposure:
  • -> Accelerated linear growth
  • -> Advanced bone age
  • -> Progressive pubertal clinical changes
  • -> Pubertal levels of FSH and LH (GnRH test: LH dominant with levels >5)
  • -> Pubertal levels of oestradiol in girls, T in boys
  • Ix with GnRH (leucrin) stimulation test
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5
Q

Causes of central precocious puberty

A
  1. Idiopathic (F>M)
  2. Loss of hypothalamic inhibition: structural growths
    - -> Hypothalamic hamartomas
  3. CNS tumours e.g. astrocytoma, pineal gland tumours, optic gliomas
  4. Acquired CNS insults e.g. CNS irradiation, hydrocephalus, subarachnoid cysts, CP, tub sclerosis
  5. Neurofibromatosis type 1 (optic glioma)
  6. Previous excess sex steroid exposure e.g. poorly controlled CAH
  7. Genetic e.g. gain of function mutation of kisspeptin gene, MKRN3 gene mutation (imprinting)
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6
Q

Treatment of central precocious puberty

A
  • Administration of Leuprolide depot every 3mths
  • GnRH analogue: provides constant serum GnRH which over-rides pulsatility of endogenous GnRH –> secondary feedback inhibition
  • Effects: initially see a surge in LH/FSH, then as the GnRH receptor becomes desensitised, subsequent secondary inhibition
  • Protocol: 11.25mg IM 3mthly with a review with LH level 1hr post-dose
  • -> LH <2 = adequate suppression
  • F/u: annual GnRH test and bone age
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7
Q

Long term outcomes after treatment with Leuprolide in central precocious puberty

A
  1. Height: greatest height gain seen in girls with onset of puberty <6yo (average gain 9-10cm)
  2. Menstrual cycles and fertility appear normal as adults
  3. Possible increased incidence of PCOS
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8
Q

McCune-Albright Syndrome

A

Cafe-au-lait spots
- Irregular “Coast of Maine” lesions
- Rarely cross midline
- Increases with age
Peripheral precocious puberty (cyst-related)
Polyostotic fibrous dysplasia (develops slowly over time)
- Need to continuously screen for it
Other manifestations: phosphate wasting, GH excess, Cushing’s, thyrotoxicosis, cardiac arrhythmias, cholestasis

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9
Q

Pathogenesis of McCune-Albright Syndrome

A
  • Somatic mutation - not inherited
  • Constitutive activation of alpha-subunit of G3 protein that activates adenylyl cyclase
  • Affects signal transduction of multiple G protein coupled receptors e.g. LH, FSH, GHRH, TSH, ACTH, PTH, catecholamines etc
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10
Q

Causes of gonadotrophin-independent (peripheral) precocious puberty in girls

A 
McCune Albright Syndrome
Ovarian cysts
Ovarian tumours
Exogenous oestrogen exposure
Adrenal tumours (aromatisation of T)
CAH
Primary hypothyroidism (TSH cross-reacts w/ LH/FSH-R)
Pituitary gonadotrophin secreting tumours (rare)
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11
Q

Causes of gonadotrophin-independent (peripheral) precocious puberty in boys

A

McCune Albright Syndrome
Leydig cell tumours
HCG secreting tumours
Familial male-limited precocious puberty (LH-R mutation)
Exogenous oestrogen exposure
Adrenal tumours
CAH
Primary hypothyroidism (testicular enlargement only)
Pituitary gonadotrophin secreting tumours (rare)

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12
Q

What is the primary reason for short stature in Turner Syndrome?

A

Haploinsufficiency of SHOX gene

- SHOX gene is located at distal ends of short arms of both sex chromosomes

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13
Q

Risk of germ cell tumours in DSD conditions

A

High-risk requiring gonadectomies:

  1. Dysgenetic gonads (+Y) that are intra-abdominal 15-35%
  2. PAIS (non-scrotal) 50%
  3. Frasier syndrome 60%
  4. Denys-Drash (+Y) 40%
  5. Turner (+Y - mosaic?) 12% (intermediate risk)
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14
Q

Intermediate risk for germ cell tumours

- For monitoring +/- Bx

A
  1. 17B-HSD 28%
  2. Dysgenetic gonads (+Y) - unknown risk –> Bx
  3. PAIS (scrotal glands) - unknown risk –> Bx
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15
Q

When is the best time to take a cortisol level?

A

Early morning (+/- ACTH stimulation)

  • Crucially time-dependent
  • Regulated by stress and circadian rhythm
  • By midnight –> minimal cortisol, by 2am –> start producing cortisol, by 6-9am –> maximal concentration should be reached
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16
Q

Incidence of classical CAH in female

A

1/28,000

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17
Q

When do physiological pre-pubertal gonadotrophin surges occur?

A
  1. Mid-gestation: LH/FSH levels peak, then decline/disappear by term
  2. Second surge between 30-100 days of life: “mini-puberty of infancy”, can utilise this opportunity for a “free” stimulation test
    - If ex-premature infant, perform at CGA
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18
Q

“Pro-testis” factors

A
  1. SOX9 gene: influences expression of SRY

2. SRY gene: transcription factor which promotes the development of testes, Sertoli and Leydig cells

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19
Q

Camptomelic dysplasia

A
  • AD, translocation w/ breakpoint at 17q24-25 or deletion of 17q
  • Excess female phenotype in 46XY –> absence of SOX9 –> no SRY gene product
  • CF: pierre robin sequence, short bowed limbs, dislocatable hips, 11 ribs, club feet, laryngotracheomalacia, C-spine instability
  • Early neonatal death is common
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20
Q

Genes responsible for development of bipotential gonads

A

LIM1, SF1, WT1

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21
Q

Denys Drash Syndrome

A
  • Missense mutation in WT1
  • If 46XY, cannot express full testicular development and vice versa for 46XX
  • CF: mesangial sclerosis causing early, infantile nephrotic syndrome –> early renal failure, increased risk of Wilm’s tumour (aggressive)
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22
Q

WNT4 deletion in 46XX

A
  • WNT 4 is a “pro-ovary factor” that promotes development of mullerian structures
  • 46XX DSD - no germ cells, ovarian failure and mullerian agenesis
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23
Q

Adrenal hypoplasia congenita

A

DAX1 deletion

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24
Q

Tests to consider in ovotesticular DSD/46XX testicular/46XY complete gonadal dysgenesis
i.e. “True hermaphrotidism”

A 
Blood karyotype
Scrotal skin fibroblast biopsy
Gonadal biopsy
- Need to identify genotype/karyotype 
- Usually due to mosaicism or chimerism
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25
Q

CAH: 21-hydroxylase deficiency

A
  1. No cortisol!
    - Circulatory collapse
  2. 80% - no aldosterone, 20% produce aldosterone
    - Na wasting, hyperkalemia with acidosis
  3. 46XX DSD: virilisation due to shunting of cholesterol by-products down androgen synthesis pathway
    - 46XY: normal male genitalia
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26
Q

CAH: 11-beta hydroxylase deficiency

A
  • Further down steroidogenesis pathway
    1. 11-DOC = weak mineralocorticoid (excessive amts) –> high Na, hypertension
    2. 46XX DSD (mild virilisation)
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27
Q

CAH: which enzyme deficiency causes a 46XY DSD?

A
  • 17B-hydroxysteroid dehydrogenase: involves androgen pathway only
  • 3B-hydroxysteroid dehydrogenase: able to produce DHEA, but low androstenedione; Na wasting and low cortisol
  • 17a-hydroxylase: rare, HTN and hypoK with renin suppression, sex hormones cannot be synthesised correctly
  • Reduced androgen production –> undervirilisation of 46XY
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28
Q

Differential diagnoses for an isolated micropenis

A
  1. Familial
  2. Idiopathic
  3. Hypopituitarism (assoc. undescended testes)
  4. Prader-Willi Syndrome
    - Floppy neonate with feeding problems
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29
Q

Mechanism of micropenis in hypopituitarism

A
  • Usually, there is a gonadotrophic surge in 3rd trimester, which does not occur if there is hypopituitarism
  • Underdeveloped (not ambiguous!) genitalia with micropenis and undescended testes
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30
Q

Congenital anorchia

A

“Disappearing testes”

  • 46XY DSD: undervirilised due to reduced testosterone production
  • Possible intrauterine torsion
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31
Q

Antimullerian hormone defect

A

46XY with uterus/mullerian structures

  • Normal male genitalia
  • However, due to absence of AMH, mullerian structures also persisted and developed internally
  • Usually presents with “herniation” and incidentally found during surgery
  • Normal male phenotype after removal of mullerian structures
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32
Q

Investigations for isolated micropenis

A

Rule out hypopituitarism (MRI)
Genetic testing for Prader-Willi (if suspected clinically)
At +30 days, test for testosterone, LH, FSH levels
- If abN: further Ix for central hypogonadism (DDx: Kallman syndrome)
- If normal: counsel family, ?testosterone replacement therapy

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33
Q

Investigations in neonatal period for ambiguous genitalia

A

Neonatal period:

  1. USS to assess internal organs (day 1)
  2. Karyotype (day 1)
  3. Electrolytes and BSL (day 1-2)
  4. 17-OH (day 4+)

Day 30+:

  • Testosterone, oestrogen, LH, FSH - time with “minipuberty”
  • Cloacogram (pre-surgery for planning)
  • At 18mo, if complex DSD suspected: laparoscopy with biopsy of internal structures, scrotal skin biopsy (fibroblasts) for chromosomes, androgen receptor studies
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34
Q

Management/support for DSDs

A
  1. Address Q’s regarding fertility, sexuality; avoid stereotyping/gender bias etc etc
  2. Medical treatment as required
  3. Gender surgery
    - Delay constructional surgery
    - Primary duty is to child
    - Limited evidence of good outcome
    - Base advice on evidence not personal opinion
    - Excision surgery must have clear indication
  4. Screen for malignancy: gonadectomy vs biopsy vs monitor
  5. Psych support
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35
Q

Causes of adrenal insufficiency

A
  1. Tertiary: hypothalamus
    - Tumour, malformation
    - Iatrogenic: high dose corticosteroid therapy
  2. Secondary: pituitary
    - CRH receptor defect, isolated ACTH def
    - Panhypopit
  3. Primary: adrenals
    - Acquired vs congenital
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36
Q

Waterhouse-Friederichsen syndrome

A

Haemorrhage into adrenal glands –> acquired adrenal insufficiency

  • Meningococcus septicaemia
  • Stressed neonate (e.g. extreme preterm)
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37
Q

Natural course of autoimmune Addison’s disease

A
  1. Antibody formation against 21-OH, SCC, 17-OH
  2. Increasing resting plasma RENIN
  3. Raised afternoon ACTH
  4. Depressed ACTH-stimulated cortisol response
  5. When 90% of adrenal function depleted = disease manifestation - decreased aldosterone and cortisol
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38
Q

APECED Syndrome

A
  • Mutation in AIRE gene (21q22.3) - autoimmune regulator

- Autoimmune adrenalitis, hypoparathyroidism, mucocutaneous candidiasis

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39
Q

Autoimmune polyendocrinopathy (APS) 2

A

Autoimmune adrenalitis
Autoimmune thyroiditis
T1DM (dififcult to control due to adrenal antibodies)

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40
Q

Other features common to APS 1 and 2

A

Chronic active hepatitis (cause of mortality), malabsorption, alopecia, vitiligo, pernicious anaemia and hypogonadism

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41
Q

Pathogenesis of hyperpigmentation in Addison’s

A

ACTH and MSH formed from POMC –> excess ACTH can bind cutaneous melanocortin-1 receptor

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42
Q

Triple A syndrome

A
  1. Adrenal insufficiency
  2. Alacrima
  3. Achalasia
  4. Neurological impairment with early onset dementia
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43
Q

Long term steroid (cortisol) replacement

A

Hydrocortisone:
- Suppressive dose = 10-15mg/m2/day
–> CAH: suppress androgens to reverse virilisation
- Replacement dose = 6-10mg/m2/day
–> Secondary adrenal failure (20% higher than baseline production)
- Stress (e.g. infection): 3-5 fold increase in HC dose
- Surgery: IV 100mg/m2/day on day 1 and 2
Fludrocortisone: ~0.1mg/day

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44
Q

Monitoring hydrocortisone dose long term in CAH patients

A

Monitor with height velocity and bone age

  1. Excessive HC: weight gain –> reduced growth velocity –> delayed bone age –> decrease dose
  2. Insufficient HC: continue androgen production –> increased height velocity –> increased bone age (leading to short stature) –> reduce dose
    - If androgen control still poor, add fludrocortisone
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45
Q

Effect of pH on plasma calcium

A
  • Low pH: increased ionised calcium

- High pH: decreased ionised calcium

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46
Q

Hormones that affect plasma Calcium

A

Increase plasma Ca:

  • GH (through IGF1)
  • Thyroxine
  • Oestrogens

Decrease plasma Ca:
- Glucocorticoids: inhibits osteoclast formation+activity, long term - decreases protein synthesis in osteoblasts, decreases intestinal absorption of Ca, increase Ca excretion

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47
Q

Phosphate

A
  • Major control of P: renal
  • -> Increased excretion mediated by PTH binding to receptors in proximal tubule
  • -> Reabsorption primarily occurs in proximal tubule - easily saturable process –> urinary spillover if high P
  • Buffered by Ca and bone
  • Gut absorption is linearly related to dietary intake
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48
Q

PTHrP

A
  • Critical for normal foetal development
  • -> Most important hormone in maternal-foetal Ca transfer
  • -> Widely expressed in many tissues, modulator of cell growth and differentiation
  • Paraneoplastic phenomena: mediator of syndrome of “humoral hypercalcemia of malignancy”
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49
Q

Effects of PTH

A

Chromosome 11, 1/2 life = 10min
Stimulated by hypocalcemia and hyperphosphatemia
Mechanism:
- Major = bone mobilisation - increased osteoclast activity
- Increased renal reabsorption at DCT, increased PO excretion
- Stimulates 1a-hydroxylase enzyme to increase Vit D hydroxylation

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50
Q

Effects of Vitamin D (1,25-VD)

A
  1. Major: Increased Ca and PO reabsorption in small intestine (jejunum)
  2. Increases osteoclast activity in bone
  3. Increased renal tubular reabsorption of calcium and phosphate
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51
Q

Major source of vitamin D

A
  1. Skin (>80%): 7 dehydrocholesterol in skin –> Vit D3 by UVB light
  2. Diet (10%): Vitamin D2 (ergocalciferol)
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52
Q

Risk factors for Rickets of Prematurity

A

Ca and P deficiency - def of Phos > Ca

  • Prematurity (80% of Ca/P transfer in utero occurs in 3rd trim)
  • BW <1000g
  • Cholestatic jaundice
  • Complicate neonatal course
  • Prolonged TPN
  • Soy formula/breast milk without fortification
  • Medications: corticosteroids, diuretics
  • Poor vitamin D intake
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53
Q

Risk factors for Vitamin D Deficiency Rickets

A
  • Unsupplemented, prolonged breastfeeding + late weaning (BM Vit D = <25IU/L)
  • Maternal Vit D deficiency
  • Dark skin ethnicity
  • Decreased sun exposure
  • Malabsorption
  • AEDs
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54
Q

Biochemical abnormalities in Vitamin D Deficiency Rickets

A
  • Hypocalcemia
  • N/Low phosphate –> P wasting due to PTH activity
  • High PTH and ALP
  • Low Vitamin D (esp 25-D = storage form)
  • -> Monitor response to therapy by measuring 25-D levels
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55
Q

Biochemical abnormalities in Rickets of Prematurity

A
  • Hypophosphatemia (inadequate intake/reduced in utero transfer)
  • -> Appropriate renal response = low P in urine
  • Calcium levels are variable (low/N/high)
  • -> 1,25-D activated due to low P –> increased intestinal absorption, unable to be stored in bone (due to low P - cannot form hydroxyapetite), excreted in urine
  • Normal 25-D, N/high 1,25-D (low P activates renal 1a-hydroxylase)
  • High ALP (>x5-6 ULN is suggestive of diagnosis)
  • -> Increased bone demineralisation
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56
Q

PHEX gene

A

Phosphate regulating endopeptidase on X chromosome

  • Present predominantly in bone and teeth
  • Product of PHEX gene degrades and inactivates hormone-like substances that promote phosphate excretion + impair bone mineralisation
  • Indirectly inactivates FGF23
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57
Q

Fibroblast growth factor 23 (FGF-23)

A

Humoral mediator that decreases renal tubular reabsorption of phoshate and decreases activity of renal 1a-hydroxylase activity

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58
Q

Familial hypophosphatemic rickets

a.k.a Vitamin D resistant rickets

A
  • X-linked mutation in PHEX gene –> increased levels of FGF-23
  • Males are affected with full phenotype, affected mothers may only have fasting hypophosphatemia
  • Defect in PO reabsorption (renal wasting) –> phosphaturia
  • Defect in hydroxylating 25-Vit D
  • CF: rickets esp lower limbs, poor growth, delayed dentition, tooth abscesses
  • Ix: Low PO, Low 1,25 Vit D, normal Ca/25-Vit D/PTH, high ALP due to poor mineralisation
  • Tx: oral phosphate and calcitriol
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59
Q

Excess 1,25-Vit D (excessive doses of calcitriol)

A

Hypercalcaemia –> hypercalciuria (renal reabsorption mechanism becomes saturated) –> nephrocalcinosis

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60
Q

Excessive phosphate supplementation

A

High P –> reduced Ca (increased binding, decreased 1,25-D conversion)
Stimulates PTH –> worsens bone reabsorption –> decreased mineralisation and #

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61
Q

Calcitonin

A

Produced by parafollicular cells of thyroid in response to hypercalcemia
Stimulates Ca deposition in bones
Decreases Ca absorption in intestines
Promotes Ca excretion in kidneys

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62
Q

Calcium-sensing receptor

A
  • CaSR of parathyroid gland continuously senses serum ionised Ca
  • Class C G-protein coupled receptor –> phosphoinositide turnover
  • Rapidly adjusts PTH release for even minute changes in ionised Ca levels
  • -> When active, inhibits PTH secretion
  • CaSR in renal tubules has direct effect on calcium reabsorption
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63
Q

Biochemical defects in hypoparathyroidism

A

Normally, PTH: increases bone resorption –> increase Ca, increases renal PO excretion

  • Low serum Ca, normal/high PO4
  • Low urinary Ca
  • Inappropriately normal or low PTH
  • ALP low/normal

Other: calcification of basal ganglia, cataracts, long QT

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64
Q

Pseudohypoparathyroidism Type 1A - clinical features:

- Inactivating mutation of GNAS (maternally inherited mutation)

A
  1. TSH resistance - <2yrs, usually presents first,
  2. PTH resistance - presents in infancy or later
  3. GHrH resistance in pituitary - contributes to short stature
  4. FSH/LH resistance - menstrual irregularities in older girls
    Other: brachydactyly 3-5th fingers, syndactyly 2-3rd toes, subcutaneous calcifications, cataracts, short stocky build with round face, flat nasal bridge and short neck, mental retardation
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65
Q

Pseudopseudohypoparathyroidism

A

Same inactivating mutation of GNAS inherited from father = Albright hereditary osteodystrophy phenotype without endocrine dysfunction

Recall: tissue-specific parental imprinting of GNAS

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66
Q

Vitamin D deficiency

A
  • Based on 25-OH Vit D level
  • Deficiency = <50nmol/L
  • Insufficiency = 50-<75nmol/L
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67
Q

Treatment of Vitamin D Deficiency (acute therapy)

A
  • Age <1mth: 1000IU (25microg) daily for 3/12
  • Age 1-12mth: 3000IU (75microg) daily for 3/12
  • Age >12mth: 5000IU (125microg) daily for 3/12

OR Stoss therapy (noncompliance risk): high dose of Vit D3 at beginning of winter to maintain Vit D level

  • 300,000 - 500,000IU as once off dose
  • Vit D3 stored in fat –> very long half life
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68
Q

DDx for vitamin D deficiency rickets

A
  • Calcium deficiency
  • Type 1 Vit D dependent rickets: 1-alpha hydroxylase deficiency
  • Type 2 Vit D dependent rickets: mutation in vit D receptor, end-organ resistance to 1,25-OH
  • Hypophosphatemic rickets
  • -> X-linked
  • -> RTA
  • -> Hereditary hypophosphatemic rickets w/ hypercalciuria
  • -> Nutritional phosphate deficiency
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69
Q

Primary hyperparathyroidism - causes

A
  • Sporadic, single adenoma
  • MEN (multiple endocrine neoplasia) type 1 and type 2a
  • -> Type 1: hyperplasia or neoplasia of pancreas, anterior pituitary, parathyroid
  • -> Type 2A: pheo, medullary thyroid carcinoma, hyperparathyroidism
  • McCune-Albright Syndrome
  • Familial hyperparathyroidism - jaw tumour syndrome
70
Q

Investigations for hyperparathyroidism

A
  • Bloods: Ca, P, Vit D, PTH, ALP
  • CaSR mutation analysis
  • USS neck
  • Sestimibi nuclear medicine scan
  • Other markers of MEN disease
  • Check Ca levels in first degree relatives
71
Q

DDx for adrenal mass with hypercalcemia

A 
Malignancies:
- Pheochromocytoma
- Neuroblastoma
- Adrenocortical carcinoma
Non-malignant:
- TB
- Sarcoidosis
72
Q

Causes of calcium and phosphate abnormalities in malignancy

A

Paraneoplastic:

  • PTHrP - hypercalcemia
  • -> Acts on PTH receptor, mimics PTH effect on bone and kidney, resultant hyperCa suppresses endogenous PTH secretion
  • FGF23 - phosphate wasting, normal Ca
  • 1a-hydroxylase activity - hypervitaminosis D –> hypercalcemia, hyperphosphatemia
73
Q

Treatment of acute hypercalcemia

A
  1. ECG monitoring
  2. Maximise urinary Ca excretion: hydration/hyperhydration with saline and loop diuretics
  3. Inhibit bone resorption: bisphosphonates, calcitonin
  4. Glucocorticoids
  5. Dialysis with low Ca dialysate (last resort)
74
Q

Bisphosphonates

A
  • MOA: phosphatase resistant pyrophosphate analogue that absorb to surface of bone hydroxyapetite. Inhibits Ca release by interfering with metabolic activity of osteoclasts + cytotoxic to osteoclasts
  • SE: flu-like Sx, GI symptoms, hypoCa
  • In emergency: IV pamidronate 0.25-1mg/kg over 8hrs, single dose lating up to 2-4/52. Can be repeated
75
Q

Calcitonin (emergency treatment)

A
  • MOA: rapid transient lowering of Ca levels by increasing Ca renal excretion and inhibiting osteoclast activity
  • Dose: 2-4U/kg subcut 6-12hrly
  • SE: tachyphylaxis with repeated doses
76
Q

Kenny-Caffey Syndrome

A
  • Medullary stenosis of long bones, short stature, delayed bone age, delayed closure of fontanelles, eye abnormalities
  • Idiopathic hypoparathyroidism have been found leading to episodic hypocalcemia
  • AD and AR forms, mutation in TBCE gene disturbs microtubule organisation in cells
77
Q

Biochemical abnormalities in Type 1 and Type 2 Vitamin D dependent rickets

A
  1. Type 1 = defect in renal 1-alpha hydroxylase –> decreased hydroxylation of 25-D to active 1, 25-D
    - Low Ca/P, high ALP and PTH, normal/high 25-D, low 1,25-D
  2. Type 2 = defect in VItamin D receptor, preventing normal physiologic response of 1,25-D
    (AKA hereditary vitamin D-resistant rickets)
    - Low Ca/P, high ALP and PTH, normal/high 25-D, very high 1,25-D
78
Q

Biochemical defects of pseudohypoparathyroidism

A
  • Low Ca, high PO4, high PTH, high ALP

- Other: High TSH (resistance)

79
Q

Familial hypoparathyroidism (hypercalciuric hypocalcemia)

A
  • Activating mutation of Ca-sensing receptor –> inhibits PTH secretion when hypocalcemic
  • Low Ca, high PO, low PTH with high urinary Ca –> nephrocalcinosis
80
Q

Familial hypocalciuric hypercalcemia

A
  • AD, inactivating mutation of Ca-sensing receptor –> PTH secretion ongoing despite hypercalciemia
  • High Ca, low PO, high PTH with low urinary Ca excretion
  • Urinary Ca/Creat clearance ratio low <0.01
  • Usually asymptomatic
81
Q

Drugs that block peripheral conversion of T4 to T3

A

Propanolol
Glucocorticoids
Propylthiouracil
Amiodarone

82
Q

Drugs that block the release of T3 and T4 from thyroid

A

Lithium

Iodine

83
Q

TSH regulates…

A

Uptake of iodide (Na/I- co-transporter)

Endocytosis of thyroglobulin containing T3&T4

84
Q

Relationship between thyroid hormone and GH

A
  1. T4 facilitates GH release from pituitary –> if hypothyroid, cannot interpret GH test rests
  2. T4 promotes chondrocyte hypertrophy
    - GH mediates proliferation of pre-chondrocytes and stimulation of IGF-1. IGF-1 drives differentiation of pre- to chondrocytes
  3. Low T4: slows growth and epiphyseal ossification –> thin growth plates
  4. High T4: accelerates epiphyseal fusion –> advances bone age
85
Q

Effects of thyroid hormone

A
  • T4/T3 increases sensitivity of target tissues to catecholamines: lipolysis, gluconeogenesis, glycogenolysis
  • T3 increases B-adrenergic receptors in heart, sk muscles, adipose and lymphocytes
  • Increases basal metabolic rate by increasing Na/K-ATPase activity
86
Q

Half life of Thyroid hormone

A

7 days

Shorter at birth: 3 days

87
Q

Thyroid function after birth

A

At birth, TSH surge which peaks at ~30min of life –> rise in T3 and T4. Falls after day 1 of life
- Adaptive mechanism to produce heat after birth as foetal thermogenesis is inhibited in utero

88
Q

MOA of carbimazole and propylthiouracil

A
  • MOA: methimazole targets thyroid peroxidase - prevents coupling and iodinating tyrosine residues on thyroglobulin –> reduces production of T3 and T4
  • SE: aplastic anaemia, hepatic necrosis –> failure, crosses placental
  • -> ?PTU associated with higher rates in paediatric population
  • Affects foetal thyroid hormone levels –> transient neonatal hypothyroidism (<5/7) can result
89
Q

What can thyroxine tablets bind with?

A

Soy formula and iron, therefore, crushed thyroxine (preparation for neonates) should not be mixed them

90
Q

Sick euthyroid syndrome

A 
Occurs in CRITICALLY ILL pts, can have:
- Low T3 
- Low/normal/high T4
- Normal TSH 
Low T3 occurs due to inhibition of iodothyronine B or outer -ring monodeiodinase activity and decreased rate of T3  from T4 in body tissues. No thyroid hormone replacement necessary. Fix underlying condition.
91
Q

Why is carbimazole preferred over propylthiouracil?

A
  • PTU was found to increase risk of hepatotoxicity –> hepatic failure. Do not recommend use in paediatric pts unless carbimazole cannot be tolerated
  • Carbimazole can also cause an adverse effect: 18-fold increased risk of choanal atresia, crosses the placenta more readily c.f. PTU
92
Q

Side effects of thionamides

A 
Skin rash
Aplastic anaemia/granulocytopenia
Drug fever
Nephritis
SLE-like syndrome = ANCA positive vasculitis 
Splenomegaly
93
Q

Thionamides and breastfeeding

A

Can continue to breast feed is the bottom line!

  • PTU: crosses breast milk in only small amounts and TFTs remain normalised in babies who are breast fed
  • Carbimazole: crosses breast milk readily ++, but normal TFTs, developmental and intellectual function have been reported in breast fed babies
94
Q

Treatment of neonatal thyrotoxicosis: step 1

A
  1. Lugo’s iodine (5% iodine and 1% KI) 1 drop TDS - blocks T4 release and synthesis, iodine uptake
    - -> Wolf Chaikoff effect - feedback suppression
    - -> Cease treatment once pt asymptomatic
95
Q

Treatment of neonatal thyrotoxicosis: step 2

A
  1. If tachycardic and irritable (sympathetic overstimulation), commence propanolol 1mg/kg/day
    - -> Also, stops peripheral deiodination of T4 to T3
    - -> Stop treatment once HR normalises
96
Q

Treatment of neonatal thyrotoxicosis: step 3

A
  1. Carbimazole: to inhibit coupling of iodotyrosines, oxidation and organic binding of iodide and block synthesis of thyroxine
    –> Takes several days to take effect on T4 levels
    –> Monitor weekly once stable
    Treatment will take ~3 days to take effect as circulating T4 has a half life of 3 days
97
Q

Treatment of neonatal thyrotoxicosis: step 4

A

Other treatment measures:

  • If cardiac failure: diuretics and digitoxin
  • If severely thyrotoxic: prednisolone (2mg/kg) - prevents peripheral deiodination and compensates for hypercatabolism of glucocorticoids induced by T3/T4
  • Ensure strict fluid balance and replace insensible losses
  • Ensure adequate caloric intake
  • Maintain normothermia
  • May require sedatives
98
Q

Neonatal thyrotoxicosis and cognitive function

A
  • Associated with craniosynostosis and learning difficulties
  • Microcephaly, advanced bone age may occur
  • Warn of potential learning problems + delayed milestones - close monitoring during early school years
99
Q

How long does it take before the adrenal gland starts to atrophy?

A

Depriving adrenal gland of ACTH for >2/52 causes it to atrophy –> reduced cortisol release

100
Q

Risk factors for thyroid neoplasm

A
  • History of radiation to head/neck
  • Solitary nodule >1cm with fixed, hard or irregular borders
  • FHx of MEN
  • Rapidly growing nodule that is firm or hard
  • Satellite lymph nodes
  • Hoarseness or dysphagia
101
Q

Which one is more likely to be malignant? Hot or cold thyroid nodules

A

Cold!

102
Q

Cause of obesity in craniopharyngioma

A
  • Hypothalamic damage due to tumour, surgery or radiation
103
Q

GH replacement in craniopharyngioma

A
  • Can commence GH replacement after being tumour free for 12mths
  • GH does not increase the risk of tumour recurrence
104
Q

Investigations for panhypopituiarism in a neonate (day 30)

A
  • Serum ACTH, cortisol (preferably several throughout the day)
  • -> Neonates do not have diurnal variation
  • TSH/T4 levels
  • GH level after ruling out hypothyroidism
  • -> Free GH levels in a term neonate (within first few days of life): >10 reassuring, <10 strongly suggestive of GH deficiency
  • LH/FSH/T/E - postnatal gonadotrophin surge
105
Q

When assessing panhypopit, which test is not helpful in the immediate neonatal period?

A

IGF-1 and IGFBP-3 are difficult to interpret in a neonate

106
Q

Cause of hypoglycemia in panhypopituitarism

A
  1. GH deficiency: antagonistic effect on insulin, influences metabolic actions such as CHO and lipid metabolism
  2. Hypocortisolism/ACTH deficiency
107
Q

Prolonged jaundice

A
  • Prolonged jaundice is suggestive of severe pituitary dysfunction
  • Panhypopit associated with conjugated hyperbilirubinemia
  • Hypothyroidism associated with unconjugated hyperbilirubinemia
108
Q

Management of panhypopituitarism: order of hormone replacement

A
  1. Hydrocortisone
    - Need to normalise cortisol before thyroxine replacement or precipitate Addisonian crisis
    - Maintain haemodynamic stability
  2. Thyroxine and growth hormone
    - Hypothyroidism reduces cortisol clearance and reduces BMR –> reduced need for cortisol
    - Thyroxine replacement increases cortisol requirement which the failing adrenals cannot provide
  3. Sex hormones in adolescence (~12yo) if hypogonad
109
Q

Treatment of hypogonadotropic hypogonadism

A

For pts who wish to be fertile:
- Gonadotropin treatment (e.g. HCG = LH, HMG = FSH) would stimulate development of gonads/increase testicular vol, induce T production by Leydig cells, induce spermatogenesis

Simple/practical method:
- Induce secondary sexual characteristics by giving testosterone (or oestrogen) preparation IV or PO

110
Q

Kallman Syndrome

A

KAL gene on Xp22.3

Familial isolated gonadotropin deficiency and anosmia

111
Q

Rickets

A

Bone malformation due to any abnormality in production or excretion of Ca and Phos –> undermineralisation of GROWTH PLATE
Mineral deficiency prevents normal process of bone mineral deposition. If mineral deficiency affects growth plates –> retarded bone age

112
Q

Pattern for height velocity

A
  1. Infants grow very quickly - height velocity is not useful in this age group
    - Commence monitoring height velocity at 2-3yo
  2. Height velocity gradually declines in childhood, nadir just prior to pubertal onset
  3. Puberty-associated growth spurt (peak M: 10.3cm, F: 9cm) typically lasts ~2yrs
  4. Gradual decline in height velocity, stops at time of epiphyseal closure
113
Q

Constitutional growth delay

A
  • Short, slow growth, delayed puberty, delayed bone age
  • FHx of delayed puberty often present
  • Longer period of prepubertal growth, slightly smaller before puberty
  • Pubertal growth spurt occurs normally, albeit at later time –> attain normal adult height as they had prolonged period of prepubertal growth
114
Q

DDx for short stature

A
  1. Primary growth abnormalities
    - Osteochondrodysplasias
    - IUGR
  2. Secondary growth abnormalities
    - Malnutrition
    - Chronic diseases e.g. GI, resp, renal disease, haematological
    - Psychosocial deprivation
  3. Chromosomal abnormalities
  4. Endocrine disorders
  5. Acquired causes that disrupt to HPA axis
    - E.g. tumours, infiltrative dz, infection, trauma
    - Iatrogenic: craniospinal radiation, steroid Tx
  6. Constitutional growth delay
115
Q

Endocrine causes of short stature

A
  1. Hypothyroidism (T4 facilitates GH release)
  2. Cushing syndrome (cortisol excess - suppress GH)
  3. Pseudohypoparathyroidism (poor bone mineralisation)
  4. Rickets (poor bone mineralisation, nutritional def)
  5. IGF/GH deficiency
    - GH deficiency due to hypothal/pit dysfunction
    - GH insensitivity
    - Primary defects in IGF synthesis/transport/clearance
    - IGF resistance: defects of IGF-1 receptor, post-receptor defects
116
Q

Genetically inherited conditions that can cause familial short stature (short parents, short child)

A
  1. Neurofibromatosis type 1 - often assoc. w/ GH abN
  2. Pseudohypoparathyroidism
  3. Thyroid disease
  4. Osteochondroplasias e.g. Leri-Weill dyschondrosteosis with madelung deformity
  5. Renal disease
  6. Haematological dz e.g. thalassemias
117
Q

True onset of puberty is defined by…

A

Boys: testicular volume >4mL
Girls: breast development

118
Q

Normal upper body:lower body segment ratio

A

Neonate: 1.7
Childhood (4-5yrs): 1.4
Pre/pubertal (10-12yrs): 1.0
- Children grow in craniocaudal direction

119
Q

Normal arm span to height ratio

A

1.0

120
Q

Important chromosomal causes of short stature

A 
Turner syndrome
Noonan's syndrome
Down syndrome
Prader-Willi syndrome
SHOX gene abnormalities
121
Q

Intrauterine causes of growth failure

A
  1. Foetal causes: chromosomal abN, syndromes such as Russel Silver, Prader Willi Syndrome, TORCH infections
  2. Placental causes: impaired uteroplacental function/insufficiency
  3. Maternal causes: malnutrition, GDM, HTN, drugs
    - Most non-dysmorphic children will catch up by age of 5, provided no underlying medical condition causing IUGR
122
Q

Achondroplasia

- MC cause of genetic disproportionate short stature

A
  • AD or de novo mutation in FGFR3 gene
  • Neonates: rhizomelic shortening of limbs, macrocephaly, brachydactyly, narrow chest
  • CF: face - midface retrusion and frontal bossing, hypotonia leading delayed acquisition of motor milestones (compounded by macrocephaly), trident configuration of hands, genu varus, thoracic kyphosis and exaggerated lumbar lordosis
  • XR: square ilia, horizontal acetabular, narrow sacrosciatic notch, prox radiolucency of femur, diffuse metaphysial abN
  • Normal life span and intelligence unless complicated by hydrocephalus or craniocervical junction compression
123
Q

Causes of GH therapy failure

A
  1. Technical problems: measurement error, poor compliance, improper handling/storage/injection, incorrect dose
  2. Other conditions: subclinical hypothyroidism, chronic dz or poor nutritional status, glucocorticoid therapy, previous epiphyseal fusion
  3. Failure of GH: anti-GH antibodies (GH1 gene mutations), GH resistance syndromes, incorrect diagnosis
124
Q

Endocrinopathy in Prader-Willi Syndrome

A

Secondary to abN in hypothalamic signalling

  • GH deficiency common: GH Tx has definite benefits on linear growth + body composition, developmental milestones
  • Hypogonadotropic hypogonadism with cryptoorchidism
  • -> Requires pubertal induction with sex hormone replacement
  • Adrenal insufficiency
  • Hypothyroidism: primary and secondary
  • Obesity with hyperphagia (hypothalamus related)
  • Insulin resistance and T2DM high risk
125
Q

DDx for disproportionate tall stature

A

Marfan syndrome (nil learning/behavioural problems)
Homocystinuria
Klinefelter syndrome

126
Q

Investigations for short stature

A
  1. Bone age (+/- limited skeletal survey)
  2. Bloods:
    - FBC/ESR: anaemia, infection, inflammation
    - Chem20, bone chemistry: renal, malabsorption, Ca/P/Vit D disorders
    - pH, HCO3: RTA
    - TTG, Total IgA: coeliac disease
    - TSH/T4: hypothyroidism
    - IGF-1: GHD
    - FSH (if <2yo or >9yo) and karyotype: Turner syndrome
    - Urine pH, protein, blood: renal disease
  3. Pituitary function testing: provocation tests
127
Q

Adrenarche

A
  • Maturational increase in adrenal androgen production - biochemically apparent at ~6yo for both M & F. Due to developmental change in pattern of adrenal response to ACTH.
  • Weak adrenal androgens contribute to pubarche, sebaceous gland + apocrine gland development in “seuxal” areas of skin
  • DHEA becomes predominant 17-ketosteroid in blood = marker of adrenarche
128
Q

When does adrenarche and puberty become dissociated?

A
  • Hypogonadism

- Normally, clinical manifestations of adrenarche closely follow puberty

129
Q

Testosterone and DHT

A
  1. Testosterone:
    - Synthesised from chol in Leydig cells and androstenedione secreted by adrenal cortex
    - Maturation of wolffian duct structures, formation of male internal genitalia, increased muscle mass, development of male sex drive and libido
  2. DHT:
    - T converted to DHT by 5a-reductase in target cells
    - Formation + maturation of external genitalia, enlargement of prostate and penis, facial hair, acne and temporal recession of hair line
130
Q

Normal onset of puberty in F and M

A

Girls:

  • Onset: 10.5-11yo
  • Lower: 8yo
  • Upper: 13yo

Boys:

  • Onset: 11.5-12yo
  • Lower: 9yo
  • Upper: 14yo
131
Q

Progression of puberty: females

A

Thelarche –> pubarche –> growth spurt –> menarche

  • Tempo: 6-9mo per stage
  • 3-6mo after thelarche –> pubarche
  • Growth spurt during Tanner stage 2 and 3 (~12yo)
  • Most rapid growth has occurred by menarche
  • Pubertal growth: 23-28cm, height velocity average 8.3cm/yr
  • Menarche ~12.9yrs, during Tanner stage 3 and 4 (2yr post thelarche)
132
Q

Progression of puberty: males

A

Testicular enlargement (>4mL) –> pubarche –> penile growth –> growth spurt –> spermarche, facial hair

  • Tempo: 9-12mo per stage
  • Peak growth during 13-14yo (testicular vol 10-12mL, stage 4-5)
  • Pubertal growth: 30-31cm, height velocity average 9.5cm/yr
  • Axillary hair mid-puberty
133
Q

Delayed puberty

A
  • If >5yo have passed between beginning and completion of puberty
  • Boys: no secondary sexual characteristics >14yo
  • Girls: no secondary sexual characteristics >13yo
134
Q

Bone age and precocious puberty

A

Bone age gives substantial information on presence of prolonged sex steroid exposure

  • With progressive oestrogen exposure, bone age will be significantly higher than chronological age
  • Remeber: oestrogen increases GH prod’n, leads to epiphyseal fusion and cessation of growth
135
Q

Common clinical manifestations in McCune Albright Syndrome

A

Baltimore Study 1996

  1. Most common manifestation OVERALL = precocious puberty
  2. MC in boys: acromegaly/gigantism
  3. MC in girls: precocious puberty
  4. Associated malignancy: osteosarcomas (rare - 2%)
136
Q

Investigations for gonadotropin-independent precocious puberty (peripheral) in boys

A
  1. Imaging: abdo and adrenal USS +/- CT
  2. Androgen profile:
    - Androstenedione
    - Testosterone: free testosterone
    - SHBG
    - DHEAS
    - 17-OHP (for CAH)
  3. Consider tumour markers: B-HCG, AFP, urinary VMA and metanephrine
137
Q

Buserelin stimulation test

A

Buserelin is a potent GnRH agonist - produces more effective and sustained stimulation of gonadotrophs resulting in LH and FSH secretion

  • Interpretation:
  • -> LH and FSH <5: hypogonadotropic hypogonadism
  • -> LH and FSH >10: normal pituitary axis
  • -> LH and FSH 5-10: probably normal pit axis
  • LH <5 has sensitivity of 100%, sepcificity 96% and PPV 89% of HH
138
Q

CHARGE syndrome and hypogonadism

A

Mutation in CDH7 - positive regulator of neural stem cell proliferation

  • Thought to have critical role in development and maintenance in GnRH neurons for regulating puberty and fertility
  • Hypogonadotropic hypogonadism
139
Q

Causes of hypogonadotropic hypogonadism

A
  1. Genetic: KAL-1, FGFR1, GnHR, DAX-1
  2. Tumours: craniopharyngioma, germinomas, meningiomas, gliomas, astrocytomas
  3. Post-head trauma
  4. Cranial irradiation
  5. Multiple pituitary hormone deficiency
  6. Syndromal: CHARGE, Prader-Willi, Laurence-Moon-Biedel, Bardet-Biedel
  7. Chronic dz: IBD, renal failure, malnutrition and AN, hypothyroidism, hyperprolactinemia, poorly controlled T1DM, Cushing disease
140
Q

Oestrogen therapy for pubertal induction

A

Estradot patches = delivers 25 or 50microg/24H of oestradiol

  • 1/8th of 50microg patch applied twice weekly for 6/12
  • 1/4 patch applied twice weekly for 6/12
  • 1/2 patch applied twice weekly for 6/12
  • Whole patch
  • When spotting occurs, change to COCP or Estalis, which is a continuous oestradiol and norethisterone transdermal patch
  • Gradual increase in dose to prevent growth plate closure
141
Q

Testosterone therapy for pubertal induction

A

Testosterone esters 50mg IM monthly

Increase dose 6mthly to adult dose of 250mg monthly

142
Q

GH and E therapy in Turner’s Syndrome

A

Combinging ultra low doses oestrogen and growth hormone seem to improve height
(Prior to pubertal induction in TS, measure FSH –> if high, confirms gonadal failure)

143
Q

Craniospinal radiation

A
  1. GH deficiency with poor spinal growth from radiation

2. Precocious puberty –> slowing of puberty with evolving depletion of FSH/LH –> pubertal arrest and failure

144
Q

Pubertal induction in boys after chemo/radiation therapy

A
  • Testosterone Tx alone will suppress the HPG axis –> persistence of pre-pubertal gonadotropin levels
  • -> This leads to induction of puberty, but spermatogenesis remains immature
  • Induction with HCG and rFSH –> effective testicular growth, spermatogenesis
145
Q

Hypergonadotraphic Hypogonadism

A

Boys:
- Vanishing testes syndrome/congenital anorchia
- Chemotherapy/radiotherapy
- Syndromes: Noonan, Klinefelter, XX males
- Infection (e.g. mumps), torsion, trauma
- Cystic fibrosis
Girls:
- Syndromes: Turner, Noonan, XX gonadal dysgenesis, 45X/46XY gonadal dysgenesis
- Galactosaemia
- Bloom syndrome, Werner Syndrome, Fanconi anaemia, Ataxia-telangiectasia (ovarian hypoplasia)
- APECED - autoimmune ovarian failure
- Chemtherapy and radiation: streak ovaries

146
Q

Hypopituitarism causing isolated ACTH deficiency

A

TBX19 or PCSK1

147
Q

Female presentation in 3B-hydroxysteroid dehydrogenase deficiency

A
  • 3BHSD Def –> blocks Na, cortisol and androstenedione production, DHEA still produced
  • Classical: Mild virilisation, Na wasting and low cortisol; after infancy - features of adrenarche with axillary and pubic hair due to DHEA
  • Non-classical: PCOS with hirsutism, acne, menstrual disorders and infertility
148
Q

Female presentation in 17a-hydroxylase deficiency

A
  • Rare
  • 17aOH def: prevents pregnenolone –> 17OH-pregnenolone i.e. blocks entry into cortisol and sex steroid pathway
  • HTN, hypokalemia with suppressed renin and aldosterone (feedback suppression)
  • No 46XX DSD as adrenal androgen production is suppressed, but at puberty, failure of sexual development c.f. 46XY DSD
149
Q

Precocity

A

Ask:
- What’s affected?
–> Sequential: testes/breast development with pubic hair = central precocity
–> Pubic and axillary hair, body odour, normal blood markers = premature adrenarche only
–> Is it oestrogen and testosterone effects that are not sequential/sparing gonads in boys = peripheral precocity
E.g. Girls: breast development, menses
E.g. Boys: external virilisation with penile enlargement, advanced bone age
***Remember: in this group, if bone maturation nearing pubertal age –> hypothal takes over to cause central precocity
–> Virilisation of female: at birth = CAH or maternal conditions/drugs, gonadal dysgenesis; after postnatal period, consider adrenocortical tumour

150
Q

Adrenal rest testicular tumours

A

Occurs in boys with 3B-HSD, 21-hydroxylase deficiency or 11B-OH deficiency who have not had appropriate corticosteroid therapy

  • Can develop unilateral or bilateral adrenal rest tumours
  • These can regress with appropriate therapy
  • Complication: infertility
151
Q

Carney complex

A

AD inheritance
Blue naevus, cardiac and skin myxomas, sexual precocity, primary pigmented adrenocortical disease, growth hormone producing pituitary adenomas, thyroid tumours, melatonin schawnnomas

152
Q

Lifetime risk of T1DM and first degree relatives

A 
Monozygotic twin: 33-50%
HLA-identical sib: 16%
Father: 6-9%
Sibling: 5-6%
Mother: 1-4%
153
Q

Antibodies associated with T1DM

A

Zinc transporter 8 - ZnT8A and insulinoma-associated antigen - IA-2 Ab is seen in <8yo
Glutamic acid decarboxylase - GAD Ab and IA-2 Ab is seen in adolescents
Insulin Ab = newly discovered

154
Q

HLA and associated T1DM risk

A

High risk with HLA-DR3 and DR4

  • Presence of 1 increases risk 2- to 3-fold
  • Presence of both increases risk 7- to 10-fold
155
Q

DKA

A

BSL >11
Mild: pH <7.3 or HCO3 <15, and presence of ketones (>3)
Mod: pH <7.2 or HCO3 <10, ketones
Severe: pH <7.1 or HCO3 <5, ketones

156
Q

Infections associated with diabetes

A

Congenital rubella
CMV
Enterovirus

157
Q

Genetic syndromes associated with diabetes

A 
T21
Turner syndrome
Prader-Willi syndrome
Klinefelter syndrome
Friedreich's ataxia 
Myotonic dystrophy
Porphyria
158
Q

Permanent neonatal diabetes

A
  • 50-66% have an activating mutation in KCNJII gene and ABCC8 gene –> Kir6.2 and SUR1 subunits of ATP-K channel in Beta-cells
  • Other mutations: homozygous GCK mutation (7p13), homozygous IPF-1 gene and mutations in insulin gene
  • PC: Can be normoglycemic at birth, develops hypoglycemia between birth to 6mo (median = 5wo)
  • 20% have severe phenotype = DEND syndrome (Kir6.2 mutation)
  • Tx: Responds well to sulfonylurea –> great glycemic control and QoL
159
Q

Which mutation causing neonatal diabetes can be less responsive to sulfonylureas?

A

Mutation in ABCC8 gene –> abN SUR1 subunit which is the binding site for sulfonylurea
- Variable response

160
Q

Transient neonatal diabetes

A
  • 70% have mutation in chr6p24 - paternally expressed gene with maternal gene silencing (imprinting disease)
  • Overexpression of ZAC and HYMA1 genes
  • Mechanisms: paternal UPD, duplication of 6p24 on paternal allele, hypomethylation of maternal allele (imprinting defect)
  • PC: transient hyperglycemia, severe growth retardation, large tongue and umbilical hernia
  • -> Pronounced glycosuria –> dehydration and metablic acidosis
  • Tx: BD intermediate acting insulin (1-2u/kg/day)
161
Q

Disease course of transient neonatal diabetes

A
  • Remission in early infancy period with normal OGTT
  • Relapse of diabetes occurs between 4-25yo
  • Loss of first phase insulin secretion as seen in T2DM
  • -> 50-60% of pts develop permanent diabetes
162
Q

MODY

A

Maturity onset diabetes of the young

  • Usually single gene mutation/inheritable diabetes –> defect in B-cell maturation and abnormal insulin secretion
  • -> Non-ketotic as insulin secretion is still maintained, albeit at higher glycemic threshold
163
Q

MODY 1

A
  • HNF4-alpha mutation –> transcription factor involved in B-cell development and fxn
  • Progressive insulin secreting defect
  • PC: neonatal HYPOglycemia, progressive hyperglycemia
  • Low HDL and apolipoproteins A and C –> lipid profile similar to T2DM
  • Very sensitive to sulfonylurea
164
Q

MODY 2

A
  • GCK gene mutation on ch7p13 - heterozygous mutation
  • Glucokinase enzyme is important in B-cell glucose sensing
  • PC: stable, mild hyperglycemia with small increment increase (<4.5mmol/L) in BSL on OGTT, usually normal BMI with no microvascular complications
  • Responds to sulfonylurea and insulin
165
Q

MODY 3

A
  • HNF1-alpha mutation (most common)
  • Strong family history, progressive B-cell failure and thus progressing from mild to severe dz overtime
  • PC: symptomatic hypoglycemia with glycosuria secondary to reduced renal reabsorption, high HDL-C
  • Prone to developing microvascular complications
  • Very sensitive to sulfonylureas
166
Q

MODY 4

A
  • IPF-1 gene mutation

- Necessary for pancreatic development –> homozygous mutation causes agenesis of pancreas

167
Q

MODY 5

A
  • HNF1-beta mutation
  • Important = multisystem manifestations
  • -> Renal cysts and other malformations, hypospadias, uterine abN, joint laxity, learning difficulties, abN LFTs
  • Pancreatic atrophy with co-existing EXOcrine pancreatic insufficienty
  • Does not respond to oral agents, requires insulin
168
Q

Summary of MODY

A
  • MODY 1 and 3: progressive beta cell failure, both have strong FHx and are at risk of microvascular complications. MODY 1 has low HDL and apolipoproteins, MODY 3 has high HDL and renal glycosuria, both sensitive to sulfonylureas
  • MODY 2: very mild hyperglycemia in a patient with normal BMI with very low risk of microvascular Cx
  • MODY 5: multisystem involvement and associated exocrine pancreatic insufficency due to pancreatic atrophy
169
Q

Monitoring during pubertal induction

A
  • 6 monthly bone age, FSH, LH

- IGF-1 for growth hormone dosing (if concurrent)

170
Q

Endocrine changes seen in pts with anorexia nervosa

A
  • Hypothalamic suppression with low gonadotrophin levels
  • Pubertal regression
  • Sick euthyroid syndrome
  • Decelerated linear growth
  • Reduced bone mineral density
  • Low IGF-1 and low thyroxine levels

Paediatrics (16 decks)

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