Endocrine Flashcards
Diagnosis of diabetes
- Fasting BSL >7mmol/L (no caloric intake for 8hrs)
- 2hr plasma glucose >11.1 during OGTT (glucose load of 1.75g/kg, max 75g)
- Random BSL >11.1 in a pt with Sx of hyperglycemia or DKA
- HbA1c >6.5% (paediatric patients = 6.35%)
Premature thelarche
- Isolated breast development - slow progression
- Absence of other secondary sexual features
- Normal linear growth
- Normal bone age - important
- Peaks at around 2yo and again at 6-8yo
- Soy based formulas, lavender oil and tea tree oil - ??increased risk of premature thelarche
When to investigate “premature thelarche”
- Progressive secondary sexual development
- Increasing height velocity
- Accelerated bone maturation
GnRH dependent (central) precocious puberty
- 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
Causes of central precocious puberty
- Idiopathic (F>M)
- Loss of hypothalamic inhibition: structural growths
- -> Hypothalamic hamartomas - CNS tumours e.g. astrocytoma, pineal gland tumours, optic gliomas
- Acquired CNS insults e.g. CNS irradiation, hydrocephalus, subarachnoid cysts, CP, tub sclerosis
- Neurofibromatosis type 1 (optic glioma)
- Previous excess sex steroid exposure e.g. poorly controlled CAH
- Genetic e.g. gain of function mutation of kisspeptin gene, MKRN3 gene mutation (imprinting)
Treatment of central precocious puberty
- 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
Long term outcomes after treatment with Leuprolide in central precocious puberty
- Height: greatest height gain seen in girls with onset of puberty <6yo (average gain 9-10cm)
- Menstrual cycles and fertility appear normal as adults
- Possible increased incidence of PCOS
McCune-Albright Syndrome
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
Pathogenesis of McCune-Albright Syndrome
- 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
Causes of gonadotrophin-independent (peripheral) precocious puberty in girls
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)
Causes of gonadotrophin-independent (peripheral) precocious puberty in boys
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)
What is the primary reason for short stature in Turner Syndrome?
Haploinsufficiency of SHOX gene
- SHOX gene is located at distal ends of short arms of both sex chromosomes
Risk of germ cell tumours in DSD conditions
High-risk requiring gonadectomies:
- Dysgenetic gonads (+Y) that are intra-abdominal 15-35%
- PAIS (non-scrotal) 50%
- Frasier syndrome 60%
- Denys-Drash (+Y) 40%
- Turner (+Y - mosaic?) 12% (intermediate risk)
Intermediate risk for germ cell tumours
- For monitoring +/- Bx
- 17B-HSD 28%
- Dysgenetic gonads (+Y) - unknown risk –> Bx
- PAIS (scrotal glands) - unknown risk –> Bx
When is the best time to take a cortisol level?
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
Incidence of classical CAH in female
1/28,000
When do physiological pre-pubertal gonadotrophin surges occur?
- Mid-gestation: LH/FSH levels peak, then decline/disappear by term
- 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
“Pro-testis” factors
- SOX9 gene: influences expression of SRY
2. SRY gene: transcription factor which promotes the development of testes, Sertoli and Leydig cells
Camptomelic dysplasia
- 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
Genes responsible for development of bipotential gonads
LIM1, SF1, WT1
Denys Drash Syndrome
- 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)
WNT4 deletion in 46XX
- WNT 4 is a “pro-ovary factor” that promotes development of mullerian structures
- 46XX DSD - no germ cells, ovarian failure and mullerian agenesis
Adrenal hypoplasia congenita
DAX1 deletion
Tests to consider in ovotesticular DSD/46XX testicular/46XY complete gonadal dysgenesis
i.e. “True hermaphrotidism”
Blood karyotype Scrotal skin fibroblast biopsy Gonadal biopsy - Need to identify genotype/karyotype - Usually due to mosaicism or chimerism