Congenital Adrenal Hyperplasia Flashcards
What are some features of Congenital Adrenal Hyperplasia in clinical practice?
- Typically, an autopsy finding
- Autosomal Recessive pattern of inheritance
- Mutation of genes for enzymes involved in steroidogenesis lead to a defect in normal steroidogenesis
- Leads to deficiency in steroid end products and accumulation of precursors proximal to the block
- There can also be an excess of other steroid end products
What are some enzyme defects in Congenital Adrenal Hyperplasia?
- 21 hydroxylase deficiency - 1:15,000
- 11β hydroxylase deficiency - 1:100,000
- 3β hydroxysteroid deficiency - rare
- 17α hydroxylase deficiency - 1:1,000,000
- 5α reductase deficiency
- Cytochrome P450 oxidoreductase deficiency 1:200,000
What are clinical features of CAH?
Due to Increase ACTH secretion
- Hyperpigmentation
Due to decreased cortisol biosyntheisis
- Poor Appetite
- Poor weight gain
- Fatigue
- Vomiting
- Weakness
- Hypoglycaemia
Due to mineralocorticoid biosynthesis
- Dehydration
- Hyponatraemia
- Hyperkalaemia
Due to Increased adrenal androgen biosynthesis
- Virilization
Decrease adrenal androgen biosynthesis
- Undermasculinisation
What is the spectrum of genital development in males with 21 Hydroxylase deficiency?
Males have a more generous penis
What is the spectrum of genital development in females with 21 Hydroxylase deficiency?
Females have less develop reproductive organ. Features can include:
- Prominent Clitoris
- Urethral opening in perineum
- Labia Roguse and partially fused
- No palpable gonads
What are biochemical tests for diagnosis of Congenital Adrenal Hyperplasia?
- ACTH
- 17-hydroxy Progesterone
- Deoxycortisol
- Renin
- Aldosterone
- Cortisol
- Synacthen Test
- DHEAS
- Androstenedione
- Testosterone
- Plasma Electrolytes: K+, Na+, Urea
What are methods for urine steroid profiling for steroid metabolites?
- Thin layer chromatography
- Gas chromatography
- Gas chromatography – mass spectrometry (GC/MS)
- Liquid chromatography tandem mass spectrometry (LC/MS/MS)
What are features of liquid chromatography tandem mass spectrometry for urine steroid proiling for steroid metabolites?
Superior to immunoassays. Gives Two types of data
- Quantitative data for individual metabolites
- Diagnostic ratios of precursor metabolites to product metabolites
In what conditions can urine steroid profiling for steroid metabolites be used for CAH?
Female:
- 21-hydroxylase deficiency
- 3β-hydroxysteroid deficiency
- 11β hydroxylase deficiency
Male:
- 3β-hydroxysteroid deficiency
- 17α hydroxylase deficiency
- 5α reductase efficiency
- Cytochrome P450 oxidoreductase deficiency
What are some genetic classifications of 21 hydroxylase deficiency?
- Class C – non classical
- Class B - classical simple virilising
- Class A – classical simple virilising
- Null – Classical salt wasting
What are biochemical features of 21 Hydroxylase deficiency?
- Increase Androgen formation in Zona Reticularis (androstenedione and testosterone)
- High Progesterone and 17-hydroxy progesterone
- High ACTH
- Low cortisol and aldosterone
What is the presenation of 21 Hydryoxylase deficiency?
- High potassium
- Low/normal sodium
- Not feeding
- Sleeping
- Drowsy
- Hyperpigementation
- Larger Penis
What is the treatment for 21 Hydroxylase deficiency?
- Hydrocortisone
- Fludrocortisone
- Sodium Chloride
- Monitor 17-OHP, androstadienes, ACTH, Testosterone, Renin and Electrolytes every 3-4 months
What are features of 11β-hydroxylase deficiency CAH?
- 2nd most common cause of CAH (1 in 100,000 to 200,000)
- CYP11B1 is located on chromosome 8 accounts for 5-8% of cases
- More common in Israeli population of Moroccan Jewish origin (1 in 5000 to 7000)
- Characterised by Hypertension
What is the biochemical presentation of 11β-hydroxylase deficiency CAH?
- High Renin
- High Androgen
- Low Cortisol
- High 11-Deoxycorticosterone and 11-deoxycortisol
- USP: Looks at 11 deoxycortisol metabolites to cortisol metabolites
How is 11β-hydroxylase deficiency CAH managed?
- Explain CAH to Parents
- Hydrocortisone (no fludrocortisone)
- Monitor blood ACTH, 11-DOC, and Androgens
What are features of 17α-hydroxylase defects?
- Rare, 1:50,000 new-borns. Accounts for about 1% cases worldwide
- Gene for CYP P450C17 on chr 10q24
- 17α-hydroxylation & 17,20-lyase involved
What is the biochemical presentation of 17α-hydroxylase defects?
- Chronic High ACTH
- Mild Glucocorticoid deficiency, not life threatening
- High Deoxycortisol and Corticosterone
- Low Renin
- Low Sex steroids (Normal female appearance, no adrenarche and puberty and Undervirilisation in males)
- Sodium Retention and Hypertension
- Hypokalaemia
What are forms of of 3β-HSD-II deficiency CAH?
Classical (severe)
- Steroid synthesis in both adrenal cortex & gonads (testes, ovary) is affected
- ∆5 > ∆4 compounds
- Excess circulating androgen precursor steroids (DHEA) converted to androgens outside the adrenal (eg. liver)
- 46XX: mild virilisation of females
- 46XY: undervirilisation of males
Non-classical (mild)
- Females: Premature adrenarche, hirsutism, virilism, oligomenorrhoea
What are types of 3β-HSD-II deficiency CAH?
- Type I: placenta, peripheral tissues
- Type II: adrenals, gonads
Wht are biochemical abnormalities of 3β-HSD-II deficiency CAH?
- High DHEA which gets converted into a small amount of androenstiodine in other tissues
- High 17-OHP
- Low sodium, high potassium
What is PORD?
P450 oxidoreductase (POR) is a mandatory electron donor enzyme to all microsomal cytochrome P450 (CYP) enzymes
What are key enzymes affects in PORD?
Multiple key enzymes indirectly affected
- 17α-hydroxylase (CYP17A1)
- 21-hydroxylase (CYP21A2)
- P450 aromatase (CYP19A1)
What is the effect of PORD?
Partial deficiency in steroidogenesis involving
- Glucocorticoid leads to partial adrenal insufficiency
- Sex steroid synthesis leads to undervirilisation in 46XY and virilisation of 46XX
Skeletal abnormalities leads to Antley-Bixler syndrome
