Endocrine/Reproductive - Congenital adrenal hyperplasia

Question 1

Definition

Answer 1

Group of autosomal recessive disorders involving impaired synthesis of cortisol, usually due to a deficiency in the enzyme 21-hydroxylase (>90% of cases)

Question 2

Classification of congenital adrenal hyperplasia

Answer 2

• Classical CAH (severe): 75% of classical CAH is the salt-wasting type, arising due to mineralocorticoid deficiency. Virilisation of the genitalia is also present
• Classical CAH (moderate): 25% have the simple virilising type, where ambiguous genitalia may present in the absence of salt-wasting.
• Non-classical CAH (mild): this is more common than classical CAH, presenting with mild symptoms and typically diagnosed during adolescence

Question 3

When should CAH be suspected in women

Answer 3

Who are virilised (masculinisation) at birth, or those with precocious puberty

Question 4

When should CAH be suspected in men

Answer 4

Virilisation in childhood

Question 5

Pathophysiology

Answer 5

Cortisol deficiency causes positive feedback on the hypothalamo-pituitary axis, leading to a rise in ACTH production and subsequent adrenal hyperplasia . This results in excessive synthesis of androgens, as these pathways are unimpaired by the enzyme deficiencies, as well as increases in precursor molecules in the pathways blocked by the enzyme deficiency. Other less commonly affected enzymes include 17 alpha-hydroxylase and 11 beta-hydroxylase.

Question 6

Signs and symptoms Males (Severe CAH)

Answer 6

Exhibit features of mineralocorticoid and glucocorticoid deficiency soon after birth
- Hyponatraemia
- Hypoglycaemia
Dehydration,
Poor feeding,
Weight loss
Also exhibit virilised genitalia (large penis sizes).

Question 7

Signs and symptoms Males (mild CAH)

Answer 7

• Unlikely to have mineral imbalances and overtly ambiguous genitalia
• Males may be asymptomatic
• Males may have an enlarged penis, small testicles, early puberty and a deep voice
• Both sexes may appear taller for their age during childhood but become short as adults if untreated

Question 8

Signs and symptoms Females (Severe CAH)

Answer 8

• Virilised genitalia (male-appearing) genitalia from birth
• May also exhibit features of mineralocorticoid and glucocorticoid deficiency soon after birth

Question 9

Signs and symptoms Females (mild CAH)

Answer 9

• Unlikely to have mineral imbalances and overtly ambiguous genitalia
• Abnormal or absent periods.
• Deeper voice, early puberty and facial hair
  Both sexes may appear taller for their age during childhood but become short as adults if untreated

Question 10

Diagnosis

Answer 10

CAH must be suspected in infants born with ambigious gentialia
- FIRST LINE: Serum 17-hydroxyprogesterone levels = precursor of the enzyme, 21-hydroxylase and is diagnostic of classical 21-hydroxylase deficiency (21-OHD)
- Serum electrolytes: to assess for hyponatraemia, hyperkalemia, and acidosis in suspected salt-washing CAH.
- Serum hormone levels: elevated ACTH and renin will be expected in salt-wasting CAH, with associated low cortisol and aldosterone

Question 11

Treatment

Answer 11

Salt-wasting forms of CAH:
- Glucocorticoids : Replace cortisol deficiency and suppress excess androgen production with hydrocortisone, typically taken 2-3 times a day.
- Mineralocorticoids : Replace aldosterone deficiency with fludrocortisone
- Sodium chloride supplementation: For infants with salt-wasting CAH to prevent hyponatremia

Virilisation forms of CAH:
- Surgical correction: If required for ambiguous genitalia or other anatomical abnormalities
- Psychological therapy: offered to those struggling with gender identity issues

Question 12

Complications

Answer 12

• Adrenal crisis
• Infertility
• Short stature
• Peripheral precocious puberty
• Metabolic abnormalities : obesity, insulin resistance, dyslipidemia. These tend to be caused by over-treatment with glucocorticoids, resulting in Cushing syndrome.
• Psychological issues: relating to gender identity and body image