Monogenic Endocrine Disorders: Congenital Adrenal Hyperplasia, Pituitary Dwarfism, Congenital Hypothyroidism
Monogenic endocrine disorders arise from mutations affecting hormone synthesis, secretion, receptors, or transcription factors involved in endocrine gland development and function. They often present at birth or in early childhood and can cause growth failure, metabolic disturbances, electrolyte imbalance, and sexual development abnormalities.
Key examples include:
- Congenital adrenal hyperplasia (CAH)
- Pituitary dwarfism (isolated or combined pituitary hormone deficiency)
- Congenital hypothyroidism
I. CONGENITAL ADRENAL HYPERPLASIA (CAH)
Congenital adrenal hyperplasia is a group of autosomal recessive disorders caused by enzyme deficiencies in adrenal steroid biosynthesis, leading to:
- impaired cortisol synthesis,
- compensatory ACTH overproduction,
- adrenal hyperplasia,
- hormonal imbalance affecting mineralocorticoids and sex steroids.
Genetic and Molecular Basis
- Inheritance: Autosomal recessive
- Most common cause (>90%): 21-hydroxylase deficiency
- Gene: CYP21A2 (chromosome 6p21.3)
Other rarer enzyme defects
- 11β-hydroxylase (CYP11B1)
- 17α-hydroxylase (CYP17A1)
- 3β-hydroxysteroid dehydrogenase
Normal Adrenal Steroid Pathway
Cholesterol → cortisol, aldosterone, and sex steroids If a step is blocked:
- precursors accumulate,
- synthesis is diverted to androgen pathway,
- cortisol deficiency removes negative feedback on ACTH.
Pathophysiology
- 1. Enzyme defect blocks cortisol synthesis.
- 2. ↓ Cortisol → loss of negative feedback on pituitary.
- 3. ↑ ACTH secretion → adrenal cortex hyperplasia.
- 4. Steroid precursors shunted toward androgen production.
- 5. Depending on enzyme involved:
- aldosterone deficiency → salt-wasting,
- androgen excess → virilization.
Clinical Forms of 21-Hydroxylase Deficiency
Clinical Features
- Females (46,XX):
- Ambiguous genitalia at birth (virilization)
- Males (46,XY):
- Normal genitalia at birth
- Early puberty, rapid growth but short final height
- Both sexes:
- Failure to thrive
- Vomiting, dehydration (salt-wasting type)
- Hypoglycemia
Diagnosis
- Elevated 17-hydroxyprogesterone (screening test)
- Electrolyte abnormalities (salt-wasting)
- ACTH stimulation test
- Genetic testing confirms mutation
Management
- Glucocorticoid replacement (hydrocortisone)
- Mineralocorticoid replacement (fludrocortisone)
- Salt supplementation
- Surgical correction of ambiguous genitalia (selected cases)
- Lifelong endocrine follow-up