Congenital Adrenal Hyperplasia

• The adrenal gland consists of two distinct endocrine systems: the cortex and the medulla.

• Adrenal Medulla:
  • Develops from sympathetic neural tissue derived from the ectoderm.
  • Secretes catecholamines (e.g., adrenaline, noradrenaline).
• Adrenal Cortex:
  • Develops from the mesoderm.
  • Responsible for secreting steroid hormones (e.g., cortisol, aldosterone).
  • Development begins around 4-6 weeks of gestation and becomes functional by 8-9 weeks.
• Adrenal Cortex in the Fetus:
  • Composed of the fetal cortex (constituting about 80% of the gland) and the true cortex.
  • The fetal cortex primarily secretes dehydroepiandrosterone (DHEA), a precursor for estrogen synthesis in the placenta.
• Postnatal Development:
  • The fetal cortex gradually shrinks and disappears by the 6th month of postnatal life, leaving the adult form of the adrenal cortex.

• Adrenocorticotropic Hormone (ACTH):
  • Acts as a trophic hormone on the adrenal cortex, stimulating the secretion of glucocorticoids, mineralocorticoids, and androgens.
• Cortisol:
  • Has a negative feedback effect on both the pituitary gland and the hypothalamus, inhibiting further secretion of ACTH and corticotropin-releasing hormone (CRH).
• Mineralocorticoids:
  • Controlled primarily by the renin-angiotensin system.
  • Responsible for maintaining sodium and water homeostasis by promoting sodium retention and potassium excretion in the kidneys.
• Glucocorticoids:
  • Have anti-inflammatory, immunosuppressive, and counter-regulatory effects on glucose metabolism.
  • In large amounts, they can also cause sodium and water retention, contributing to increased blood pressure.

• Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders resulting from enzyme deficiencies involved in steroidogenesis.
• These enzyme deficiencies cause cortisol deficiency, leading to a loss of negative feedback on the hypothalamus (HYP) and pituitary gland (PIT). Consequently, there is an increased release of adrenocorticotropic hormone (ACTH), which promotes the growth of the adrenal glands (adrenal hyperplasia).
• The excessive stimulation of the adrenal glands by ACTH leads to increased metabolism along alternate steroid pathways, resulting in abnormal production of mineralocorticoids and/or androgens.

Enzyme Deficiencies in CAH

• 21-Hydroxylase Deficiency: Most common, accounting for 90-95% of cases.
• 3β-Hydroxysteroid Dehydrogenase Deficiency: Less common, about 5%.
• 11β-Hydroxylase Deficiency: Occurs in 5-8% of cases.
• 17α-Hydroxylase Deficiency: Rare.
• Desmolase Deficiency (Lipoid Hyperplasia): Rare.

21-Hydroxylase Deficiency (21-OH Deficiency)

• 21-Hydroxylase Deficient Congenital Adrenal Hyperplasia (CAH):
  • In 21-hydroxylase deficiency, there is impaired conversion of progesterone to deoxycorticosterone in the mineralocorticoid pathway and 17α-OH progesterone to deoxycortisol in the glucocorticoid pathway.
  • This leads to reduced cortisol and aldosterone synthesis and compensatory overproduction of androgens, causing virilization and electrolyte disturbances.
• Incidence: Varies globally, with an average of about 1 in 15,000 to 20,000 births.
• Prevalence: More common in populations with high rates of consanguineous marriages, such as those in Alaska and among Ashkenazi Jews.
• 21-hydroxylase deficiency is the most common form of CAH and can present with a range of clinical manifestations depending on the extent of enzyme deficiency and resulting hormone imbalances.

CAH can present in two major forms based on the presence or absence of salt-wasting symptoms:

1. Non-Salt Losers (25% of CAH cases):
   • Males:
     • Present with precocious isosexual puberty (early development of male secondary sexual characteristics) around 4-5 years of age.
   • Females:
     • Often born with ambiguous genitalia due to prenatal androgen exposure.
     • Later present with precocious heterosexual puberty, showing male secondary sexual characteristics.
2. Salt-Losers (75% of CAH cases):
   • Symptoms typically start shortly after birth and include:
     • Weight loss or failure to regain birth weight.
     • Dehydration and shock due to mineralocorticoid deficiency.
     • Vomiting and cyanosis due to electrolyte imbalance.
   • In females, ambiguous genitalia at birth may heighten suspicion for CAH.
   • In males, the diagnosis can be missed initially since they do not present with ambiguous genitalia, but symptoms of adrenal crisis may prompt further investigation.

Salt-losing CAH is more severe and requires urgent diagnosis and management to prevent life-threatening complications such as adrenal crisis.

Clinical Index of Suspicion:

• Babies with ambiguous genitalia: Particularly in female infants where the genitalia are not clearly male or female.
• Hyperpigmentation: Suggests excess ACTH due to cortisol deficiency.
• Family History: Babies with a history of previously affected siblings or unexplained neonatal deaths.

Laboratory Investigations:

• Elevated 17-Ketosteroids: Increased levels in blood and urine, indicating excessive androgen production.
• Increased DHEAS (Dehydroepiandrosterone sulfate): A marker of adrenal androgen production.
• Electrolyte Imbalance:
  • Decreased sodium (Na) and chloride (Cl).
  • Increased potassium (K).
  • Elevated urea and renin levels due to mineralocorticoid deficiency.

Prenatal Diagnosis and Management:

• Diagnosis:
  • Chorionic villus biopsy with DNA analysis, performed at 14-16 weeks of gestation, can confirm the diagnosis of CAH.
• Treatment:
  • Maternal dexamethasone therapy starting from the 8th-9th week of gestation to reduce the risk of virilization in a female fetus.
  • The treatment is discontinued if the fetus is determined to be male.

1. Glucocorticoid Therapy:
   • Hydrocortisone: Administered at a dose of 20-25 mg/m²/day, divided into two daily doses (2DD). This helps to replace deficient cortisol, suppress excess ACTH production, and reduce adrenal androgen overproduction.
2. Mineralocorticoid Therapy (for salt-wasting CAH):
   • 9α-Fluorocortisol (Fludrocortisone): Given at a dose of 0.05-0.1 mg daily to replace aldosterone, maintaining sodium and potassium balance and preventing dehydration and shock.
3. Sodium Chloride Supplementation:
   • Salt Supplements: Additional sodium chloride may be required for salt-losing patients to correct hyponatremia and maintain normal fluid and electrolyte balance.
4. Surgical Management:
   • Surgical intervention may be necessary for female patients with ambiguous genitalia to achieve a more typical female genital appearance and function. This is often done in consultation with endocrinologists, surgeons, and psychologists to ensure a comprehensive approach to care.

Effective management of CAH requires a multidisciplinary approach involving endocrinologists, pediatricians, surgeons, and mental health professionals to address the medical, psychological, and social aspects of the condition.