Congenital Adrenal Hyperplasia (CAH)

Steroidogenesis Pathway

Definition and Pathophysiology

1. Adrenocortical hyperplasia
2. Accumulation of steroid precursors proximal to the enzymatic block
3. Shunting of precursors toward androgen synthesis

21-Hydroxylase Deficiency (Most Common Form)

Genetics and Epidemiology

• Incidence: 1 in 5,000-15,000 in the US and Europe
• Highest incidence: 1 in 490 in Yupik Alaskan Eskimo population
• Gene locus: chromosome 6p21.3 within the HLA complex, transmitted autosomal recessively
• The CYP21A2 gene lies adjacent to an inactive pseudogene (CYP21PA1) that is 98% homologous - gene conversion during meiosis is a major mutational mechanism
• ~10 mutations account for 90-95% of alleles; over 200 different CYP21 mutations have been reported

Clinical Forms

• Complete or near-complete 21-hydroxylase deficiency
• Aldosterone deficiency + cortisol deficiency + androgen excess
• Presents in neonates within 10-21 days of life: failure to thrive, vomiting, progressive weight loss, dehydration
• Life-threatening: hyperkalemia, hyponatremia, shock, adrenal crisis
• In males: often mistakenly diagnosed as pyloric stenosis or urosepsis
• In females: ambiguous genitalia at birth (always present since virilization begins at ~10 weeks gestation)

• Partial 21-hydroxylase deficiency with residual aldosterone synthesis
• No salt wasting
• Females: virilization of external genitalia (clitoromegaly, labial fusion, urogenital sinus)
• Males: may appear normal at birth - diagnosis often delayed until signs of isosexual precocious puberty appear

• Mildest, most common form overall
• Often presents at puberty or adulthood
• Females: hirsutism, irregular menses, acne, short stature, oligomenorrhea (mimics PCOS)
• Males: may be asymptomatic or have acne/infertility

Prader Classification of Virilization (Females)

• Grades I-V reflecting progressive degrees of genital ambiguity, from clitoromegaly alone (I) to complete penile urethra (V)

11β-Hydroxylase Deficiency (~5% of CAH)

• Block at conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone
• DOC and 11-deoxycorticosterone accumulate - DOC has mineralocorticoid activity
• Features: virilization (like 21-OHD) plus hypertension (from DOC excess) and no salt wasting
• Hypokalemia may occur

Diagnosis

Newborn Screening

• Nationwide in all 50 US states and >40 countries
• Measures 17α-hydroxyprogesterone (17-OHP) on filter paper blood spot (elevated in 21-OHD)
• Has dramatically improved time to diagnosis and survival, especially in males with salt-wasting form

Laboratory Markers

• ACTH stimulation test: 1 μg or 250 μg cosyntropin IV; 17-OHP >10,000 ng/dL at 60 min = classic CAH; 1,000-10,000 = non-classic
• Prenatal diagnosis: elevated 17-OHP or 21-deoxycortisol in amniotic fluid; genetic testing via CVS or amniocentesis

Treatment

Glucocorticoid Replacement

• Hydrocortisone: 10-20 mg/m²/day in 2-3 divided doses (first-line in children)
• Goal: suppress 17-OHP to 300-900 ng/dL (morning levels)
• Monitor: growth velocity, bone age, hormone levels - both overreplacement and underreplacement cause premature epiphyseal closure and short stature
• Adults: prednisolone or dexamethasone can be used (longer half-life, easier compliance), but dexamethasone carries higher risk of Cushingoid effects

Mineralocorticoid Replacement

• Fludrocortisone (Florinef): 0.05-0.2 mg/day orally
• Required in all patients with 21-OHD (even simple virilizers have subclinical aldosterone deficiency)
• Goal: suppress plasma renin activity to <5 ng/mL/hr
• Dietary salt supplementation in infants

Adrenal Crisis Management (Acute)

• Aggressive IV fluids (normal saline) for volume support
• Hydrocortisone IV: 1.5-2.0 mg/kg bolus, then 25-250 mg/day in divided doses
• Glucose supplementation
• Electrolyte correction

Stress Dosing ("Sick Day Rules")

• Double or triple the daily glucocorticoid dose during fever, illness, or surgery
• Parenteral hydrocortisone if unable to take oral medications

Surgical Management

• Females with ambiguous genitalia may need clitoral recession and vaginoplasty
• Timing is debated; the child must be of appropriate size for optimal outcome

Prenatal Treatment

• Dexamethasone given to the at-risk mother crosses the placenta and can reduce or prevent virilization of an affected female fetus
• Risks: maternal hypercortisolism, possible neurodevelopmental effects on infant
• Controversial - benefit only for affected females (~1/8 of all pregnancies at risk)

Complications and Long-term Issues

Key Points Summary

• CAH is the most common cause of ambiguous genitalia in 46,XX females
• 21-hydroxylase deficiency accounts for 95% of cases
• The classic triad in salt-wasting form: hyponatremia + hyperkalemia + elevated 17-OHP
• Salt-wasting form can be life-threatening in the first 2-3 weeks of life
• 11β-hydroxylase deficiency is the second most common and uniquely presents with hypertension (not salt wasting)
• Treatment is lifelong glucocorticoid + mineralocorticoid replacement
• All patients require stress dosing during illness or surgery