Congenital Adrenal Hyperplasia (CAH)

Overview

• Goldman-Cecil Medicine, p. 2515

Steroidogenesis Pathway

Enzyme Defects and Forms of CAH

• Campbell-Walsh Urology, p. 1291

21-Hydroxylase Deficiency (Most Common Form)

Epidemiology

• Responsible for ~95% of all CAH cases
• Incidence: 1 in 5,000-15,000 in the US and Europe
• Highest incidence: 1 in 490 in the Yupik Alaskan Eskimo population
• Gene: CYP21A2 on chromosome 6p21.3, within the HLA complex

Genetics

• The CYP21A2 gene sits adjacent to a nearly identical pseudogene (CYP21PA1), which is 98% homologous but encodes no functional protein
• During meiosis, gene conversion transfers inactivating segments from the pseudogene to the functional gene
• ~10 mutations account for 90-95% of alleles; over 200 different CYP21 mutations have been described
• Campbell-Walsh Urology, p. 1291

Clinical Classification (Three Forms)

• Both aldosterone AND cortisol deficient
• Life-threatening salt-wasting crisis in the neonatal period: hyponatremia, hyperkalemia, hypotension, shock
• Virilization of females at birth
• Males often diagnosed only after salt-wasting crisis (no obvious genital abniguity)

• Cortisol deficient; aldosterone synthesis preserved
• Virilization without salt wasting
• Female: ambiguous genitalia at birth
• Male: precocious puberty

• Mild enzyme impairment; no virilization or salt wasting at birth
• Presents at or after puberty with hirsutism, menstrual irregularity, acne, reduced fertility in females
• Associated with family history of hirsutism
• Goldman-Cecil Medicine, p. 2550

Clinical Manifestations

In Females (46,XX)

• Classic forms cause virilization beginning at 10 weeks' gestation (formation of external genitalia)
• Clitoromegaly and labial fusion are present at birth in nearly all classic cases
• Vagina and urethra open into a common urogenital sinus
• In severe cases, genitalia may appear as a hypospadiac penis with cryptorchidism
• Prader staging (I-V) classifies the degree of virilization
• Müllerian structures (uterus, tubes) are normal - ovaries develop normally
• Campbell-Walsh Urology, p. 1291

In Males (46,XY)

• External genitalia appear normal at birth (no obvious abnormality)
• Salt-wasting crisis at 1-3 weeks of life is often the presenting event - a potentially lethal adrenal emergency
• Simple virilizing form: precocious puberty, rapid linear growth but early epiphyseal fusion causing short adult stature
• Testicular adrenal rest tumors (TARTs): ectopic adrenal tissue in the testes; can cause gonadal damage and infertility if not controlled

Both Sexes

• Advanced bone age and accelerated growth in childhood
• Short adult stature (due to premature epiphyseal fusion)
• Risk of adrenal insufficiency under stress (illness, surgery)

11β-Hydroxylase Deficiency

• Second most common form (~5%)
• Deficiency of CYP11B1 blocks conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone
• DOC accumulation causes sodium retention and hypertension (a distinguishing feature from 21-hydroxylase deficiency, which causes salt wasting)
• Virilization occurs in females similarly to 21-hydroxylase deficiency
• Androgen excess pathway is the same (precursors shunted to androgens)

Diagnosis

Neonatal Screening

• All 50 US states and >40 countries screen newborns for CAH
• Measures 17-hydroxyprogesterone (17-OHP) on dried blood spot (elevated in 21-hydroxylase deficiency)
• Has reduced time to diagnosis and mortality, especially in males with the salt-wasting form

Hormonal Evaluation

• ACTH (cosyntropin) stimulation test with 17-OHP measurement is the gold standard for diagnosis of non-classic CAH
• Genetic testing confirms the specific CYP21A2 mutation

Karyotype

• Mandatory for any infant with ambiguous genitalia

Management

Glucocorticoid Replacement

• Hydrocortisone is the preferred agent in children (15-20 mg/m²/day in 2-3 divided doses)
• Suppresses ACTH, reduces adrenal androgen overproduction, prevents virilization progression
• In adults: hydrocortisone or prednisone
• Dose must be increased during illness, surgery, or physiological stress ("sick day rules")

Mineralocorticoid Replacement (Salt-Wasting Form)

• Fludrocortisone (0.05-0.2 mg/day) to replace aldosterone
• Sodium supplementation in infants (1-2 g/day)

Monitoring

• Growth, bone age, blood pressure
• 17-OHP, androstenedione, testosterone, renin levels
• Avoid over-treatment (causes iatrogenic Cushing syndrome and growth suppression)

Surgical Management

• Feminizing genitoplasty in severely virilized females: vaginoplasty and clitoroplasty
• Timing and extent remains controversial; trend toward deferring to adolescence or adulthood when possible (patient autonomy)

Prenatal Treatment (Investigational/Controversial)

• Dexamethasone (crosses placenta) given to the mother from early first trimester can reduce virilization of an affected female fetus
• Requires early diagnosis via chorionic villus sampling; risk-benefit ratio is debated

Adrenal Crisis Management

• IV hydrocortisone (50-100 mg/m² bolus) + IV saline/dextrose
• A medical emergency requiring immediate treatment

Other Rarer Forms

• Most severe form; impairs the first step (cholesterol → pregnenolone)
• Adrenal glands become large and lipid-laden
• 46,XY individuals have female or ambiguous external genitalia
• Present in neonatal period with severe adrenal insufficiency, salt wasting, hyponatremia, hyperkalemia, metabolic acidosis
• Common in Japanese, Korean, and Palestinian populations
• Campbell-Walsh Urology, p. 1292

• Affects both adrenal and gonads (common early pathway)
• Both sexes: salt-wasting and adrenal insufficiency
• Males: undervirilization (decreased testosterone); females: mild virilization (DHEA elevation)

• Sex steroid synthesis impaired in both adrenal and gonads
• Result: sexual infantilism, primary amenorrhea in 46,XX; ambiguous/female genitalia in 46,XY
• Hypertension and hypokalemia from DOC and corticosterone accumulation

Key Points Summary

• CAH = autosomal recessive enzyme defect → cortisol deficiency → ACTH excess → adrenal hyperplasia + precursor accumulation → androgen excess
• 21-hydroxylase deficiency (CYP21A2) = 95% of cases; three forms: salt-wasting, simple virilizing, non-classic
• Salt-wasting crisis in neonates is a medical emergency
• Neonatal screening using 17-OHP is standard worldwide
• Treatment = lifelong glucocorticoid ± mineralocorticoid replacement
• 46,XX females with classic CAH have normal internal (Müllerian) structures but virilized external genitalia
• Males with classic CAH have normal external genitalia but may present with adrenal crisis