Congenital Adrenal Hyperplasia (CAH)

Definition

• Goldman-Cecil Medicine, p. 2515
• Creasy & Resnik's Maternal-Fetal Medicine

Steroid Biosynthesis Pathway

Enzymatic Defects and Relative Frequency

• Campbell-Walsh-Wein Urology; Emery's Medical Genetics

21-Hydroxylase Deficiency (Most Common Form)

Genetics

• Gene: CYP21A2 on chromosome 6p21.3, within the HLA complex
• Transmitted in autosomal recessive pattern
• Adjacent pseudogene CYP21PA1 is 98% homologous - gene conversion events during meiosis are a major mutation mechanism

• 200 mutations identified; 95% of causative mutations are known

• Incidence: 1 in 5,000-15,000 in general populations; as high as 1 in 490 in Yupik Alaskan Eskimos
• Campbell-Walsh-Wein Urology

Pathophysiology

• Progesterone → Deoxycorticosterone (mineralocorticoid pathway)
• 17-OH Progesterone → 11-Deoxycortisol (glucocorticoid pathway)

Clinical Subtypes

• Robbins & Cotran Pathologic Basis of Disease; Creasy & Resnik

Salt-Wasting Crisis

• Hyponatremia, hyperkalemia, metabolic acidosis
• Hypotension, cardiovascular collapse, potentially fatal
• Males are often not diagnosed until the crisis occurs (normal appearing genitalia at birth)
• Robbins & Cotran

Clinical Features by Enzyme Deficiency

In 46,XX Females (Virilization)

• In utero: Clitoral hypertrophy, labial fusion, urogenital sinus - degrees of difference in sexual development (DSD)
• Childhood: Rapid somatic growth initially, then premature epiphyseal closure → short adult stature without treatment
• Adolescence/adulthood (non-classic): Hirsutism, acne, oligomenorrhea, PCOS-like picture

In 46,XY Males

• Typically normal genitalia at birth (endogenous androgens are sufficient)
• Salt-wasting crisis in first 2 weeks is the presenting feature in severe forms
• Testicular adrenal rest tumors (TARTs) are a long-term complication - can cause severe testicular damage and infertility
• Non-classic: Oligospermia, subfertility

Adrenomedullary Dysfunction

• Robbins & Cotran, p. 2614-2615

Pathological Morphology (Robbins)

• Bilateral adrenal hyperplasia: glands may reach 10-15x normal weight
• Cortex is thickened and nodular, brown on cut section (lipid depletion)
• Proliferating cells: compact, eosinophilic, lipid-depleted cells intermixed with lipid-laden clear cells
• Anterior pituitary: hyperplasia of corticotroph (ACTH-producing) cells

Diagnosis

Biochemical

• 17-Hydroxyprogesterone (17-OHP): elevated in 21-hydroxylase deficiency - the key diagnostic marker
  • Classic CAH: markedly elevated basally
  • Non-classic: may require ACTH stimulation test; exaggerated 17-OHP rise (>1,500 ng/dL)
• Renin/aldosterone ratio: elevated plasma renin in salt-wasting forms
• Electrolytes: hyponatremia, hyperkalemia in salt-wasting crisis
• Androstenedione, testosterone: elevated

Newborn Screening

• Most countries screen for 21-hydroxylase deficiency via elevated 17-OHP on heel-prick blood spot (day 2-5 of life)
• Cannot detect non-classic CAH on routine newborn screening

Genetic Testing

• CYP21A2 genotyping confirms diagnosis and guides prognosis
• Prenatal diagnosis: elevated 17-OHP or 21-deoxycortisol in amniotic fluid, or molecular testing via CVS/amniocentesis
• Berek & Novak's Gynecology; Creasy & Resnik

Treatment

Glucocorticoid Replacement

• Hydrocortisone: 10-20 mg/m² body surface area/day in divided doses (preferred in children to minimize growth suppression)
• Goal: suppress morning 17-OHP to 300-900 ng/dL, normalize androgen levels
• Overreplacement causes Cushingoid effects and impairs growth; underreplacement allows continued androgen excess and epiphyseal advancement
• In adults: prednisone or dexamethasone can be used

Mineralocorticoid Replacement

• Fludrocortisone: indicated in salt-wasting forms; many guidelines recommend it even in simple virilizing forms
• Goal: suppress plasma renin activity to <5 ng/mL/hr
• Sodium supplementation in infants

Stress Dosing

• Double or triple glucocorticoid dose during febrile illness, surgery, or trauma to prevent adrenal crisis

Monitoring

• Children: growth velocity, bone age, hormone levels (17-OHP, androstenedione)
• Adults: 17-OHP, androstenedione, renin, blood pressure, BMI
• Males: testicular ultrasound for TART surveillance

Surgical Management

• Females with ambiguous genitalia: clitoral recession and vaginoplasty - timing is debated; most centers perform in early childhood but the decision involves multidisciplinary input and, increasingly, patient/family preference
• A multidisciplinary team should guide sex-of-rearing decisions and any interventions
• Berek & Novak's Gynecology; Creasy & Resnik; Campbell-Walsh-Wein Urology

Pregnancy and CAH

1. Adrenal androgens suppressing ovulation (direct ovarian effect + GnRH suppression)
2. Elevated progesterone reducing LH pulse frequency and thickening cervical mucus

• Switch dexamethasone to hydrocortisone (dexamethasone crosses the placenta; hydrocortisone is inactivated by placental 11β-HSD)
• Target progesterone <0.6 ng/mL for optimal fertility
• Fludrocortisone continued in salt-losing forms
• 100% of offspring are carriers if the partner is unaffected; 25% of offspring are affected if both parents are carriers

• Creasy & Resnik's Maternal-Fetal Medicine

11β-Hydroxylase Deficiency (Second Most Common)

• ~5% of CAH cases
• Defect: CYP11B1; blocks conversion of 11-deoxycortisol → cortisol and deoxycorticosterone → corticosterone
• Deoxycorticosterone accumulates → hypertension and hypokalemia (mineralocorticoid excess)
• Paradoxically, aldosterone synthesis is low but DOC compensates
• Also causes androgen excess and virilization (similar to 21-hydroxylase deficiency)
• Campbell-Walsh-Wein Urology; Robbins & Cotran

Non-Classic CAH

• Partial 21-hydroxylase deficiency; most common form overall in the general population
• Presents in adolescence or adulthood with hirsutism, acne, oligomenorrhea, PCOS-like picture
• Cannot be identified by newborn screening
• Diagnosed by ACTH stimulation test (exaggerated 17-OHP response)
• Males: oligospermia; infertility may be reversed with glucocorticoid therapy at lower doses
• Treatment: low-dose glucocorticoids when symptomatic; OCP + anti-androgens are alternatives

Key Summary Points

1. Fundamental defect: Impaired cortisol synthesis → elevated ACTH → adrenal hyperplasia + androgen excess
2. Most common: 21-hydroxylase deficiency (CYP21A2), >95% of cases
3. Three classic subtypes: Salt-wasting, simple virilizing, non-classic
4. 46,XX: Virilized genitalia (DSD) at birth; 46,XY: normal genitalia but salt crisis at 5-15 days
5. Diagnosis: Elevated 17-OHP is the key marker; confirmed by genetic testing
6. Newborn screening detects classic forms
7. Treatment: Hydrocortisone (glucocorticoid replacement) + fludrocortisone (mineralocorticoid) + salt supplementation in infants
8. Long-term risks: Short stature, infertility, testicular adrenal rest tumors (males), metabolic syndrome