Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to a group of disorders caused by autosomal recessive variants that reduce or eliminate the activity of enzymes responsible for synthesizing adrenal steroid hormones (e.g., cortisol, aldosterone). CAH is characterized by reduced cortisol, elevated adrenocorticotropic hormone (ACTH), adrenal hyperplasia, and often androgen excess, with or without aldosterone deficiency. Clinical features vary by karyotype (i.e., 46,XX or 46,XY) and type and severity of the enzyme deficiency. The most common type of CAH is caused by a deficiency of 21β-hydroxylase. Classic 21β-hydroxylase deficiency may be recognizable at birth in 46,XX individuals because it can cause atypical external genitalia. Neonates with the salt-wasting subtype of 21β-hydroxylase deficiency may present with adrenal crisis (e.g., shock, vomiting, poor feeding) within a few weeks of birth. Routine neonatal screening is performed within 48 hours of birth to identify neonates with the condition before symptoms manifest. The simple virilizing subtype of classic 21β-hydroxylase deficiency typically manifests in childhood with early adrenarche and precocious puberty, while nonclassic 21β-hydroxylase deficiency is a milder form of CAH that is often not diagnosed until adolescence or adulthood. Other types of CAH (e.g., 11β-hydroxylase deficiency and 17α-hydroxylase deficiency) are rare. Treatment varies depending on the karyotype and type and severity of the enzyme deficiency and may include glucocorticoid and mineralocorticoid replacement, hypertension management, androgen inhibition or replacement, and/or surgery for atypical genitalia.

Hypocortisolism is seen in all forms of CAH.

• Congenital adrenal hyperplasia (CAH) is caused by autosomal recessive genetic variants that reduce or eliminate the activity of enzymes responsible for synthesizing adrenal steroid hormones (e.g., cortisol, aldosterone).
  • 21β-hydroxylase deficiency → ↓ cortisol and ↓ aldosterone ^[2]
  • 11β-hydroxylase deficiency and 17α-hydroxylase deficiency → ↓ cortisol and ↑ 11-deoxycorticosterone (DOC)
• ↓ Cortisol → ↑ ACTH → adrenal hyperplasia
  • In 21β-hydroxylase deficiency and 11β-hydroxylase deficiency, adrenal hyperplasia results in accumulation of cortisol precursors → ↑ androgens
  • In 17α-hydroxylase deficiency, production of cortisol precursors is blocked → ↓ androgens
• ↑ DOC (a mineralocorticoid) → sodium retention, urinary excretion of potassium, volume expansion, hypertension → renin-angiotensin-aldosterone system suppression → ↓ aldosterone ^[6]

“1 DOC:” If the deficient enzyme starts with 1 (11β-hydroxylase, 17α-hydroxylase), there is increased DOC. “AND 1:” If the deficient enzyme numeral ends with 1 (21β-hydroxylase, 11β‑hydroxylase), androgens are increased.

Specific features of CAH vary by subtype; see "Subtypes and variants" for details. General features suggestive of CAH include: ^[1][2][3]

• Atypical genitalia
• Clinical features of adrenal crisis (e.g., vomiting, diarrhea, shock, dehydration, poor feeding) within 3 weeks of birth
• Signs of virilization (e.g., early adrenarche, precocious puberty, advanced bone age, acne) in prepubertal children
• Amenorrhea and/or absent secondary sexual characteristics in adolescents
• Signs of hyperandrogenism in adolescent or adult female individuals
• Hypertension in children
• Stress-induced hypoglycemia
• Hyperpigmentation

Infants with 21β-hydroxylase deficiency may present with shock in the first 3 weeks of life due to hypoaldosteronism. ^{[11] [2]}

Individuals with a 46,XX karyotype and virilizing CAH are more likely to experience gender dysphoria.

• Precocious pseudopuberty
• Primary adrenal insufficiency
• PCOS
• Hyperprolactinemia
• Cushing Syndrome

Nonclassic CAH may be difficult to distinguish from polycystic ovarian syndrome. ^[9]

The differential diagnoses listed here are not exhaustive.

Diagnostics ^[1]

Refer to endocrinology to assess for enzyme deficiency in patients with:

• Positive newborn screen for 21β-hydroxylase deficiency
• Clinical features of CAH, regardless of initial screen or test results

Management ^[1][12]

Management of CAH is provided by endocrinology.

• Type-specific treatment
  • Usually aimed at replacing deficient hormones and reducing excess androgen production
  • See the respective sections in "Subtypes and variants" for details.
• General management of CAH
  • All patients
    • Offer referral for genetic counseling, especially for patients planning pregnancy.
    • Screen routinely for psychosocial concerns , and refer for mental health counseling as needed.
  • All pediatric patients: Offer referral to surgery to discuss options for genital reconstructive surgery based on shared decision-making.
  • Glucocorticoid-dependent patients
    • Educate about indications for steroid stress dosing to prevent adrenal crisis.
    • Provide an emergency hydrocortisone administration kit.
    • Consider bone mineral density assessment, especially in patients with a nontraumatic fracture.
  • Patients who require treatment: Recommend carrying a medical identification card or jewelry.

Provide steroid stress dosing during severe infection, critical illness, and perioperatively to prevent adrenal crisis. ^[1]

• The three most common subtypes are:
  • 21β-hydroxylase deficiency (∼ 95% of CAH) ^[7]
  • 11β-hydroxylase deficiency (∼ 5% of CAH) ^[13]
  • 17α-hydroxylase deficiency (rare) ^[3]
• Other rare subtypes include: ^[3]
  • 3β-hydroxysteroid dehydrogenase deficiency
  • Cytochrome P450 oxidoreductase deficiency
  • Lipoid CAH

Epidemiology

• Classic 21β-hydroxylase deficiency
  • Prevalence: rare (1:14,000–1:18,000 live births) ^[1]
  • Most common in genetically isolated populations (e.g., Alaskan Yupik) ^[7][14]
• Nonclassic 21β-hydroxylase deficiency
  • Prevalence: most common type (∼ 1:200) ^[15]
  • Most common in Mediterranean and Ashkenazi Jewish populations ^[15]

Clinical features

• The clinical features of 21β-hydroxylase deficiency occur on a spectrum based on the level of enzyme activity. ^[1]
  • Classic 21β-hydroxylase deficiency: <2% of normal enzyme activity levels
  • Nonclassic 21β-hydroxylase deficiency: 20–50% of normal enzyme activity levels

All individuals with classic 21β-hydroxylase deficiency have some level of salt-wasting and androgen excess regardless of subtype. ^[2]

Individuals with nonclassic 21β-hydroxylase deficiency and XY karyotype are often asymptomatic before puberty. ^[7]

Newborn screening ^[1][12][14]

Newborn screening for 21β-hydroxylase deficiency is performed routinely. ^[7]

• Sample collection: within 24–48 hours of birth via heel stick test ^[14]
• Screening test: 17-hydroxyprogesterone (17-OHP) immunoassay ^[1][12]
• Immediate follow-up for elevated 17-OHP immunoassay:
  • Evaluate newborns for clinical features of adrenal crisis.
  • Obtain serum electrolytes, glucose, and additional tests in urgent consultation with pediatric endocrinology.

If the newborn screen is negative but there are clinical features of adrenal insufficiency, perform additional testing to rule out CAH caused by other enzyme deficiencies. ^[11]

Diagnosis ^[1][2]

The diagnosis is based on clinical findings and evidence of enzyme deficiency.

• Initial test: serum 17-OHP level by liquid chromatography-mass spectrometry
  • Perform before 8:00 a.m.
  • 17-OHP > 200 ng/dL suggests deficiency. ^[15]
• Confirmatory test: ACTH stimulation test
  • Perform > 24–48 hours after birth. ^[1]
  • Method: Measure 17-OHP levels before and after administration of exogenous ACTH. ^[1]
  • 17-OHP > 1000 ng/dL is typically considered positive. ^[2]
• Additional testing
  • Electrolyte and/or acid-base studies
  • Genetic testing is recommended for:
    • Diagnostic uncertainty
    • Pregnancy planning
  • Bone age in children: to determine skeletal maturation
  • Pelvic or testicular ultrasound: to assess for reproductive organ anomalies

Management ^{[1][2] [12]}

Management is provided by an endocrinologist and includes general management of CAH. For management of adrenal salt-wasting crisis, see "Adrenal crisis."

Classic 21β-hydroxylase deficiency

• Pharmacological treatment
  • Glucocorticoids: Lifelong replacement therapy is required in all patients.
    • Infants and children: hydrocortisone
    • Adolescents and adults: Hydrocortisone is preferred, but other glucocorticoids may be used.
  • Fludrocortisone
    • Infants: required in all
    • Older individuals: used only if mineralocorticoid deficiency persists
  • NaCl supplementation: required only in infants
  • Oral hormonal contraception: may be used for the management of hyperandrogenism in women
• Monitoring ^[1]
  • All ages: weight, blood pressure, biochemical markers
  • Children: linear growth velocity, bone age ^[1][16]
  • Male individuals beginning in adolescence: testicular ultrasound ^[1]

Individuals with classic 21β-hydroxylase deficiency require lifelong glucocorticoid replacement therapy. ^[1]

Monitor for signs of mineralocorticoid and glucocorticoid excess (e.g., decreased linear growth velocity, delayed bone age, weight gain, hypertension) as well as signs of inadequate treatment response. ^[1]

Nonclassic 21β-hydroxylase deficiency

• Indications for glucocorticoids include:
  • Children with precocious puberty, accelerated linear growth velocity, and/or advanced bone age ^[1][15]
  • Infertility
  • Patients with oligomenorrhea and/or anovulatory cycles who are planning pregnancy
• Adolescent and adult women with signs of hyperandrogenism (e.g., hirsutism)
  • First line: combined oral contraceptive ± direct hair removal methods (e.g., electrolysis) ^[15]
  • For refractory symptoms, consider:
    • Antiandrogen medications (e.g., spironolactone, finasteride) ^[15]
    • Glucocorticoids

Most adult male individuals do not require glucocorticoid treatment. ^[1]

Combined oral contraceptives are first-line therapy for women with signs of hyperandrogenism who are not planning pregnancy. ^[1][15]

Clinical features

Individuals with classic 11β-hydroxylase deficiency typically have hypertension due to higher residual mineralocorticoid enzyme activity. ^[9]

Diagnosis ^[3][9]

The diagnosis is based on clinical findings and evidence of enzyme deficiency.

• Suspected 11β-hydroxylase deficiency: Refer to endocrinology for the following studies.
  • Basal or ACTH-stimulated serum 11-deoxycortisol and DOC ^[9]
  • Electrolyte studies: to evaluate for hypokalemia
  • Genetic testing: to determine the type of CYP11B1 variant

17-OHP levels cannot be used to distinguish between 11β-hydroxylase deficiency and 21β-hydroxylase deficiency because they are typically elevated in both types. ^[9]

Management ^[9]

Management is provided by an endocrinologist and includes general management of CAH.

• Glucocorticoid replacement therapy
• Management of hypertension with potassium-sparing diuretic (e.g., spironolactone to block mineralocorticoid receptors)
• Regular monitoring of growth, blood pressure, signs of virilization, and biochemical markers

During acute illness, some patients may have mineralocorticoid deficiency, which requires short-term replacement therapy. ^[9]

Clinical features ^[3][17]

Clinical features of 17α-hydroxylase deficiency include the following:

• 46,XX individuals: typical female external genitalia at birth
• 46,XY individuals: 46,XY DSD due to hypoandrogenism
  • Female external genitalia with a blind-ending vagina
  • Testes located in the abdomen or the inguinal canal
• Hypertension and/or hypokalemia ^[3]
• Hypergonadotropic hypogonadism: delayed puberty with primary amenorrhea and absence of secondary sexual characteristics ^[3]

Diagnosis ^[3]

The diagnosis is based on clinical findings and evidence of enzyme deficiency.

• Suspected 17α-hydroxylase deficiency: Refer to endocrinology for the following studies.
  • Corticosterone, DOC, and progesterone levels ^[3]
  • Electrolyte studies: to evaluate for hypokalemia
  • Genetic testing: to determine the type of CYP17A1 variant

The diagnosis is often not made until adolescence or early adulthood.

Management ^[3]

Management is provided by an endocrinologist and includes general management of CAH.

• Management of hypertension and hypokalemia with one or more of the following:
  • Glucocorticoid therapy ^[3]
  • Mineralocorticoid receptor antagonist (e.g., spironolactone)
• Estrogen replacement therapy for 46,XX individuals identifying as female, starting in early puberty ^[3]
• Treatment for infertility ^[3]