Congenital Adrenal Hyperplasia

• Elizabeth Brown, M.D.
• Patrick Nsereko, M.D.

 Basic Information

Definition

Congenital adrenal hyperplasia (CAH) is a spectrum of disorders resulting from a deficiency or complete lack of one of the enzymes in the cortisol synthesis pathway. These autosomal recessive genetic disorders are usually characterized by cortisol deficiency and virilization, with or without salt wasting.

Synonyms

1. 21-Hydroxylase deficiency (equivalent to CYP21A2 deficiency)

2. 11β-Hydroxylase deficiency

3. 3β-Hydroxysteroid dehydrogenase deficiency

4. 17-Hydroxylase deficiency

5. Lipoid adrenal hyperplasia

6. Adrenal virilism

7. Adrenogenital syndrome

8. Virilizing adrenal hyperplasia

ICD-10CM CODES
E25.0	Congenital adrenogenital disorders associated with enzyme deficiency

Epidemiology & Demographics

1. •

   About 95% of cases of CAH are caused by 21-hydroxylase deficiency, of which two-thirds are the salt-wasting form.

2. •

   Autosomal recessive inheritance.

3. •

   The “classic” form presents in childhood, and the “nonclassic” form is the mild, late-onset form.

4. •

   Incidence is estimated at about 1:10,000 to 1:20,000 live births (Hispanic >American Indian >white >black >Asian).

5. •

   Most common cause of ambiguous genitalia in 46,XX females.

Clinical Presentation

“Classic” salt-wasting form (impaired cortisol and aldosterone synthesis):

1. •

   Adrenal crisis in first weeks of life with vomiting, poor weight gain, lethargy, dehydration, hyponatremia, hyperkalemia, and elevated plasma renin.

2. •

   Females are born with ambiguous genitalia (Fig. E1) that often leads to diagnosis before adrenal crisis occurs.

   

3. •

   Males may have greater penile size and smaller testes than expected during childhood. Males may also develop adrenal rests, or ectopic islands of adrenal cortical tissue in the testes, in childhood and may experience infertility as adults.

4. •

   If patients survive infancy, their overall life expectancy is not compromised.

5. •

   Both males and females may exhibit rapid growth in childhood due to early epiphyseal closure, which then results in short stature in adulthood.

6. •

   Precocious puberty is common in both males and females.

“Classic” non–salt-wasting or simple virilizing form (impaired cortisol synthesis only):

1. •

   Females present with ambiguous genitalia at birth.

2. •

   The normal appearance of male genitalia in the simple virilizing form makes this a difficult diagnosis in male infants.

3. •

   Characterized by precocious puberty, short stature, and testicular adrenal rests, as in the salt-wasting form.

“Nonclassic” or mild, late-onset form (varying degrees of androgen excess):

1. •

   Usually presents in adolescence or adulthood and is not detected on newborn screening

2. •

   Often asymptomatic but can be associated with mild virilization

3. •

   PCOS-like symptoms occur in women (hirsutism, oligomenorrhea, acne, infertility, insulin resistance, and abnormal menses)

4. •

   Associated with infertility in males

Etiology

In 21-hydroxylase deficiency, the pathways for aldosterone production (from the conversion of progesterone to deoxycorticosterone) and cortisol production (from the conversion of 17-hydroxyprogesterone to 11-deoxycortisol) by the cP450 enzyme 21-hydroxylase are interrupted. The production of ACTH is thus stimulated by a negative feedback mechanism, leading to adrenal hyperplasia and mineralocorticoid deficiency as the intermediaries in aldosterone and cortisol synthesis are shunted to the androgen biosynthesis pathway (Fig. E2, A and B). A recombination event between the active CYP21A2 gene on chromosome 6p21.3 and the CYP21A1 pseudogene is thought to create the deficient 21-hydroxylase enzyme.

Diagnosis

Differential Diagnosis

1. •

   Precocious puberty

2. •

   Polycystic ovarian syndrome (PCOS)

3. •

   Androgen resistance syndromes

4. •

   Pseudohermaphroditism

5. •

   Mixed gonadal dysgenesis

6. •

   Testicular carcinoma

7. •

   Leydig cell tumors

8. •

   Adrenocortical carcinoma

9. •

   Addison’s disease

10. •

    Pituitary adenoma

Laboratory Tests

1. •

   Prenatal: chorionic villus sampling for history; genetic testing or measurement of 17-hydroxyprogesterone if family history.

2. •

   Serum 17-hydroxyprogesterone level, which is included in the newborn screen in all states, is the first-line test for suspected CAH.

3. •

   Adrenocorticotropin (ACTH) stimulation test is the next step to confirm the diagnosis and identify type of CAH.

4. •

   Additional tests that may be useful include plasma renin activity, aldosterone level, and electrolytes.

Imaging Studies

1. •

   Abdominal ultrasound to evaluate adrenal glands can accelerate diagnosis.

2. •

   Ultrasound to identify a uterus in cases of ambiguous genitalia.

3. •

   Ultrasound is preferred to rule out testicular adrenal rest tumors (found in classic and nonclassic forms) and should be done beginning in adolescence.

Treatment

Nonpharmacologic Therapy

1. •

   Surgical correction of ambiguous genitalia may be necessary.

2. •

   Monitoring: serum 17-hydroxyprogesterone and androstenedione, renin, electrolytes, blood pressure, bone age and density, Tanner staging, growth velocity, weight.

3. •

   Bilateral laparoscopic adrenalectomy with lifelong glucocorticoid and mineralocorticoid replacement (controversial).

4. •

   Gene therapy (hypothetical).

5. •

   Psychological counseling.

Chronic Rx

1. •

   Glucocorticoids to partially suppress adrenal androgen secretion. During periods of physiologic stress, they may need to be doubled or tripled.

   1. 1.

      In children, hydrocortisone is preferred because of its short half-life, which minimizes the risk of iatrogenic short stature. After patients are fully grown, long-acting glucocorticoids can be used.

   2. 2.

      Adolescents and adults: dexamethasone 0.25 to 0.75 mg PO QHS (also used to treat adrenal rests) or prednisone 5 to 7.5 mg/day in two divided doses.

2. •

   Mineralocorticoids (e.g., fludrocortisone) to normalize electrolytes and plasma renin activity.

   1. 1.

      In infants, salt supplementation is also required.

3. •

   Treatment of simple virilizing form: similar to salt-wasting form, but mineralocorticoid replacement is unnecessary.

4. •

   Treatment of nonclassic form:

   1. 1.

      In adolescent and adult women: oral contraceptives, glucocorticoids, and/or antiandrogens.

   2. 2.

      In children and adult males, usually no treatment is necessary.

   3. 3.

      Prenatal glucocorticoid treatment is controversial but may decrease virilization in female fetuses.

Pearls & Considerations

Comments

1. •

   Consider the diagnosis of classic salt-wasting CAH in infants with failure to thrive.

2. •

   There is believed to be an increased prevalence of CAH in patients diagnosed with adrenal “incidentalomas”—adrenal gland lesions detected unexpectedly on imaging, usually by MRI or CT scanning.

3. •

   Cushing’s syndrome may result from overtreatment of CAH with glucocorticoids.

4. •

   Patients with CAH may have gender identity disorders and sexual dysfunction.

5. •

   Table E1 summarizes diagnosis and treatment of CAH.

Prevention

1. •

   Prenatal: Early CVS sampling. Use of dexamethasone 20 to 25 mg/kg daily beginning at 5- to 8-wk gestation for female fetuses only is controversial because long-term studies are unavailable.

2. •

   Neonatal screening.

3. •

   Genetic counseling.

Suggested Readings

• H. Falhammar, et al.: Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine. 41 (3):355–373 2012 22228497

• I.L. Pezzuti, et al.: A three-year follow-up of congenital adrenal hyperplasia newborn screening. J Pediatr (Rio J). 90 (3):300–307 2014 24560529

• P.W. Speiser, et al.: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 95:4133–4160 2010 20823466