This is part of a comprehensive chapter on CAH on the emedicine site.

Background: The term congenital adrenal hyperplasia encompasses several autosomal recessive disorders that share complete or partial deficiency of an enzyme involved in cortisol or aldosterone synthesis. All disorders of this group share the common feature of a deficiency or relative defect in cortisol or aldosterone synthesis resulting in some degree of cortisol and/or aldosterone deficiency.

Pathophysiology: The clinical manifestations of the disease relate to the degree of cortisol and/or aldosterone deficiency and, in some cases, to the accumulation of precursor adrenocortical hormones. These precursors cause abnormalities such as virilization or hypertension when present in supraphysiologic concentrations. The phenotype depends on which particular protein is affected and the severity of the mutation or degree of deletion of the particular gene encoding for the protein involved in steroidogenesis. The phenotype can vary from clinically inapparent disease (occult or cryptic adrenal hyperplasia) to a mild form of disease, which is expressed in adolescence or adulthood (nonclassical adrenal hyperplasia), to severe disease resulting in adrenal insufficiency in infancy, with or without virilization and salt wasting (classical adrenal hyperplasia). Adrenal hyperplasia due to a deficiency of 21-hydroxylase activity is divided clinically into a simple virilizing form and a salt wasting form.

Many of the enzymes involved in cortisol and aldosterone syntheses are cytochrome p450 proteins designated CYP. CYP21 refers to 21-hydroxylase, CYP11B1 refers to 11-beta-hydroxylase, and CYP17 refers to 17-alpha-hydroxylase.

Frequency:

• In the US: The most common form of congenital adrenal hyperplasia is due to 21-hydroxylase (CYP21) deficiency. This deficiency accounts for more than 90% of cases of adrenal hyperplasia. Mutations or partial deletions of CYP21 are common with an estimated frequency ratio as high as 1:3 in individuals in selected populations (ie, Ashkenazi Jews) to 1:7 in New York City. Estimated incidence is 1 per 60 individuals in the general population. Two copies of an abnormal gene are required for disease to occur and not all mutations and partial deletions result in disease.

  Nonclassic adrenal hyperplasia may occur with a frequency ratio as high as 1:27 to 1:100. Classic adrenal hyperplasia because of severe deletions and loss of CYP21 function occurs with an overall incidence of 1 per 13,000 to 1 per 16,000. Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency accounts for 5-8% of all patients with congenital adrenal hyperplasia.

• Internationally: 11-beta-hydroxylase deficiency is observed more commonly among Moroccan and Iranian Jews. Other forms of congenital adrenal hyperplasia are far less common.

Mortality/Morbidity: The morbidity of the various forms of adrenal hyperplasia is best understood in the context of the steroidogenic pathway used by the adrenal glands and gonads (Picture 1). By analyzing the location of the enzyme deficiency, the accumulation of precursor hormones, and the physiological action of those hormones, the clinical phenotype can be understood.

• Severe forms of congenital adrenal hyperplasia are potentially fatal if unrecognized and untreated because of the severe cortisol and aldosterone deficiency that result in salt wasting, hyponatremia, hyperkalemia, dehydration, and hypotension. Females with some forms of adrenal hyperplasia (ie, CYP21 deficiency, CYP11B1, partial 3-beta-hydroxysteroid-dehydrogenase deficiency) have ambiguous genitalia at birth (classical virilizing adrenal hyperplasia) or subsequently become virilized in childhood (simple virilizing adrenal hyperplasia) or in adolescence and adulthood (nonclassical virilizing adrenal hyperplasia). Males with CYP21 deficiency generally are not diagnosed in the neonatal period because their genitalia are normal. If the defect is severe resulting in salt wasting, these male infants will be seen at 1-4 weeks of age because of failure to thrive, recurrent vomiting, dehydration, and shock. Some infants are misdiagnosed initially with gastroenteritis or pyloric stenosis. Hyponatremia and hyperkalemia should raise the possibility of adrenal insufficiency. Children with simple virilizing 21-hydroxylase or 11-hydroxylase deficiencies have early pubic hair, phallic enlargement, and accelerated growth.

• Males with steroidogenic acute regulatory (StAR) deficiency, classical 3-beta-hydroxysteroid-dehydrogenase deficiency, or CYP17 deficiency generally have ambiguous genitalia or female genitalia because of inadequate testosterone production in the first trimester of fetal life. A female with CYP17 deficiency will appear phenotypically female at birth but fail to develop breasts and menstruate in adolescence because of inadequate estradiol production.

• Two forms of adrenal hyperplasia (CYP11B1 deficiency and CYP17 deficiency) result in hypertension. Hypertension occurs because of the accumulation of supraphysiologic concentrations of deoxycorticosterone. This weak mineralocorticoid has little consequence at physiological concentrations, but results in sodium retention and hypertension at the supraphysiological concentrations that occur in the presence of CYP11B1 deficiency or CYP17 deficiency. One form of adrenal hyperplasia results in isolated aldosterone deficiency without affecting the synthesis of cortisol or sex steroids. This occurs because of a defect in enzyme activities that variously have been termed CMO I, CMO II, 18-hydroxylase and 18-hydroxycorticosterone dehydrogenase but is currently thought to represent one protein termed aldosterone synthetase or CYP11B2.

Race: Congenital adrenal hyperplasia occurs among all races. Congenital adrenal hyperplasia secondary to CYP21 deficiency is particularly common among the Yupik Eskimos.

Sex: Since all forms of congenital adrenal hyperplasia are autosomal recessive disorders, both sexes are affected equally.

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