Excerpt from Congenital Adrenal Hyperplasia

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Background

The term congenital adrenal hyperplasia encompasses a group of autosomal recessive disorders, each of which involves a deficiency of an enzyme involved in the synthesis of cortisol,¹ aldosterone, or both. 

Pathophysiology

The clinical manifestations of each form of congenital adrenal hyperplasia are related to the degree of cortisol deficiency and/or the degree of aldosterone deficiency. In some cases, these manifestations reflect the accumulation of precursor adrenocortical hormones. When present in supraphysiologic concentrations, these precursors cause abnormalities such as virilization or hypertension.

The phenotype depends on the degree or type of gene deletion or mutation and the resultant deficiency of the steroidogenic enzyme. The enzymes and corresponding genes are displayed in Media file 1. Two copies of an abnormal gene are required for disease to occur, and not all mutations and partial deletions result in disease. The phenotype can vary from clinically inapparent disease (occult or cryptic adrenal hyperplasia) to a mild form of disease that is expressed in adolescence or adulthood (nonclassic adrenal hyperplasia) to severe disease that results in adrenal insufficiency in infancy with or without virilization and salt wasting (classic adrenal hyperplasia). The most common form of adrenal hyperplasia (due to a deficiency of 21-hydroxylase activity) is clinically divided into 3 phenotypes: salt wasting, simple virilizing, and nonclassic.

CYP21A  is the gene that codes for 21-hydroxylase, CYP11B1 codes for 11-beta-hydroxylase, and CYP17 codes for 17-alpha-hydroxylase. Many of the enzymes involved in cortisol and aldosterone syntheses are cytochrome P450 (CYP) proteins.

Frequency

United States

The most common form of congenital adrenal hyperplasia is due to mutations or deletions of CYP21A, resulting in 21-hydroxylase deficiency. This deficiency accounts for more than 90% of adrenal hyperplasia cases. Mutations or partial deletions that affect CYP21A are common, with estimated frequencies as high as 1 in 3 individuals in selected populations (eg, Ashkenazi Jews) to 1 in 7 individuals in New York City. The estimated prevalence is 1 case per 60 individuals in the general population.

Classic adrenal hyperplasia has an overall prevalence of 1 case per 16,000 population; however, in selected populations (eg, the Yupik of Alaska), the prevalence is as high as 1 case in 400 population. Congenital adrenal hyperplasia caused by 11-beta-hydroxylase deficiency accounts for 5-8% of all congenital adrenal hyperplasia cases.

International

Congenital adrenal hyperplasia caused by 21-hydroxylase deficiency is found in all populations. 11-beta-hydroxylase deficiency is more common in persons of Moroccan or Iranian-Jewish descent.

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 (see Media file 2). The clinical phenotype can be understood by analyzing the location of the enzyme deficiency, the accumulation of precursor hormones, and the physiologic action of those hormones (see History).

Severe forms of congenital adrenal hyperplasia are potentially fatal if unrecognized and untreated because of the severe cortisol and aldosterone deficiencies that result in salt wasting, hyponatremia, hyperkalemia, dehydration, and hypotension.

Race

Congenital adrenal hyperplasia occurs among people of all races. Congenital adrenal hyperplasia secondary to CYP21A1 mutations and deletions is particularly common among the Yupik Eskimos.

Sex

Because all forms of congenital adrenal hyperplasia are autosomal recessive disorders, both sexes are affected with equal frequency. However, because accumulated precursor hormones or associated impaired testosterone synthesis impacts sexual differentiation, the phenotypic consequences of mutations or deletions of a particular gene differ between the sexes.

Age

Classic congenital adrenal hyperplasia is generally recognized at birth or in early childhood because of ambiguous genitalia, salt wasting, or early virilization. Nonclassic adrenal hyperplasia is generally recognized at or after puberty because of oligomenorrhea or virilizing signs in females.

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