What is congenital adrenal hyperplasia?

Causes and Symptoms

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive conditions that affect the production of hormones by the adrenal glands. It is caused by an inherited deficiency in one of the enzymes that is necessary to convert cholesterol to cortisol. About 95 percent of cases of CAH are caused by a deficiency in the enzyme 21-hydroxylase, but deficiencies in 3-beta hydroxysteroid dehydrogenase, 11-beta-hydroxylase, 17-alpha-hydroxylase, or cholesterol desmolase can also cause the condition.

If an individual has a mutation in one copy of the gene that codes for one of these enzymes, then he or she will not have any clinical symptoms but is considered a carrier of CAH. If both parents are carriers, then there is a 25 percent chance that their child will inherit both of these mutations. Individuals with two mutated copies of a gene will have a deficiency of the corresponding enzyme and will be clinically affected with CAH.

Individuals with CAH have reduced levels of cortisol production. They may also have decreased aldosterone production and increased production of androgens, such as testosterone.

Girls who are born with classic CAH often have virilized or ambiguous external genitalia, while boys may have enlarged penises. Affected infants may also experience weight loss, dehydration, vomiting, and salt-wasting crises. If left untreated, affected individuals may experience very early puberty, irregular menstrual cycles, infertility, and short stature in adulthood. There is also a nonclassic form of CAH that is less severe and develops in late childhood or early adulthood.

A diagnosis of CAH is usually made based on biochemical testing. Affected individuals typically have decreased serum levels of cortisol, aldosterone, sodium, chloride, and total carbon dioxide. They also have elevated levels of the steroid hormone 17-hydroxyprogesterone (17-OHP) and serum DHEA sulfate (an androgen). Genetic testing for CAH is also available. Newborn screening for CAH is routine and is done by measuring the concentration of 17-OHP on a filter paper blood spot sample.

Treatment and Therapy

The principal treatment for CAH is lifelong hormone replacement therapy. The aim of this therapy is to replace deficient glucocorticoid, reduce the production of androgens, prevent the development of secondary male sex characteristics in females, optimize growth, and promote fertility.

In children, oral hydrocortisone is usually given in two to three daily doses. Individuals with the salt-wasting form of CAH may also need supplemental sodium chloride and mineralocorticoids. Serum concentrations of 17-OHP and other hormones must be checked regularly to assess hormonal control. Overtreatment with glucocorticosteroids can result in elevated cortisol levels and can lead to Cushing’s syndrome. Signs of Cushing’s syndrome include an accumulation of fat between the shoulders; a full, rounded face; muscle weakness; stretch marks on the skin of the abdomen, thighs, and breasts; high blood pressure; and bone loss.

Girls with virilization or genital ambiguity may need corrective surgery to ensure proper urinary, sexual, and reproductive functioning. Males are at risk for testicular adrenal rest tumors and require periodic imaging of the testes with ultrasound or magnetic resonance imaging (MRI).

If a couple is known to be at risk for having a pregnancy affected with CAH, then oral dexamethasone can be given to the mother during pregnancy to prevent virilization of a female fetus. To be effective, however, treatment must be started early in the pregnancy, before testing can be done to determine the sex of the fetus or if the fetus is affected with CAH. This often results in unnecessary treatment of a male or unaffected fetus. However, universal screening of all newborn infants improves early detection of the often fatal salt-wasting form of CAH in both girls and boys.

Perspective and Prospects

Luigi De Crecchio, an Italian anatomist, is credited with the earliest known description of a case of probable CAH. In 1865 he wrote an account of Joseph Marzo, a man who had passed away following an episode of vomiting and diarrhea. Although Marzo had a male appearance, he had ambiguous external genitalia and internal female reproductive organs.

J. Phillips helped to identify CAH as a genetic condition when he reported in 1887 the case of a family with four children who had been born hermaphrodites and passed away in early infancy with wasting
disease. Then, in 1905, J. Fibiger noted that some infants with prolonged vomiting and dehydration had enlarged adrenal glands.

Lawson Wilkins, a researcher at Johns Hopkins Medical School, concluded that the impaired ability to produce cortisol led to adrenal hyperplasia and overproduction of adrenal androgens in individuals with CAH. In 1950, he reported that adrenal cortical extracts could be used to treat children with CAH. By the late 1950s, hydrocortisone, fludrocortisone, and prednisone were available and could be used for treatment. By 1990, many of the causative genes and enzymes had been identified.

Research continues on improving the hormone replacement regimen for individuals with CAH. Excess adrenal androgen secretions need to be suppressed while still allowing for normal growth and development. There is also continuing research on the psychological effects of CAH. The degree to which prenatal androgen exposure may affect psychosexual development in females with CAH is an ongoing subject of research.

Bibliography:

"Congenital Adrenal Hyperplasia (CAH)." Eunice Kennedy Shriver National Institute of Child Health and Human Development, April 3, 2013.

Hsu, C. Y., and Scott A. Rivkees. Congenital Adrenal Hyperplasia: A Parents’ Guide. Bloomington, Ind.: AuthorHouse, 2005.

Kliegman R. M., et al. “Congenital Adrenal Hyperplasia and Related Disorders.” In Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders/Elsevier, 2011.

Mayo Clinic. "Congenital Adrenal Hyperplasia." Mayo Clinic, March 4, 2011.

Parker, Philip M. Congenital Adrenal Hyperplasia: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, Calif.: ICON Group, 2004.

Stresing, Diane. "Congenital Adrenal Hyperplasia." Health Library, November 26, 2012.