Deborah P. Merke, MD; Stefan R. Bornstein, MD; Nilo A. Avila, MD; George P. Chrousos, MD
An edited summary of a Clinical Staff Conference held on 30 June 1999 at the National Institutes of Health, Bethesda, Maryland.
Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference: Bornstein SR. Animal model for 21-hydroxylase deficiency. In: Merke DP, moderator. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med. 2002; 136:322-5.
Note: Dr. Merke is a Commissioned Officer in the U.S. Public Health Service.
Acknowledgments: The authors thank Margaret F. Keil, RN, and members of the nursing staff at the Warren Grant Magnuson Clinical Center for assistance in the care of their patients. They also thank Mr. David Cho and Ms. Sarah L. Mehlinger for assistance in the preparation of the manuscript.
Requests for Single Reprints: Deborah P. Merke, MD, Warren Grant Magnuson Clinical Center, Clinical Building 10, Room 13S260, 10 Center Drive MSC 1932, Bethesda, MD 20892-1932.
Current Author Addresses: Dr. Merke: Warren Grant Magnuson Clinical Center, Clinical Building 10, Room 13S260, 10 Center Drive MSC 1932, Bethesda, MD 20892-1932.
Dr. Bornstein: Klinik für Endokrinologie, MNR Universität Düsseldorf, Mooren Strasse 5, 40001 Düsseldorf, Germany.
Dr. Avila: Diagnostic Radiology Department, Warren Grant Magnuson Clinical Center, Clinical Building 10, Room 1C-660, 10 Center Drive MSC 1182, Bethesda, MD 20892-1182.
Dr. Chrousos: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Clinical Building 10, Room 9D42, 10 Center Drive MSC 1583, Bethesda, MD 20892-1583.
Congenital adrenal hyperplasia describes a group of inherited autosomal recessive disorders characterized by an enzymatic defect in cortisol biosynthesis, compensatory increases in corticotropin secretion, and adrenocortical hyperplasia. 21-Hydroxylase deficiency is responsible for more than 95% of cases and is one of the most common known autosomal recessive disorders. The classic or severe type presents in the newborn period or early childhood with virilization and adrenal insufficiency, with or without salt loss; the mild or nonclassic form presents in late childhood or early adulthood with mild hyperandrogenism and is an important cause of masculinization and infertility in women. This wide range of phenotypic expression is mostly explained by genetic variation, although genotype-phenotype discrepancies have been described.
Reproductive, metabolic, and other comorbid conditions, including risk for tumors, are currently under investigation in both forms of the disease. A high proportion of patients with adrenal incidentalomas may be homozygous or heterozygous for 21-hydroxylase deficiency. Women with congenital adrenal hyperplasia often develop the polycystic ovary syndrome. Ectopic adrenal rest tissue is often found in the testes of men with congenital adrenal hyperplasia; characteristic clinical and radiologic findings help differentiate this tissue from other tumors. Levels of corticotropin-releasing hormone are elevated in patients with depression and anxiety and are expected to be elevated in patients with congenital adrenal hyperplasia; it is unknown whether patients with 21-hydroxylase deficiency have an increased incidence of these psychiatric disorders. Abnormalities in both the structure and function of the adrenal medulla have been shown in patients with classic congenital adrenal hyperplasia, and the degree of adrenomedullary impairment may be a biomarker of disease severity.
The 21-hydroxylase-deficient mouse has provided a useful model with which to examine disease mechanisms and test new therapeutic interventions in classic disease, including gene therapy. Treatment of this condition is intended to reduce excessive corticotropin secretion and replace both glucocorticoids and mineralocorticoids. However, clinical management is often complicated by inadequately treated hyperandrogenism, iatrogenic hypercortisolism, or both. New treatment approaches currently under investigation include combination therapy to block androgen action and inhibit estrogen production, and bilateral adrenalectomy in the most severely affected patients. Other approaches, which are in a preclinical stage of investigation, include treatment with a corticotropin-releasing hormone antagonist and gene therapy.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.leftmiddleACTHright
The 10 most common genetic mutations found in 21-hydroxylase deficiency.SLNSLNCCYP21B
The 21-hydroxylase-deficient mouse.Top.StARnPMiddle.Bottom.arrows
Patients with salt-losing 21-hydroxylase deficiency.topbottomtopbottom
An investigational approach to the treatment of classic congenital adrenal hyperplasia.
Mechanisms of adrenal hyperandrogenism.
Venn diagram including the overlapping populations of women with insulin resistance, the polycystic ovary syndrome (PCOS), and nonclassic congenital adrenal hyperplasia (NCCAH).
Characteristic radiologic features of testicular adrenal rest tumors.arrowABCDEF
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Merke DP, Bornstein SR, Avila NA, Chrousos GP. Future Directions in the Study and Management of Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. Ann Intern Med. 2002;136:320-334. doi: 10.7326/0003-4819-136-4-200202190-00012
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Published: Ann Intern Med. 2002;136(4):320-334.
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