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American Family Physician
March 1, 1999 v59 i5 p1190(1)
Congenital Adrenal Hyperplasia: Not Really a Zebra.
by Michael A. Deaton, John E. Glorioso and David B. Mclean COPYRIGHT 1999 American Academy of Family
hyperplasia have 21- hydroxylase deficiency.2-4,6 Physicians
Because this enzyme functions in both glucocorticoid and mineralocorticoid synthesis, some patients with 21- Congenital adrenal hyperplasia was once considered a hydroxylase deficiency have insufficient amounts of rare inherited disorder with severe manifestations. Mild cortisone and aldosterone (Figure 2). These persons have congenital adrenal hyperplasia, however, is common, the "salt-wasting" form of congenital adrenal hyperplasia, affecting one in 100 to 1,000 persons in the United States with hyponatremia, hypovolemia, hyperkalemia and and frequently eluding diagnosis. Both classic and hypotension.1-4,6 The enzyme 21-hydroxylase is a nonclassic forms of the disease are caused by deficiencies chromosome 6, human leukocyte antigen (HLA)Elinked, in the adrenal enzymes that are used to synthesize cytochrome P450 enzyme that is found in the smooth glucocorticoids. The net result is increased production endoplasmic reticulum. Its DNA sequence can be altered from the adrenal gland of cortisol precursors and by at least nine mutations, many of which leave the androgens. Even mild congenital adrenal hyperplasia can enzyme impaired but not totally inactive.2,3,6 The result in life-threatening sinus or pulmonary infections, incidence of classic congenital adrenal hyperplasia is orthostatic syncope, shortened stature and severe acne. especially high in Madagascar and certain areas of Alaska. Women with mild congenital adrenal hyperplasia often Mild congenital adrenal hyperplasia occurs more present with hirsutism, oligomenorrhea or infertility. frequently in Ashkenazi Jews, and in Hispanic, Slavic and Congenital adrenal hyperplasia is diagnosed by demonstration of excess cortisol precursors in the serum during an adrenal corticotropic hormone challenge. Diagnosis of congenital adrenal hyerplasia in fetuses that are at risk for congenital adrenal hyperplasia can be Deficiency of 11-b hydroxylase is found in 8 to 9 percent of determined using human leukocyte antigen haplotype or patients with congenital adrenal hyperplasia.2,5 by demonstration of excess cortisol precursors in amniotic Glucocorticoid synthesis remains impaired but, in this fluid. Treatment includes carefully monitored hormone disorder, deoxycortisol accumulates (Figure 3). replacement therapy. Recognition of the problem and Deoxycortisol and its metabolites have mineralocorticoid timely replacement therapy can reduce morbidity and properties and may cause hypertension when they enhance quality of life in patients that are affected by accumulate.2,3,7 Thus, simple blood pressure measurements may help determine the underlying type of congenital adrenal hyperplasia. The enzyme 11-b Classical congenital adrenal hyperplasia is rare, affecting hydroxylase is a chromosome 8, cytochrome P450 only one in 14,000 patients, but mild forms of the disease enzyme located in the mitochondria. Known gene may occur in one of every 100 to 1,000 persons.1,2 The abnormalities include insertions, deletions, condition is caused by a deficient synthesis of cortisol; mis-sense/nonsense codons, and point mutations. Some most cases are related to 21-hydroxylase or 11-b of these abnormalities result in severe dysfunction of the hydroxylase deficiency3-5 (Figure 1). The affected enzyme enzyme while others result in only partial impairment.3-5 can be totally or partially impaired. The degree of enzyme Classic 11-b hydroxylase deficiency occurs in insufficiency determines the severity of the condition.2,5 approximately one per 100,000 births and occurs more frequently in Moroccan Jews. Mild congenital adrenal The hallmark of congenital adrenal hyperplasia is hyperplasia due to 11-b hydroxylase deficiency is more inadequate production of glucocorticoids.1 Patients with common, however, and may be responsible for 1 to 2 mild congenital adrenal hyperplasia are frequently unable percent of cases of hirsutism and oligomenorrhea in to mount sufficient stress responses to trauma and infection. Glucocorticoid precursors accumulate in these persons and are converted to androgenic steroids, causing Manifestations and Recognitionshortened stature, early puberty, severe acne, and virilization and infertility in females.2,3,5,6 Mineralocorticoid synthesis can also be affected, resulting in electrolyte disturbances, hypotension and syncope.5,6 The classic form of congenital adrenal hyperplasia occurs when cortisol synthesis is extremely low. The disorder Enzyme Pathways and Genetics 21-hydroxylase usually manifests in childhood. Hypersecretion of adrenal androgens causes masculinization of the external genitalia Ninety percent of patients with congenital adrenal of the female fetus. Affected infants can have ambiguous - Reprinted with permission. Additional copying is prohibited. -
American Family Physician
March 1, 1999 v59 i5 p1190(1)
Congenital Adrenal Hyperplasia: Not Really a Zebra.
genitalia or even erroneous gender assignment. Because acting and can be given in pulses that mimic natural testicles are not present to produce mullerian inhibiting cortisol secretion. Equivalent dosages of prednisone or factor, the internal female organs are intact.1,2,4 dexamethasone can be used to simplify dosing regimens in noncompliant patients; however, hydrocortisone is more Children with classic congenital adrenal hyperplasia may physiologically similar to cortisol and has a lower potential lack sufficient amounts of cortisol to mount a stress for growth suppression in children.3,4 Periods of response, and they frequently succumb to minor illnesses. physiologic stress, such as severe illness or surgery, Those who survive to adulthood experience premature require transient dosages of three to 10 times that used for puberty. Premature closure of the epiphyses results in maintenance therapy.1,3,4,8 Stress dosages are usually short stature even though these children grow at an not needed in mild illnesses such as colds or otitis accelerated rate when young. Severe acne is also a frequent problem. Adult women with classic congenital adrenal hyperplasia may have pronounced hirsutism and Corticosteroid replacement therapy must be approached carefully. Hydrocortisone dosages that return 17-hydroxyprogesterone/11- deoxycortisol levels to normal frequently induce Cushingoid features, whereas lower dosages may leave the effects of excess androgen Mild congenital adrenal hyperplasia is much more common production unchecked. Consultation with an than the classic form.2,3,5,6 Men and women with mild endocrinologist is recommended for patients who require congenital adrenal hyperplasia may have normal height compared with the general population, yet shortened stature when compared with their parents. Near-syncope Many patients benefit from multidrug therapy. Even may be a chronic or recurrent problem in these patients, normotensive patients with 21-hydroxylase deficiency and they frequently have a history of severe acne and mild (Figure 2) may have improved adrenal suppression with hyperpigmentation. Some people with mild congenital the addition of the aldosterone analog fludrocortisone adrenal hyperplasia can mount limited glucocorticoid (Florinef) at dosages of 0.05 to 0.2 mg per day to their stress responses and are thus never recognized as having the disorder. Others, however, have frequent illnesses and decompensate when challenged by common infections or The use of flutamide (Eulexin), an androgen inhibitor, in a minor trauma.1-4,6 Women with congenital adrenal dosage of approximately 10 mg per kg per day in three hyperplasia may have clitorimegaly and poorly developed divided doses, in patients with all types of congenital vaginal labia. These women may also be hirsute and adrenal hyperplasia may permit hydrocortisone to be given frequently present with oligomenorrhea, infertility or at lower dosages.8,9 Aromatase inhibitors that prevent conversion of androgens to estrogen (such as testolactone [Teslac], in a dosage of 40 mg per kg per day), may help children with mild congenital adrenal hyperplasia to achieve their height potential.1,8,9 When mild congenital adrenal hyperplasia is suspected, elevated serum levels of 17-hydroxyprogesterone suggest If one child in a family is already affected by congenital adrenal hyperplasia, the HLA haplotypes of the parents deoxycorticosterone/ 11-deoxycortisol levels suggest 11-b and the affected child should be determined. Subsequent hydroxylase deficiency (Table 1; Figures 4 and 5). In pregnancies can then be accurately evaluated for patients who have few or no symptoms of mild congenital congenital adrenal hyperplasia by HLA haplotype analysis hyperplasia, the risks of treatment may outweigh the of chorionic villus or amniotic cells.2,3 In families at risk benefits. Patients who require treatment should be given (e.g., one or both parents affected by some form of glucocorticoid replacement therapy at the lowest dosage congenital adrenal hyperplasia) but with no affected that achieves adrenal suppression; higher dosages can children, congenital adrenal hyperplasia can be diagnosed cause Cushingoid features and growth retardation.
during pregnancy by DNA analysis of chorionic villus or amniotic fluid cells or by measuring 17-hydroxy steroids in Maintenance therapy is generally achieved with the amniotic fluid.10 All women with fetuses at risk for hydrocortisone, in a dosage of 6 to 25 mg per m2 per day congenital adrenal hyperplasia should receive given in two to three divided doses.1,3,4,8 Hydrocortisone dexamethasone in a dosage of 0.02 mg per kg per day, is preferred over other glucocorticoids because it is short divided into two or three daily doses.
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American Family Physician
March 1, 1999 v59 i5 p1190(1)
Congenital Adrenal Hyperplasia: Not Really a Zebra.
Treatment should be initiated immediately on confirmation treatment of congenital adrenal hyperplasia. JAMA of pregnancy.4,10 Dexamethasone readily crosses the placenta and suppresses the fetal adrenal gland. If the fetus is male, dexamethasone therapy can be stopped 9. Laue L, Merke DP, Jones JV, Barnes KM, Hill S, Cutler until after the infant is born. Affected female fetuses, GB Jr. A preliminary study of flutamide, testolactone, and however, require treatment throughout pregnancy.
reduced hydrocortisone dose in the treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab Treatment of affected fetuses with maternal dexamethasone reduces the incidence and severity of virilization of female fetuses. Birth weight, length, head 10. Karaviti LP, Mercado AB, Mercado MB, Speiser PW, circumference and congenital anomalies of affected infants Buegeleisen M, Crawford C, et al. Prenatal whose mothers are treated with dexamethasone during diagnosis/treatment in families at risk for infants with pregnancy are comparable to those of infants who do not steroid 21-hydroxylase deficiency (congenital adrenal have congenital adrenal hyperplasia.10 Maternal hyperplasia). J Steroid Biochem Mol Biol 1992;41:445-51.
complications from treatment with dexamethasone can be expected and include excess weight gain, mood swings 11. Seckl JR, Miller WL. How safe is long-term prenatal glucocorticoid treatment? JAMA 1997;277:1077-9.
The authors thank Daniel Kopp, M.D., and Fred Pfalzgraf, M.D., for their thoughtful reviews of the manuscript.
MICHAEL A. DEATON, M.D, PH.D., is currently Chief of The opinions and assertions contained herein are the Primary Care and Community Medicine at General private views of the authors and are not to be construed as Leonard Wood Army Community Hospital, Fort Leonard official positions of the Department of Defense, the Wood, Mo. He received a doctorate in anatomy from Department of the Army or the Department of the Navy.
Vanderbilt University School of Medicine, Nashville, Tenn., and a medical degree from the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Bethesda, Md. Dr. Deaton completed 1. Cutler GB Jr, Laue L. Congenital adrenal hyperplasia a residency in family practice at Tripler Medical Center, due to 21- hydroxylase deficiency. N Engl J Med JOHN E. GLORIOSO, M.D., is currently Chief of Family 2. New MI. Genetic disorders of adrenal hormone Practice and Aviation Medicine at Yuma Proving Grounds, synthesis. Horm Res 1992;37(suppl 3):22-33.
Yuma, Ariz. He graduated from the University of Maryland School of Medicine, Baltimore, and completed a residency 3. Miller WL. Congenital adrenal hyperplasias. Endocrinol in family practice at Tripler Medical Center. He is a graduate of the Army Aviation Medicine Course.
4. New MI. Congenital adrenal hyperplasia. In: DeGroot DAVID B. MCLEAN, M.D., is currently a family physician LJ, ed. Endocrinology. 3d ed. Philadelphia: Saunders, on staff at Makalapa Clinic, Pearl Harbor, Hawaii. He received a medical degree from Virginia Commonwealth University Medical College of Virginia School of Medicine, 5. White PC, Speiser PW. Steroid 11 beta-hydroxylase Richmond, and completed a residency in family practice at deficiency and related disorders. Endocrinol Metab Clin Address correspondence to Michael A. Deaton, M.D., 6. Migeon CJ, Donohoue PA. Congenital adrenal Ph.D., Division of Primary Care and Community Medicine, hyperplasia caused by 21- hydroxylase deficiency. USA MEDDAC, General Leonard Wood Army Community Endocrinol Metab Clin North Am 1991;20:277-96.
Hospital, 126 Missouri Ave., Fort Leonard Wood, MO 65473. Reprints are not available from the authors.
7. Baskin HJ. Screening for late-onset congenital adrenal hyperplasia in hirsutism or amenorrhea. Arch Intern Med 1987;147:847-8.
8. Merke DP, Cutler GB Jr. New approaches to the - Reprinted with permission. Additional copying is prohibited. -

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