Information on the following diseases can be found in the Related Disorders section of this report:

• Addison's Disease
• Klinefelter's Syndrome
• Turner Syndrome
• Androgen-Producing Tumors
• Hermaphroditism

Common to several forms of CAH are abnormally enlarged adrenal glands (hyperplastic adrenomegaly) that produce excessive amounts of androgens (male steroid hormones) leading to abnormal sexual development. Intolerably low levels of cortisol and aldosterone make about 75% of affected persons inclined to adrenal crisis involving both dehydration and shock. Lacking early diagnosis and treatment, death is not uncommon.

In females, the external genitalia may develop male characteristics (masculinization or virilization) including abnormal clitoral growth. In acute cases female babies may be mistaken for males. Boys may not display genital malformations but continued androgen excess may cause early aging (progeria) or fast body growth, premature puberty and premature completion of growth leading to short stature.

21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia is the most common form of CAH and accounts for approximately 95 percent of cases. Both males and females are affected. In females it may cause pseudohermaphroditism; this form of the disorder is not usually apparent in males until later in life. Females are born with abnormalities of the external genitalia including an abnormally enlarged clitoris (clitorimegaly) and the folds of the skin at the opening of the vagina (labia) that are joined. The infant appears to have a penis and undescended testes. The internal female organs are present; however, fusion of the labial folds may seal the opening of the vagina. These children are frequently raised as boys until the small size of the penis becomes more obvious around the age of 4 years.

In very rare cases of 21-Hydroxylase Deficiency, genetic females (two X chromosomes) have lived their lives as males. Untreated females do not have regular menstrual periods and are unable to conceive. Physical growth may initially be rapid, but growth retardation occurs fairly soon, and adult stature is short.

Male infants with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia appear normal at birth. At 3 to 4 years of age, signs of early sexual development (precocious puberty) may become apparent. Unusually rapid growth, acne, voice deepening, enlargement of the penis, pubic hair, and underarm (axillary) hair may appear. Abnormally high levels of androgens (male hormones) suppress other hormones that are required for the onset of normal puberty, development of the testes, and the production of sperm (spermatogenesis). There is risk of an unexpected, potentially life- threatening crisis as a result of deficiencies of glucocorticoid or mineralocorticoid hormones in males who have this disorder but remain undiagnosed.

About one-third of the individuals with 21-Hydroxylase Deficiency also have a deficiency of the hormone aldosterone. This results in the elimination of the abnormally high levels of salt in the urine (natriuresis), possible excessive loss of water (dehydration), low circulating blood volume (hypovolemia), and abnormally low blood pressure (hypotension). Symptoms associated with this form of CAH are usually apparent about 5 to 10 days after birth, and include profound weakness, vomiting, diarrhea, and circulatory collapse. If left untreated, this form of the disorder may be life-threatening.

In Congenital Lipoid Hyperplasia (adrenal cortex male pseudohermaphroditism or 20-22 desmolase deficiency), the most prominent feature is the physical appearance of both male and female characteristics in a male (pseudohermaphroditism). This is characterized in males by failure of the external genitalia to appear normal and by the abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias). The activity of male hormones is typically impaired. This form of CAH may be life-threatening to infants.

3-Beta Hydroxysteroid Dehydrogenase (HSD) Deficiency occurs early in the chain of chemical reactions required to create adrenal hormones. Androgens, glucocorticoids, and mineralocorticoids are not produced. In males, both male and female characteristics appear or ambiguous genitalia (pseudohermaphroditism) and hypospadias. In females, the development of male sex characteristics (virilization) may not be as noticeable or may not occur at all. Adrenal crisis is frequently caused by salt loss and infants usually do not survive more than a few hours unless they are diagnosed and treated rapidly.

Incomplete forms of 3-Beta Hydroxysteroid Dehydrogenase Deficiency have been described in the medical literature. Symptoms occur later in childhood and may include menstruation at age 4 to 6, an abnormally enlarged clitoris (clitorimegaly), acne, and/or advanced maturity of the bones. Other individual symptoms may not appear until adulthood. The late-onset form is characterized by irregular menstrual periods and a male pattern of hair growth (hirsutism).

17-Hydroxylase Deficiency CAH deprives the developing male fetus of androgens (male hormones) which are essential to the development of male sex characteristics. These genetically male infants (with an X and a Y chromosome) are born with external genitalia which appear female. The testes may remain buried within the abdominal cavity (cryptorchidism). If the testes remain undescended, they may become malignant later in life. Other symptoms may include failure to develop secondary sexual characteristics, the absence of a regular period (amenorrhea), abnormally high blood pressure (hypertension), and abnormally low levels of circulating potassium (hypokalemia).

17-20 Desmolase Deficiency results in genetic males (XY) having female or ambiguous external genitalia. The adrenal glands are normal in size, and production of glucocorticoids and mineralocorticoids is adequate.

11-Beta Hydroxylase Deficiency causes the development of male secondary sex characteristics (virilization). The onset of puberty occurs very early in males (precocious puberty). Both males and females have abnormally high blood pressure (hypertension) and unusually short stature.

17-Alpha Hydroxylase Deficiency CAH usually goes unnoticed until adolescence because secondary sexual characteristics do not develop in males and females. Genetic males (XY) have external genitalia which appear female and the testes do not produce androgens. Genetic females (XX) do not have regular menstrual periods, develop breasts, or produce estrogen. Low levels of blood potassium (hypokalemia) and high blood pressure (hypertension) are other important characteristics of this form of CAH.

A less severe form of 21-hydroxylase deficiency CAH due to a more common genetic mutation is called Nonclassical Adrenal Hyperplasia. Symptoms include infertility, premature sexual development, severe acne, excessive facial hair in women, and short stature in men. These symptoms are all caused by excess androgen production starting at or before puberty.
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Most forms of CAH are inherited as an autosomal recessive genetic trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Autosomal recessive disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but will usually not show symptoms. The risk for two carrier parents to both pass the defective gene, and therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

In some forms of the disease, the location of the gene that causes the disorder is known. The defective gene that causes 21-Hydroxylase Deficiency is located on the short arm of chromosome 6 (HLA). The defective gene that causes 11-Beta Hydroxylase Deficiency is located on the long arm of chromosome 8. The defective gene that causes 3-beta Hydroxysteroid Dehydrogenase Deficiency is located on the short arm of chromosome 1. The defective gene that causes Lipoid Adrenal Hyperplasia (20-22 Demolase Deficiency) has been mapped to chromosome 15.
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The most common form of CAH, 21 Hydroxylase Deficiency, affects approximately 1:5,000 to 1:15,000 people in the United States and Europe. Among the Yupik Eskimo, the occurrence of the salt-wasting form of this disorder may be as high as 1 in 282 individuals. Other forms of CAH are much rarer.

Non classical CAH affects approximately 1 in 30 Ashkenazi Jews, 1 in 40 Hispanic persons, 1 in 50 Yugoslavians, and 1 in 300 Italians. Thus far, 1 in 100 individuals in the non-Jewish groups who have been studied, have the nonclassical form of this disorder.
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Symptoms of the following disorders can be similar to those of Congenital Adrenal Hyperplasia. Comparisons may be useful for a differential diagnosis:

Addison's Disease is a rare disorder characterized by chronic, usually progressive, insufficient functioning of the outer layer of the adrenal glands (adrenal cortex) resulting in abnormally low levels of sodium and chloride, and abnormally high levels of potassium. Major symptoms include fatigue, gastrointestinal discomfort, and changes in skin color (pigmentation). Extremely low levels of adrenocortical hormones (adrenal or "Addisonian" crisis) can occur and may be life-threatening. The crisis may begin with a sudden loss of strength, severe pain in the abdomen or lower back, or kidney failure. (For more information on this disorder, choose "Addison" as your search term in the Rare Disease Database.)

In Klinefelter's Syndrome there is an excess number of X chromosomes in males. It is characterized in males by small testes, lack of sperm, enlarged mammary glands, and an abnormally small penis. Other symptoms include retarded development of sex organs, an absence of beard and body hair, a high-pitched voice, and lack of muscular development. (For more information on this disorder, choose "Klinefelter" as your search term in the Rare Disease Database.)

Turner Syndrome is a rare genetic disorder of females characterized by a lack of sexual development at puberty. Other characteristics may include short stature, a webbed neck, heart defects, and various other abnormalities. Affected individuals have female characteristics, but do not develop secondary sexual characteristics (puberty) because they have immature ovaries that do not produce estrogen. (For more information on this disorder, choose "Turner" as your search term in the Rare Disease Database.)

Virilization of female fetuses and children, or accelerated sexual maturity in males, may also result from androgen-producing tumors or maternal ingestion of androgenic substances. The absence at birth (congenital) of gonads and cryptorchidism can also result in abnormal sexual development.

Hermaphroditism is characterized by the presence of both ovaries and testes in the same individual. The reproductive organs can contain eggs or sperm. Most affected persons have a mixture of female and male external genitalia. (For more information on this disorder, choose "Heraphroditism" as your search term in the Rare Disease Database.)

During the first three months of pregnancy, the diagnosis of some types of CAH can be made by prenatal testing (chorionic villus sample) and tissue typing (DNA analysis or HLA typing). Chromosome analysis reveals the sex of the fetus (XX or XY). After the first trimester, the diagnosis can be established by measuring estriol levels in the fluid that surrounds the developing fetus (amniotic fluid).

Early diagnosis of Classic CAH and determination of the genetic sex of the child are extremely important to prevent unexpected circulatory crises and for early surgical modification of the external genitalia, if necessary. Oral corticosteroid drug therapy corrects the endocrine deficiency and must continue throughout life. Glucocorticoids are replaced orally, with hydrocortisone, or prednisone. Females treated with corticosteroid drugs menstruate and may have normal pregnancies. In males, androgen suppression permits normal puberty, development of the testes, and the production of viable sperm.

If a deficiency of mineralocorticoid is not corrected by oral corticosteroids, then intravenous corticosteroid therapy, desoxycorticosterone acetate or fludrocortisone, may be necessary to maintain proper sodium and water balance.

Decreases in circulating androgens may cause some shrinkage of abnormally enlarged genitalia. In many cases, especially when therapy begins late, surgical reconstruction of the external genitalia of females may be necessary.

Individuals with Nonclassical Adrenal Hyperplasia can be treated with oral cortisol to reverse most of the symptoms, including infertility. Often, treatment with oral contraceptives and spironolactone are adequate to treat the androgenic signs.

Genetic counseling will be of benefit for affected individuals and their families.
During the first three months of pregnancy, the diagnosis of some types of Congenital Adrenal Hyperplasia can be made by prenatal testing (chorionic villus sample) and tissue typing (DNA analysis or HLA typing). Sex and the genetic type (XX or XY) are also determined. After the first trimester, the diagnosis can be established by measuring estriol levels in the fluid that surrounds the developing fetus (amniotic fluid).

Early diagnosis of Congenital Adrenal Hyperplasia and determination of the genetic sex of the child are extremely important to prevent unexpected circulatory crises and for early surgical modification of the external genitalia if necessary. Oral corticosteroid drug therapy corrects the endocrine deficiency and must continue throughout life. Glucocorticoids are replaced orally, with hydrocortisone, cortisol, and prednisone. Females treated with corticosteroid drugs menstruate and may have normal pregnancies. In males, androgen suppression permits normal puberty, development of the testes, and the production of viable sperm.

If a deficiency of mineralocorticoid is not corrected by oral corticosteriods, then intravenous corticosteriod therapy, desoxycorticosterone acetate or fludrocortisol, may be necessary to maintain proper sodium and water balance.

Decreases in circulating androgens may cause some shrinkage of abnormally enlarged genitalia. In many cases, especially when therapy begins late, surgical reconstruction of the external genitalia of females may be necessary.

Once identified, individuals with the genes for Nonclassical Adrenal Hyperplasia can be treated with oral cortisol to reverse most of the symptoms, including infertility.

Genetic counseling will be of benefit for affected individuals and their families.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

As of August 2007, there were three studies listed within the NIH information. They are:

Since 1996, the National Institute of Child Health and Human Development (NICHD) has been conducting a study to determine whether a combination of drugs can normalize growth in children with CAH. Patients are no longer being recruited.

For information on this study, contact:
Deborah P. Merke, MD
NIH/Institute of Child Health and Human Development
Section on Pediatric Endocrinology
Tel: (301) 496-0718

NICHD is recruiting patients with CAH to participate in a study comparing the effects of intense exercise on the production of catecholamines among individuals affected by CAH and among healthy individuals. Catecholamines (adrenaline and noradrenaline) are adrenal hormones involved in the body’s mechanisms for handling stresses of various kinds. Contact the NIH Patient Recruitment Office listed above or read about this study on www.clinicaltrials.gov.

The National Institute of Mental Health (NIMH) is sponsoring a study of brain imaging among children affected by childhood onset psychiatric disorders and endocrine disorders, and healthy children. Quantitative measures of brain structure and function will be compared across age, gender and diagnostic groups. Correlations between brain and behavioral measures for clinical and normal groups will be identified.

Children with CAH who are 6 to 12 years old are being recruited for a study at the General Clinical Research Center, University of North Carolina, Chapel Hill. Karen Jane Loechner, MD, PhD, and colleagues are studying the addition of amlodipine to the treatment regimen for CAH so that the amount of glucocorticoid medication may be reduced. It is hoped that this decrease may translate into improved growth and bone strength. For information, contact either:

Roxanna Schock, Clinical Coordinator, (919) 966-0428 (voice mail) or Dr. Karen Loechner, (919) 966-4435 (ext. 224).

MENDELIAN INHERITANCE IN MAN, 10th Ed.: Victor A. McKusick, Editor: Johns Hopkins University Press, 1992. Pp. 1188-93.

CLINICAL PEDIATRIC ENDOCRINOLOGY, Solomon A. Kaplan: W.B. Saunders, 1990. Pp. 185-194.

TEXTBOOK OF ENDOCRINOLOGY, 8TH ED.: Jean D. Wilson and Daniel W. Foster, Editors; W.B. Saunders Co., 1992. Pp. 565-70.

CECIL TEXTBOOK OF MEDICINE, 19th Ed.: James B. Wyngaarden, and Lloyd H. Smith, Jr., Editors; W.B. Saunders Co., 1992. Pp. 1331-33, 1377.

THE MERCK MANUAL, 16th Ed.: Robert Berkow Ed.; Merck Research Laboratories, 1992. Pp. 2224-26.

McKusick VA. Ed. On-line Mendelian Inheritance in Man. Johns Hopkins University,

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University;

OMIM # Disorder Last Update

201910 CAH, DUE TO 21-HYDROXYLASE DEFICIENCY 3/5/02
201710 LIPOID CONGENITAL ADRENAL HYPERPLASIA 2/27/02
202010 CAH, DUE TO 11-BETA-HYDROXYLASE DEFICIENCY 2/26/02
202110 CAH, DUE TO 17-ALPHA-HYDROXYLASE DEFICIENCY 2/14/02
201750 CAH, DUE TO DEFECTS IN STEROID-BIOSYNTHETIC ENZYMES 11/12/95
201810 ADRENAL HYPERPLASIA II 3/2/01

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Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2381-82.

Berkow R., ed. The Merck Manual-Home Edition. Whitehouse Station, NJ: Merck Research Laboratories; 1997:1297-98.

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Wilson JD, et al., Textbook of Endocrinology. 8th ed. Philadelphia, PA: W. B. Saunders Co; 1992:565-70, 907-15.

Sperling MA., ed. Pediatric Endocrinology. Philadelphia, PA: W. B. Saunders Company; 1996:283-96.

REVIEW ARTICLES
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Merke D, Kabbani M. Congenital adrenal hyperplasia: epidemiology, management, and practical drug treatment. Paediatr Drugs. 2001;3:599-611.

New ML. Factors determining final height in congenital adrenal hyperplasia. J Pediatr Endocrinol Metab. 2001;14 Suppl 2:933-37.

Farkas A, Chertin B. Feminizing genitoplasty in patients with 46XX congenital adrenal hyperplasia. J Pediatr Endocrinol Metab. 2001;14:713-22.

Pang S. Congenital adrenal hyperplasia owing to 3 beta-hydroxysteroid dehydrogenase deficiency. Endocrinol Metab Clin North Am. 2001;30:81-99, vi-vii.

White PC. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am. 2001;30:61-79, vi.

Speiser PW. Congenital adrenal hyperplasia owing to 21-dehydroxylase deficiency. Endocrinol Metab Clin North Am. 2001;30:31-59, vi.

Migeon CJ, Wisniewski AB. Congenital adrenal hyperplasia owing to 21-dehydroxylase deficiency. Growth, development and therapeutic considerations. Endocrinol Metab Clin North Am. 2001;30:193-206.

Meyer-Bahlburg HF. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30:155-71.

Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30:15-30.

Schnitzer JJ, Donahoe PK. Surgical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30:137-54.

Merke DP, Cutler GB Jr. New ideas for the medical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30:121-35.

New ML. Prenatal treatment of congenital adrenal hyperplasia. The United States experience. Endocrinol Metab Clin North Am. 2001;30:1-13.

Collett-Solberg PF. Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, Part 2. Clin Pediatr (Phila). 2001;40:125-32.

Collett-Solberg PF. Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, Part 1. Clin Pediatr (Phila). 2001;40:1-16.

Brosnan CA, Brosnan PG. Methodological issues in newborn screening evaluation with special reference to congenital adrenal hyperplasia. J Pediatr Endocrinol Metab. 2000;13:1555-62.

Speiser PW. New Developments in the treatment and diagnosis of congenital adrenal hyperplasia. National Adrenal Diseases Foundation (NADF). n.d., 5pp.

INTERNET
eMedicine - Congenital Adrenal Hyperplasia : Article by Thomas A Wilson MD

www.emedicine.com/ped/topic48.htm