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

• Addison's disease
• androgen-producing tumors
• disorder of sex development

Common to several forms of CAH are abnormally enlarged adrenal glands (hyperplasticadrenomegaly) 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 salt-wasting 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 severe cases female babies may be mistaken for males. Boys with 21-hydroxylase deficiency do not display genital malformations but continued androgen excess may cause early pubertal maturation, fast body growth, 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. It is an autosomal recessive trait, inherited by both males and females in equal proportions. However, since females with the classic, severe form have genital ambiguity, they are usually recognized at birth, wherease unless subjected to newborn screeningthe disorder is not usually apparent in males until adrenal crisis ensues at several weeks of life, or precocious pseudopuberty becomes apparent. 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.

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 if patients are not properly treated.

Male infants with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia appear normal at birth. At 1- 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 two-thirds to three-fourths 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 7 to 21 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 the very rare Congenital Lipoid Adrenal Hyperplasia (adrenal cortex male disorder of sex development ), the most prominent feature is the physical appearance of both male and female characteristics in a male (disorder of sex development, formerly termed 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 HydroxysteroidDehydrogenase (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 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 .

Incomplete forms of 3-Beta HydroxysteroidDehydrogenase Deficiency have been described in the medical literature. Symptoms occur later in childhood and may includeprecocious pseudopuberbty, 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. Symptoms in XX individuals may include uterine and ovarian hypoplasia, failure to develop secondary sexual characteristics and the absence of a menstrual periods (amenorrhea). Both males & females suffer 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 premature & progressive 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.


A less severe late onset form of 21-hydroxylase deficiency CAH due to a more common genetic mutation is calledNonclassical Adrenal Hyperplasia. Symptoms include, premature pubertal development, severe acne, excessive facial hair in women,. A small proportion of the nonclassic patient population has sub-fertility.These symptoms are all caused by excess androgen production starting at or before puberty.

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 HydroxysteroidDehydrogenase Deficiency is located on the short arm of chromosome 1. One of the 2 types of defective genes that cause Lipoid Adrenal Hyperplasia (20-22 Demolase Deficiency) has been mapped to chromosome 15.

The most common form of CAH, 21 Hydroxylase Deficiency, affects approximately 1:10,000 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, about 1 in 100 individuals in the Caucasian non-Jewish groups who have been studied, have the nonclassical form of this disorder.

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). Due to the rather non-specific nature of symptoms, often the disease goes unrecognized for years before a correct diagnosis is made. 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.)


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.

Disorder of Sex Development 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 " Disorder of Sex Development " 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).

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.,

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. In some cases, treatment with oral contraceptives and spironolactone are used exclusively or in combination 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) (DNA analysis). Sex and the genetic type (XX or XY) are also determined.

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.

A deficiency of mineralocorticoid is corrected by oral corticosteriods, together with fludrocortisone and sodium supplement.,

Decreases in circulating androgens may prevent further enlargmentof 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 web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

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

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

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