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Congenital Adrenal Hyperplasia (CAH)

View the CAH Handbook [.doc]

What is CAH?

CAH is a family of genetic disorders that alter the way your adrenal glands make steroid hormones . These hormones are essential for life. They are active in the sexual development of the fetus and in adolescence and are important responders to stress. There are severe and mild forms of CAH that result from deficiencies in enzymes necessary for the synthesis of steroid hormones in the adrenal gland. All are readily treatable. There are six enzyme defects that cause different forms of CAH. The most common are 21-hydroxylase deficiency (21-OHD) and 11b-hydroxylase deficiency (11b-OHD) CAH; 90% of all cases of CAH are due to 21-hydroxylase deficiency. Because of this, the term "CAH" usually refers to 21-hydroxylase deficiency.

Disorders of Androgen Excess

What is 21-Hydroxylase Deficiency CAH?

The most common form of CAH results from a deficiency of the enzyme 21-hydroxylase. There are two forms of 21-hydroxylase congenital adrenal hyperplasia, a) a severe form, termed "classical CAH," with profound 21-hydroxylase deficiency, and b) a mild form, called "nonclassical CAH," which has a lesser deficiency of 21-hydroxylase. The severe, classical form is divided into simple virilizing and salt-wasting forms. The severe, or classical, form of 21-hydroxylase deficiency CAH is due to complete or nearly complete deficiency of an enzyme (21-hydroxylase) necessary for the adrenal to synthesize cortisol, a steroid hormone essential for life. The salt-wasting form lacks aldosterone, the principal salt-retaining hormone in the human. The simple virilizing form does not lack aldosterone. The classical form of 21-hydroxylase deficiency CAH may be life-threatening if untreated.

21-Hydroxylase deficiency in the classical forms, both salt-wasting and simple virilizing, results not only in reduced secretion of cortisol but also increased secretion of male-like hormones from the adrenal. These male-like hormones masculinize the female fetus in utero so that the genitalia are ambiguous. In the nonclassical form, the male-like hormones are not produced in sufficient amounts to masculinize the female genitalia and thus the baby girl with CAH is born with normal genitalia.

Nonclassical CAH is a frequently underdiagnosed cause of such symptoms in women as excess facial and body hair ("hirsutism"), acne, infertility, and hair loss on the head ("alopecia"). In men it is an underdiagnosed cause of decreased fertility and short stature. In children, the mild form may present with symptoms such as early pubic hair, precocious puberty, rapid growth, tall stature, and early arrest of growth; adolescents with the nonclassical form may have symptoms such as acne, early arrest of growth, and short stature.

How frequent is CAH?

Classical 21-hydroxylase deficiency CAH occurs in 1 in 15,000 live births worldwide. There is newborn screening for this disorder in most of the United States. Nonclassical 21-hydroxylase deficiency is much more frequent and may not be detected by newborn screening. In the diverse population of New York City , it occurs in 1 in 100 people, with higher frequency in some ethnic groups: in Ashkenazi Jews the frequency is 1:27; in Hispanics it is 1:40 and in Slavs it is 1:50.

Does Nonclassical CAH require treatment?

Yes. Treatment protects fertility and reverses the symptoms described.

Can CAH be detected during pregnancy?

21-Hydroxylase deficiency CAH can be diagnosed prenatally following amniocentesis or chorionic villus sampling. Classical CAH can be treated prenatally. This can prevent masculinization of the genitalia of affected females.

What is 11b-Hydroxylase Deficiency CAH?

11b-Hydroxylase deficiency is the second most common form of CAH (5-8% of cases). Like 21-hydroxylase deficiency, it causes masculinization in the female fetus, but it also cause high blood pressure in both males and females. It is diagnosed by hormone testing and DNA analysis and is treated by steroid hormone replacement. Like 21-hydroxylase deficiency, it can be prenatally diagnosed and treated, and has severe and mild forms.

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Androgen Receptor Defects and Related Disorders of Androgen Synthesis or Action

What is Androgen Insensitivity Syndrome (AIS)?

In the androgen insensitivity syndromes, androgens (the male hormones, mainly testosterone) are made normally by the testis, but they are ineffective because the body cannot respond to androgens. There are severe (Complete Androgen Insensitivity Syndrome, CAIS) and mild (Partial Androgen Insensitivity Syndrome, PAIS) forms. In CAIS, individuals are chromosomal males but female in appearance, except that they lack long, dark hairs in their underarms and external genitals. For CAIS, the diagnosis is usually made at adolescence owing to lack of menstruation but can be made earlier if an inguinal hernia is found to be caused by an undescended testis. In PAIS there is a spectrum of effects on sexual development ranging from infertility to the female body characteristic of CAIS in chromosomal males (XY). PAIS is often diagnosed at birth due to genital ambiguity.

What is 5a-Reductase 2 Deficiency?

5a-Reductase 2 deficiency is a rare disorder affecting male sexual development. Patients are born with female or ambiguous external genitals, which masculinize only at adolescence during puberty. Diagnosis is made by hormonal and genetic analysis. Treatment includes hormone replacement appropriate for the elected sex of the individual, and genital surgery is usually required only if the female gender is elected.

What is 17b-Hydroxysteroid Dehydrogenase Deficiency?

17b-Hydroxysteroid dehydrogenase deficiency is a rare disorder that severely limits the capacity of the testis to produce testosterone. Consequently, male sexual development is impaired in utero . However, like 5a-reductase 2 deficiency, masculinization progresses during puberty. Patients are treated by specialists during adolescence to manage the masculinization process commensurate with the elected gender of the individual.

What is 3b-Hydroxysteroid Dehydrogenase Deficiency CAH?

3b-Hydroxysteroid dehydrogenase deficiency is another form of CAH. In this disorder, both male and female sexual development can be affected in utero. It may also cause salt-wasting. It is diagnosed by hormone testing and DNA analysis and is treated by steroid hormone replacement.

What is 17a-Hydroxylase (CYP17) Deficiency CAH?

17a-Hydroxylase deficiency is a rare form of CAH that interferes with synthesis of male hormones. Male sexual development is affected in utero. Females appear normal at birth but have delayed puberty. This condition is also characterized by hypertension. It is diagnosed by hormone and DNA analysis and is treated by steroid hormone replacement.

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Low-Renin Hypertension

What is Apparent Mineralocorticoid Excess?

Apparent mineralocorticoid excess (AME) is an extremely rare genetic disorder that in its severe form causes severe hypertension in children and may be fatal. It is caused by abnormal hormone metabolism. Diagnosis is made by hormonal and DNA analysis. Treatment for hypertension to reduce salt retention by the kidney should begin as early as possible. A mild form of AME has been identified.

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