Congenital Adrenal Hyperplasia is a family of inherited disorders affecting the adrenal gland. The most common form is 21-hydroxylase deficiency, which is inherited in severe or mild forms. The severe form, called Classical CAH (CAH), is usually detected in the newborn period or in early childhood. The genetic frequency of Classical CAH is approximately 1 in 15,000 births. The milder form, called Nonclassical CAH (NCAH), may cause symptoms at anytime from infancy through adulthood. Nonclassical CAH is a much more common disorder than Classical CAH. It affects 1 in 100 to 1 in 1000 in the general population, depending upon the ethnic composition of a given community, since its frequency varies in different ethnic groups. For example, it affects 1 in 27 Ashkenazi Jews, 1 in 40 Hispanics, 1 in 53 Croatians, and 1 in 300 Italians. This frequency makes NCAH the most frequent genetic disorder identified to date. Fortunately, CAH can be managed with medication and affected individuals go on to live normal lives.
CAH, including NCAH, is an autosomal recessive genetic disorder. It affects males and females in equal numbers. For a child to be born with either form of CAH, both parents must carry a gene for the disorder (see Figure 1). Parents are usually asymptomatic carriers of the recessive gene, one or both parents may also be affected. Scientists have pinpointed the location of the group of genes that cause the most common forms of CAH to chromosome 6. DNA testing is now available for diagnosis of CAH and NCAH and to detect carriers of the gene mutations.
This particular group of genes contains instructions that the adrenal glands (which are located on top of the kidneys - see Figure 2) need in order to produce a certain enzyme, 21-hydroxylase (21-OHP). Without this enzyme, the adrenal glands are unable to synthesize cortisol, a hormone necessary for life, in physiologically sufficient amounts.
Cortisol is a steroid produced by the adrenal glands that is needed for our bodies to deal with physical and emotional stress, and to maintain adequate energy supply and blood sugar levels. The adrenal glands are actually controlled by the pituitary gland. The pituitary gland is a small pea-shaped gland at the base of the brain. When the pituitary gland senses that there is not enough cortisol present in the bloodstream, it releases a hormone called ACTH (adrenocoricotrophic hormone). ACTH stimulates the adrenals to produce more cortisol. However, those with CAH have insufficient amounts of the enzyme 21-OHP needed to convert a precursor molecule called 17-hydroxyprogesterone (17-OHP) into cortisol. As a result, the pituitary gland continues to sense the need for cortisol and pumps out more ACTH. This leads to an overabundance of 17-OHP, which is converted in the adrenals into excess androgens, masculinizing steroid hormones (see Figures 3 and 4). Lack of adequate cortisol also prevents the body from properly metabolizing sugar and responding to stress. The lack of this stress response can lead to drowsiness and possibly coma.
In addition, over 75% of all babies with classical CAH also lack another adrenal hormone called aldosterone, necessary for maintaining normal fluid volume of the body and potassium, which among other functions, stabilizes the heart. When this occurs it is called “salt-wasting CAH”. When the adrenals cannot make sufficient aldosterone, too much salt and water are lost in the urine, leading to dehydration and salt deficiency. High levels of potassium can cause serious disturbances of heart rhythm and cardiac arrest. These babies become very ill soon after birth if not diagnosed and treated promptly. The remaining 25% of those with classical CAH who produce sufficient aldosterone are called “simple virilizers.” The nonclassical form of CAH is not life threatening, but can affect puberty and growth in children and can cause infertility in males and females as well as other symptoms affecting quality of life.
Other forms of enzyme deficiency that belong to the congenital adrenal hyperplasia family of disorders, such as 3-beta hydroxylase deficiency, 11-beta hydroxylase deficiency and 17 alpha-hydroxylase deficiency, are much less common and are not discussed here. Articles describing 11-Beta hydroxylase deficiency and 17 alpha- hydroxylase deficiency can be found at: E_Medicine. Please contact CARES if you wish information relating to these rarer forms of CAH.