Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a genetic disorder affecting the adrenal glands. The condition is caused by a total or partial deficiency of one of the enzymes responsible for the production of glucocorticoids. CAH is the most common adrenal gland disorder of infants and children and the most common autosomal recessive genetic disorder in humans, with an incidence of approximately 1 in 10,000 to 1 in 15,000 births worldwide.

Other Names

 * 21-hydroxylase deficiency
 * Adrenogenital syndrome
 * Adrenal virilism

Types
Most (90%-95%) cases of CAH are caused by a deficiency of the enzyme 21-hydroxylase. The remainder are due to impaired or absent 11-ß hydroxylase.

There are two types of congenital adrenal hyperplasia:

Classic
Classic CAH results from significantly decreased synthesis of cortisol due to an enzyme deficiency. The resultant increase in androgens causes masculinization of the external genitalia. The internal genitalia (ovaries and uterus) are often normal. This condition is usually diagnosed in infancy or early childhood. Because of the decrease in cortisol (which controls the stress response), the effectiveness of the immune system may be affected. The excess androgen may also cause acne, abnormal hair growth and short stature. If aldosterone synthesis is decreased, symptoms may also include salt wasting which is charactized by potentially severe electrolyte imbalances.

Nonclassic (mild)
In mild CAH, varying amounts of the affected enzyme may be present. Symptoms may be mild or absent and may only be diagnosed by genotyping or homone level testing in members of a family with classic deficiency. If symptoms are present, they often include frequent dizziness, difficulty fighting infection, acne, abnormal hair growth or abnormal skin pigmentation.

Signs and Symptoms
Symptoms of the mild form of CAH may include short stature, frequent infections, dizziness with standing, early signs of puberty, short stature, acne, irregular periods and infertility (in women), and excess facial hair (in women).

Symptoms of the more severe (classic) CAH may include the above plus dehydration, low blood pressure, low blood sugar level, trouble keeping enough salt in the body (salt wasting), altered development of the external genitalia in girls which is noted at birth and may require surgery to correct, and benign testicular tumors and infertility (in men).

Causes
Congenital adrenal hyperplasia is caused by mutations in the CYP21A2 gene. Mutations that only partially impair enzyme levels or function will have milder effects than more severe mutations that eliminate or greatly reduce the affected enzyme.

The condition is inherited in an autosomal recessive manner.

The adrenal gland converts cholesterol to aldosterone (a mineralocorticoid that causes the kidney to retain salt and water) in the zona glomerulosa or outer section of the gland. It also converts cholesterol to cortisol and testosterone in the zona reticularis and zona fasciculata. Cortisol increases blood sugar, blood pressure and works to suppress the immune system in response to stress. Testosterone is the principal male sex hormone and is thought to increase energy, libido and to provide protection against osteoporosis.

When either of the enzymes 21-hydroxylase or 11-ß hydroxylase is deficient or its activity is impaired, the precursors of cortisol and aldosterone accumulate in the adrenal gland and are ultimately converted to androgen hormones. The resulting imbalance of hormones leads to the virilization, salt wasting, and abnormal stress response seen with CAH.

The pituitary gland senses that the levels of the hormones are decreased and sends a signal to the adrenal gland through an increase in ACTH (adrenocorticotropic hormone). The adrenal glands respond to the ACTH stimulus by becoming hyperplastic (an increase or proliferation of cells), hence the name adrenal hyperplasia.

Diagnosis
The diagnosis of CAH is usually straightforward and is based on physical examination and lab tests for the various affected hormone levels (testosterone, cortisol, and aldosterone) as well as tests for 17-OHP (the metabolic product just prior to cortisol synthesis) and deoxycorticosterone and 11-deoxycortisol levels (elevated in 11-ß hydroxylase deficiency)

The 17-OHP level is generally elevated in both salt-wasting and non salt-wasting forms of CAH and further evaluation is warranted. Sodium, potassium, CO2/bicarbonate and glucose levels may help determine whether or not salt-wasting is present.

The 17-OHP level is part of the newborn screening panel done soon after birth in all 50 states in the US.

Genetic testing may also be done if CAH is strongly suspected or a family history of the disease is confirmed. This testing may include chorionic villus sampling in the fetus, amniocentesis or blood testing after birth. The genes can be studied using a technique called a polymerase chain reaction (PCR), and mutations consistent with CAH can be sought.

Treatment
Mild congenital adrenal hyperplasia may not require treatment. More severe disease is usually treated with glucocorticoids. Hydrocortisone is usually the treatment of choice, because of its short duration of action. The drug is given in divided daily doses and may need dose adjustment in periods of stress or infection. The lowest possible dose should be used due to the risk of side effects.

Removal of the adrenal glands (bilateral adrenectomy) may be a surgical treatment option in children whose condition is difficult to manage medically.

Prevention
Congenital adrenal hyperplasia cannot be prevented. Genetic testing and newborn screening may help with early diagnosis and treatment. The goal is to replace the deficient hormones before long-term damage is done.

Living with
Infants with severe forms of CAH require close monitoring, since overtreatment and undertreatment both carry significant risks. Frequent lab tests are needed to determine levels of adrenal hormones and related compounds in either the urine or serum. Compliance with the treatment regimen must be ensured, which includes frequent monitoring of growth rate (including determination of bone age). Affected female infants may require surgical reconstruction to reduce the masculine appearance of their genitals. With appropriate care, a normal sex life and normal fertility may be expected.

Chances of Developing
Since CAH is inherited as an autosomal recessive disorder, two copies of the defective gene must be inherited, one from each parent. In families where both parents are known to be carriers, either through genetic testing or because of an affected child, children incur a 25% risk of having the disease. Half of subsequent offspring are expected to carry one copy of the defective gene, and about 25% are expected to carry two copies of the normal gene.

Worldwide incidence of CAH has been estimated as 1:15,000 with a carrier frequency of 1:55. These figures vary by country and race.

Related Problems
Infertility may be a result of CAH, even in mild cases. There are several different causes for the infertility and several different treatment options. Consultation with a reproductive endocrinologist may be helpful.

CAH has important reproductive consequences beyond the scope of infertility. In terms of genetic transmission, as this is a recessive disorder, there is a 100% risk that the fetus will be at least a carrier for the gene defect or deficiency. Thus, whether the fetus will be affected depends on the genotype of the partner. Assessing risk is made more complicated by the variable phenotype (classic versus nonclassic) of the disease. For instance, a patient with nonclassic disease could have two “mild” alleles, or could have one “mild” and one “severe” allele; both may present with a similar phenotype.

Genetic testing for CAH includes DNA mutation screening for the most common severe alleles. This may be performed on maternal and paternal blood, or on chorionic villi or amniocytes after invasive testing for the fetus. This screening detects 85-90% of the mutations that cause classic CAH and thus does not provide a 100% detection rate. Furthermore, DNA screening does not detect the genes contributing to the nonclassic form of CAH. Testing of amniotic fluid for increased levels of 17-hydroxyprogesterone allows for testing for the CAH phenotype, and thus can provide a higher detection rate.

Genetic transmission of the disorder to the fetus is an important consideration, but also excess maternal androgens can have a significant impact on the development of a female fetus. In a case of untreated CAH, the fetus will be exposed to excessive androgens. For a female fetus, this will contribute to irreversible masculinzation of the genitalia. To prevent this, glucocorticoids are administered at the time of diagnosis of pregnancy (if not before becoming pregnant), as these effects happen very early in development and are irreversible. Dexamethasone (20mcg/kg/day) is administered as it crosses the placenta and ensures targeted treatment. This is continued for a female fetus at risk for classic CAH. Fetal exposure to glucocorticoids can be minimized if invasive testing is chosen and demonstrates a male karyotype; at that, in classic CAH point the steroids can be changed to hydrocortisone or prednisone, which does not cross the placenta.

Steroids are not usually continued in patients with nonclassic CAH who have fetuses who are not at risk, as their health usually does not rely critically on glucocorticoid supplementation and treatment is not necessary for the fetus. However, recent research suggests that glucocorticoid treatment for these patients may improve pregnancy outcome. Much of that improvement may be in a decrease in first trimester pregnancy loss, theoretically as a result of increased androgen levels. At this time, however, expert opinion holds that patients with nonclassic CAH and fetuses that are not at risk should not be treated with long term glucocorticoids after the fetus is declared not at risk.

Clinical Trials
ClinicalTrials.gov: congenital adrenal hyperplasia trials

Research

 * Research is ongoing regarding the use of four different medicines (flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone) instead of the standard hydrocortisone and fludrocortisone to normalize growth in children with CAH.
 * Evaluation of the effect of exercise on the sympathetic nervous system and whether it can compensate for the hormone deficiencies of CAH.
 * Using Pioglitazone (a medicine used to treat diabetes) to treat the insulin resistance that is common with CAH.
 * The use of nifedipine, a calcium channel blocker used to treat high blood pressure, to decrease ACTH and lead to a decreased need for treatment of CAH with glucocorticoids.

Expected Outcome
There is no cure for congenital adrenal hyperplasia. Long-term complications depend on severity of the disease, type of enzyme deficiency, age at onset of treatment, compliance with treatment and outcome of surgery (if applicable). Fertiliity may be attained in female patients. Attaining full adult height potential remains a problem.