NORD gratefully acknowledges Phyllis W. Speiser, MD, Chief, Division of Pediatric Endocrinology, Cohen Children's Medical Center of NY; Professor of Pediatrics, Hofstra North Shore LIJ School of Medicine, for assistance in the preparation of this report.
Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH effects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: 1. corticosteroids, which gauge the body's response to illness or injury; 2. mineralocorticoids, which regulate salt and water levels; and 3. androgens, which are male sex hormones. An enzyme deficiency will make the body unable to produce one or more of these hormones, which in turn will result in the overproduction of another type of hormone precursor in order to compensate for the loss.
The most common cause of CAH is the absence of the enzyme 21-hydroxylase. Different mutations in the gene responsible for 21-hydroxylase result in different levels of the enzyme, producing a spectrum of effects. CAH due to 21-hydroxylase deficiency is responsible for 95% of all cases of CAH and is broken down further into two subcategories: classical CAH, which can be sub-divided into the salt-losing form or the simple-virilizing form, and non-classical CAH. Classical CAH is by far the more severe form and can result in adrenal crisis and death if not detected and treated. Non-classical CAH is milder, and may or may not present symptoms. Since the absence of 21-hydroxylase makes these individuals unable to make the hormone cortisol and, in the case of salt-losing CAH, aldosterone, the body produces more androgens which cause a variety of symptoms such as abnormal genital development in infant girls. There are other much rarer forms of CAH as well, including 11-Beta hydroxylase deficiency, 17a-hydroxylase deficiency, 3-Beta-hydroxysteroid dehydrogenase deficiency, congenital lipoid adrenal hyperplasia and p450 oxidoreductase deficiency which all present different symptoms. Although CAH is not curable, as long as patients receive adequate care and treatment, they can go on to lead normal lives.
Many individuals with CAH present with abnormally enlarged adrenal glands (hyperplastic adrenomegaly) that produce excessive amounts of androgens (male steroid hormones) leading to abnormal sexual development in females affected with the disease. Females with severe or classic virilizing CAH due to 21-hydroxylase deficiency will most likely have ambiguous or atypical external genitalia (masculinization or virilization), although they are genetically female and will have normal internal reproductive organs. Males with this type of CAH will not have ambiguous genitalia. Both genders can experience other symptoms such as early onset of puberty, fast body growth, and premature completion of growth leading to short stature, if they are not diagnosed and treated in early life.
About 75% of people with classical CAH due to 21-hydroxylase deficiency also have a deficiency of the hormone aldosterone, leading to the inability to retain salt and water (salt wasting). This results in excessive loss of water (dehydration), low circulating blood volume (hypovolemia), and abnormally low blood pressure (hypotension and shock). Without treatment, this severe form of CAH can lead to profound weakness, vomiting, diarrhea, and circulatory collapse due to adrenal crisis. The remaining 25% are referred to as simple-virilizers and do not have a problem regulating salt and water levels. Fortunately in the United States, and in many other developed countries, there is universal newborn screening for CAH due to 21-hydroxylase deficiency, and the vast majority of children are diagnosed and treated early to avoid these complications.
The mild form of 21-hydroxylase deficiency (non-classical CAH) is not life-threatening and is due to a more common genetic mutation. This mild form is not usually detected in our newborn screening programs, and it seldom requires early treatment. Symptoms in later childhood may include premature body hair or acne development. In adolescent females, the most common problems include excessive facial or body hair, menstrual irregularities, and pustular acne. Both genders have normal genitals. A small proportion of the non-classic CAH population has sub-fertility. Patients with CAH may or may not require treatment to improve their quality of life.
Rare forms of CAH:
11-Beta hydroxylase deficiency patients are protected from the symptoms associated with adrenal crisis, although they are subject to others such as hypertension due to salt retention and ambiguous genitalia in females.
17a-hydroxylase deficiency results in ambiguous external genitalia in males and lack of pubertal development or menstrual cycles (amenorrhea) in females.
3-Beta-hydroxysteroid dehydrogenase deficiency leads to ambiguous genitalia in males and females. In both genders it can lead to salt-wasting.
Congenital lipoid adrenal hyperplasia may cause early death due to adrenal crisis. Males have ambiguous genitalia. Both males and females, if they survive, would likely be infertile.
PORD (P450 oxidoreductase deficiency) presents with signs and symptoms that may resemble 21-hydroxylase deficiency, 17-hydroxylase deficiency, or a combination of the two enzyme deficiencies. Some cases have been associated with a skeletal disorder known as Antley-Bixler syndrome.
Deletions and mutations in the CYP21A2 gene account for all cases of the 21-hydroxylase deficiency form of CAH. Mutations in the CYP11B1, CYP17A1, HSD3B2, CYP11A1, STAR, and CYPOR genes are responsible, respectively, for 11-hydroxylase, 17-hydroxylase, 3-beta-hydroxysteroid dehydrogenase deficiencies, lipoid adrenal hyperplasia, and PORD, the other rarer forms of CAH.
All forms of CAH are inherited in an as autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal 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 is 25%. The risk is the same for males and females.
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 Eskimos, 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. In contrast, non-classical CAH affects approximately 1 in 100 to 1 in 200 individuals in the general population.
All newborns in the United States are screened for classic 21-hydroxylase deficiency. Non-classic CAH is frequently not detected in the newborn test and therefore, may not be diagnosed until childhood or early adulthood when the patient first starts showing symptoms. Genetic testing for the gene mutations associated with the various forms of CAH is available, but is most often performed when pre-pregnancy genetic counseling is indicated, after an endocrinologist confirms the diagnosis through blood hormone tests, or if results of hormone tests are not definitive.
Prenatal diagnosis is available for couples at risk for having a child affected with CAH using first trimester chorionic villus sampling and testing the fetal DNA for a particular CAH gene mutation known to occur in the family. Non-invasive determination of sex can be accomplished through testing fetal DNA in the mother’s blood. Non-invasive prenatal testing for mutations in CYP21A2 (the gene causing this disorder) is not generally available at present.
If CAH is detected in a fetus, prenatal treatment is a possibility, although it should be regarded as experimental. The oral drug dexamethasone can be given to pregnant women in a subsequent pregnancy if she has given birth to child with severe classical CAH. Such treatment does not prevent or cure the disease, but may lessen the virilization of affected female fetuses. There is limited knowledge about the long-term safety of this procedure, and this should be done only under the supervision of experienced clinicians who report to an ethical review board for human studies. This treatment is not routinely recommended, and is not curative [The Endocrine Society Clinical Practice Guidelines for CAH 2010, updated 2018].
Monitoring hormone levels in individuals with CAH is crucial throughout their post-natal life. Height and weight are important aspects that need to be monitored in order to know if treatment should be adjusted, particularly in children. Monitoring bone age is an additional tool to determine if the child is undergoing proper physical maturation. A simple x-ray of the hand can show the growth centers and provide an estimate of predicted adult height. As individuals mature, the growth centers change and have characteristic appearances at different ages. Too much sex hormone secretion can cause bones to age more rapidly, and treatment can slow this progression, if caught early.
Treatment of CAH varies greatly depending on the type and severity. CAH cannot be cured, but it can be effectively treated. Treatment of classical CAH starts soon after birth and is needed throughout the patient’s life. People with classical CAH should have a team of healthcare providers, including specialists in pediatric endocrinology, uro-gynecologic surgery (for girls), psychology and genetics. People with classical CAH can have normal, fulfilling lives. Patients with non-classical CAH may not need any treatment, depending on their symptoms. Treatment must be individualized by doctors who have experience with this condition.
The primary goal of treating classical CAH is to reduce the excess androgen production and replace the deficient hormones. Proper treatment with the correct dosage of these hormones is crucial to preventing adrenal crisis and virilization. Daily tablets including glucocorticoids (to replace cortisol), mineralocorticoids (to replace aldosterone) and salt supplements may be prescribed, particularly in infancy. During times of high stress or illness adrenal glands are normally much more active. Therefore, when ill or after major surgery or stressful event, CAH patients must be closely monitored because their bodies will require more hormones to help the body recover and meet increased demands. Hormone levels need to be adjusted and monitored throughout the patient’s life. The dose of glucocorticoids should be minimized to avoid development of Cushing’s syndrome, a disorder characterized by a variety of symptoms and physical abnormalities including weight gain; skin, muscle and bone changes. High dose mineralocorticoid supplements or salt should be avoided to prevent high blood pressure.
Surgery may be considered to correct the appearance of ambiguous genitalia and/or relieve urethra-vaginal outlet obstruction that may lead to infection. Usually surgery is thought to be easier when performed at about 6-12 months after birth. The choice to have the surgery should be reserved for infants with severe genital ambiguity, and is most often a joint decision of the parents and medical-surgical teams. Some parents choose to wait until their daughter is old enough to have a say in her surgery. Others feel the problem is severe and should be corrected immediately. If this is the case, finding a highly skilled pediatric urologic surgeon is of the utmost importance. Surgical techniques have changed over the past few decades, and cosmetic appearance and functionality have improved. It is also highly recommended that families of girls who undergo this surgery have expert psychological counseling and care.
Non-classical CAH on the other hand, is not life-threatening and relatively mild. People who have no obvious symptoms of non-classical CAH do not require surgery or medical treatment. If a patient with non-classical CAH begins to enter puberty too early, has early maturation of bones, or is a female with excess facial or body hair or other masculine features, glucocorticoid treatment is recommended. Fertility problems can also be corrected with glucocorticoids and/or fertility drugs. Women who do not wish to conceive may also be prescribed oral contraceptives. Unlike severe forms of CAH, non-classical CAH patients are free to taper and stop treatment when symptoms go away.
Please refer to the Endocrine Society Clinical Practice Guidelines for additional information regarding diagnosis and treatment of CAH (listed below in the references).
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