What is congenital adrenal hyperplasia?
Congenital adrenal hyperplasia (CAH) is a group of inherited disorders of the adrenal gland, small triangular organs located on top of the kidneys that secrete hormones. CAH is associated with deficiencies in the enzymes required for the production of the steroid hormones cortisol and/or aldosterone.
In the adrenal gland, cholesterol is turned into a precursor called pregnenolone and then several enzymes complete the production of aldosterone, cortisol, and androgens. If one or more of these enzymes is deficient or dysfunctional, then inadequate amounts of the final products are produced. Because low concentrations of cortisol cause a pituitary hormone that stimulates adrenal growth and hormone production (adrenocorticotropic hormone, or ACTH) to become elevated, the adrenal gland increases in size (CAH). However, the increased size and activity cannot overcome the block in cortisol production. Other substances (such as 17-hydroxyprogesterone) that do not need the defective enzyme will be produced in excess. The vast majority of CAH cases are due to a deficiency in the enzyme 21-hydroxylase, so this type will be the main focus of this article.
With CAH, the enzyme deficiency can cause a decrease in cortisol concentration and/or aldosterone and, in some cases, an increase in androgens, a group of "male hormones." Excess androgens can result in the development of male sexual characteristics in females (virilization), which is often noticed at birth. A baby girl's external sex organs may be ambiguous: her genitals may resemble a boy's anatomy or be somewhere in between a boy's and a girl's anatomy. While it is a rare disorder, CAH is the most common cause of ambiguous external sex organs (genitals) in newborns.
Males with this condition will appear normal at birth but may start to develop sexual characteristics of puberty in early childhood. Females may develop excess hair on the face and body (hirsutism) and other male secondary sexual characteristic during childhood and adolescence and have irregular menstruation. CAH may also lead to infertility in adults.
CAH enzyme deficiencies are due to mutations in specific genes. They are autosomal recessive, which means that it takes two copies of the gene mutation, one inherited from each parent, before a person will be affected by CAH. A person with one copy will be a carrier but will not typically have any symptoms.
About 90% of CAH cases are due to a 21-hydroxylase deficiency, which is caused by a mutation in the CYP21A2 gene. Those affected may have a classic (more severe) or nonclassic (less severe) type. About 75% of those with a classic deficiency will have a "salt-wasting" form that includes decreased aldosterone and leads to an excess loss of fluids, low sodium, and high potassium that, when severe, can be life-threatening.
The National Institute of Child Health and Human Development in the United States estimates that classic CAH affects about one in 15,000 babies worldwide, while non-classical CAH affects about one in 1,000 people. CAH can occur in people of all ethnicities but is more common among Ashkenazi Jews, Yupik Eskimos, and those of Hispanic, Slavic, or Italian descent.
Several other rare inherited enzyme deficiencies can also cause CAH. Of these, 11-beta-hydroxylase deficiency is the most common, accounting for about 5-8% of CAH cases, and 17-alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase are less common. The signs and symptoms that are experienced by males and females with CAH will depend upon which enzymes are deficient and the severity of the deficiencies. For more information on these less common types of CAH, see the links on the Related Pages page.
Symptoms associated with congenital adrenal hyperplasia (CAH) depend upon the type of enzyme deficiency and the amounts of cortisol, aldosterone, and androgens that are produced. Symptoms may vary over time and can worsen with illness and stress.
Those associated with the form of classic 21-hydroxylase deficiency CAH that causes excess loss of fluids and salt ("salt-wasting") can lead to a life-threatening adrenal crisis.
Salt-wasting CAH signs and symptoms may include:
- Abnormal heart rhythm, rapid heart rate
- Confusion
- Dehydration
- High potassium (hyperkalemia)
- Irritability
- Low blood glucose (hypoglycemia)
- Low blood pressure
- Low sodium (hyponatremia)
- Vomiting
Females with classic 21-hydroxylase deficiency may have external sex organs that are not clearly male or female (ambiguous external genitalia) but normal reproductive organs (uterus, fallopian tubes, and ovaries).
Signs and symptoms associated with excess male hormones (androgens) in both males and females in childhood and early adolescence may include:
- Accelerated skeletal growth (tall during childhood but short as adults)
- Acne
- Deep voice
- Enlarged penis (males)
- Enlargement of clitoris (females)
- Excess hair on face and body (hirsutism) in females
- Infertility or decreased fertility
- Irregular menstruation (females)
- Excess muscle growth
- Early development of pubic and armpit hair
Laboratory Tests
The goals with congenital adrenal hyperplasia (CAH) testing are to:
- Screen all newborns for 21-hydroxylase deficiency
- Help confirm the condition in those with positive newborn screens
- Help diagnose the condition in those with symptoms
- Identify the carrier status of a person who has a family member with 21-hydroxylase deficiency
- Determine the chromosomal sex (XX or XY) of a newborn with genitals that are not clearly male or female (ambiguous genitalia)
- Monitor treatment for CAH and detect overtreatment
- Evaluate and monitor the health status of a person with an adrenal crisis
- Detect 21-hydroxylase deficiency during pregnancy (sometimes)
- Identify and/or rule out other types of CAH besides 21-hydroxlase deficiency (sometimes)
Testing may include:
Screening
- Newborn screening is not currently offered in the UK as part of the national newborn screening programme
- Prenatal testing with chorionic villus sampling or amniocentesis
Detect/Diagnose
- 17-OHP – concentrations may be greatly elevated with 21-hydroxylase deficiency
- Steroid profile on a spot urine specimen – this looks at the pattern of steroids in a urine specimen, and is a very sensitive method for detecting abnormal steroid production
- ACTH stimulation – measures the level of cortisol in a person's blood before and after an injection of synthetic ACTH (Synacthen™). If the adrenal glands are functional, cortisol concentrations will rise in response to the ACTH stimulation; not performed frequently.
- Additional testing may be performed when 17-OHP is elevated,, depending upon which deficiencies and accumulations of precursors are suspected; may include several of the following:
- Androstenedione
- Testosterone
- 11-deoxycortisol
- Dehydroepiandrosterone sulfate (DHEAS)
- 17-hydroxypregnenolone
- Pregnenolone
- Aldosterone and renin – to determine if concentrations of these substances are normal
- Chromosome analysis (karyotyping) – to determine a baby's sex by evaluating their chromosomes (XX (female) or XY (male))
- Genetic testing – performed to detect gene mutations; not usually needed for diagnosis but may be used for prenatal diagnosis of 21-hydroxylase deficiency and for detecting gene mutation(s) in family members to help determine carrier status; will detect the most common mutations. If a specific mutation has been identified in a family, testing should include that mutation.
Monitor treatment, every few months:
- 17-OHP in a blood spot or saliva specimen
- Androstenedione
- Testosterone
Health status, during illness, and to monitor
- Electrolytes (especially sodium and potassium)
- Aldosterone
- Glucose
- Urea and creatinine – to check kidney function
- Liver function tests– to check liver function
Non-Laboratory Tests
- Blood pressure
- Pelvic ultrasonography to evaluate internal reproductive organs in females
- Hand X-ray or bone-age study to evaluate rate of skeletal growth