Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (classic 21-OHD CAH) affects the adrenal glands which are responsible for producing specific hormones. There are two types of classic 21-OHD CAH, the salt-wasting form and the simple-virilizing form. Symptoms include abnormal development of the external sex organs in females (ambiguous genitalia), early puberty, and short stature. The salt-wasting form also may include the inability to retain salt and water. This can lead to dehydration, low blood pressure, and a life-threatening adrenal crisis. Classic 21-OHD CAH is caused by a genetic pathogenic variant in the CYP21A2 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on the symptoms, blood hormone testing and may be confirmed by the results of genetic testing. Classic 21-OHD CAH can be diagnosed through a newborn screen.

21-hydroxylase deficiency is inherited in an autosomal recessive pattern. All individuals inherit two copies of each gene. To have 21-hydroxylase deficiency, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

People with autosomal recessive conditions inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disorder typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a:

• 25% (1 in 4) chance to have the disorder
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% (1 in 4) chance to be unaffected and not be a carrier

The symptoms of 21-hydroxylase deficiency may be different from person to person. Some people may be more severely affected than others, even people who have the same form. Not everyone with 21-hydroxylase deficiency will have the same symptoms, and some may have few or no symptoms.

There are three forms of 21-hydroxylase deficiency: the classic salt wasting form, the simple virilizing form, and the non-classic form. Most patients with 21-hydroxylase deficiency will have the classic salt-wasting form or the simple virilizing form.

Infants with the severe classic salt wasting form develop symptoms within the first few weeks of life. These include:

• Salt wasting crisis
  • low sodium levels (hyponatremia)
  • high potassium levels (hyperkalemia)
  • high levels of renin in the blood (hyperreninemia)
  • low blood volume (hypovolemic shock)
• Ambiguous genitalia in female newborns babies (genitalia that is not typical female nor male appearing), with normal internal feminine reproductive organs (ovaries, uterus, and fallopian tubes); male babies usually have normal genitalia but may have small testes and an enlarged penis.

Salt wasting crises can be life-threatening and require immediate treatment.

Infants with the classic simple virilizing form may have:

• Ambiguous external genitalia in female babies with normal internal reproductive organs; males are born with normal genitalia and may have small testes and an enlarged penis

Later in life both males and females with both classic forms of 21-hydroxylase deficiency may have:

• Puberty starting in childhood (precocious puberty)
• Excessive hair growth
• Acne
• Shorter than average adult height
• Reduced fertility
• Irregular periods (females)
• Testicular enlargement and testicular tumors (males)

Females with the non-classic type of 21-hydroxylase deficiency have normal female genitalia, but when they get older, symptoms may include excessive hair growth (hirsutism), male pattern baldness, irregular periods and reduced fertility. Males with the non-classic type may have early beard growth, an enlarged penis, and small testes. The non-classical form is not considered a rare disease and some people with this form of 21-hydroxylase deficiency may not experience any signs or symptoms.