21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH). CAH is a group of disorders that affect how the adrenal glands work. In 21-hydroxylase deficiency, a missing enzyme leads to overproduction of specific hormones made by the adrenal glands. There are three types of 21-hydroxylase deficiency that vary by the severity of symptoms. Infants with the more severe forms can experience excessive loss of salt in their urine, which can be life-threatening. Female infants may be born with genitalia that doesn't look male or female (ambiguous genitalia). Children with the less severe forms can have early puberty, excess hair growth, short stature as adults and decreased fertility.

21-hydroxylase deficiency is caused by genetic changes in the CYP21A2 gene and is inherited in an autosomal recessive pattern. Newborn screening is available in all 50 states of the US to test for this disorder at birth. The diagnosis is made based on the clinical symptoms, biochemical and genetic testing. Treatment is available and involves managing the symptoms through steroids and other medications. The long-term outlook for people with 21-hydroxylase deficiency depends on the severity of symptoms and the ability to manage the condition with medications.

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.

Treatment for 21-hydroxylase deficiency depends on the severity of symptoms and the form of the condition. The goals of treatment are to manage to symptoms. Infants identified at birth with 21-hydroxylase deficiency are treated with hormones and steroids to prevent a salt-wasting crisis. In childhood and adulthood, other medications may be used to improve growth and fertility. Males should be monitored for the growth of testicular adrenal rest tumors, a benign tumor that can cause infertility. In some cases, females with ambiguous genitalia may be offered surgical correction. Some people with this condition have psychological issues and may benefit from therapy.