Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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.^[1]

Infants with the severe classic salt wasting form develop symptoms within the first few weeks of life. These include:^[2][3][1]

• 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.

21-hydroxylase deficiency is inherited in an autosomal recessive pattern.^[3]  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

Babies born in the USA are screened at birth through newborn screening for the classic salt wasting and simple virilizing forms of 21-hydroxylase deficiency.  For babies that test positive on the newborn screen for this disorder, additional biochemical and genetic testing is done to confirm the diagnosis.^[4] The less severe, non-classical form of 21-hydroxylase def is diagnosed based on the clinical symptoms, biochemical testing to look for excess hormone production. Genetic testing may also be helpful to determine the type and severity of 21-hydroxylase deficiency.^[5]

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.^[4][6]

At least one organization has published clinical practice guidelines for 21-hydroxylase deficiency.

The long-term outlook for people with 21-hydroxylase deficiency is dependent on the severity of the symptoms, the response to medications and the presence of any other medical conditions. In general, with early diagnosis and continuous lifetime treatment, the long-term outlook for people with this disorder is good. Long term complications of this condition may include fertility and mental health issues.^[6] 

Approximately 1 in 10 to 15,000 people in the United States has congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency.^[2][1] The prevalence is higher is other parts of the world.