Knowledge on rare diseases and orphan drugs

The estimated prevalence is 1/10,000. Annual incidence ranges from 1/5,000 to 1/15,000.

The most frequent form of congenital adrenal hyperplasia (CAH) is classical CAH due to 21-hydroxylase deficiency which can further be divided into simple virilizing, salt wasting or non-classical (N) types. Girls present at birth with variable levels of virilization of external genitalia with variable degrees of clitoral enlargement and labial fusion. They have a normal uterus but abnormal vaginal development. The genital appearance of affected 46,XX infants is occasionally indistinguishable from that of male genitals but empty of gonads. Gonadal development is normal with ovarian function potentially normal. The external genitalia in boys are normal. Salt wasting forms of CAH lead to symptoms of dehydration, hypoglycemia and hypotension in the first few weeks of life and can be life threatening. Premature pubarche can be seen in children as well as accelerated growth velocity, accelerated skeletal maturation and precocious puberty (leading to reduced adult height). NCAH is often not diagnosed until adolescence when the first symptoms appear. Manifestations seen in females are hirsutism, acne, anovulation and menstrual irregularities. Males (and some females) are asymptomatic. Hirsutism continues in adulthood and women can suffer from chronic anovulation, fertility problems, and metabolic and cardiovascular disturbances. Other rare forms can present with arterial hypertension, craniofacial malformations and atypical external genitalia in both sexes.

In 90-95% of cases, CAH is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which encodes for an enzyme that controls cortisol and aldosterone production. Other genes are less frequently involved and result in the following variants of CAH: CAH due to 17-alpha-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, 11-beta-hydroxylase deficiency, cytochrome P450 oxidoreductase deficiency and congenital lipoid adrenal hyperplasia.

Diagnosis of girls with classical CAH is usually at birth when atypical genitalia are present. Babies can be screened for CAH in order to identify those with the classical forms by measuring 17-hydroxy-progesterone (17-OHP) levels. Genetic screening also confirms a diagnosis of CAH by identifying those with a CAH related gene mutation. In most European countries there are newborn screening programs in place to diagnose CAH at birth.

In adult females a tumor of the ovaries or adrenal glands can mimic the clinical manifestations of CAH with virilization. Polycystic ovarian syndrome is another differential diagnosis.

Antenatal diagnosis in families with known pathogenic genotypes is possible by screening for a disease-causing gene by amniocentesis or chorionic villus sampling. Noninvasive prenatal diagnosis has been accomplished by analysis of circulating free fetal DNA in maternal blood in proof-of-concept studies.

The disorder is autosomal recessive and genetic counseling can be offered to parents with CAH.

Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and decrease elevated androgen levels, to allow for normal growth and puberty in children. Hydrocortisone regulates menstrual cycles and promotes fertility in adult females. Hydrocortisone is usually given to children as glucocorticoid replacement therapy (dosage is monitored and should be increased during times of stress or intercurrent disease) and 9 alpha-fludrocortisone acetate for mineralocorticoid replacement. Genital reconstructive surgery in affected females is no longer considered as an emergency procedure and the ideal timing remains to be determined. Psychological support is often needed. Methods of hair removal treat hirsutism. Menstrual cycles can sometimes be regulated with oral contraceptives. Dexamethasone can be given to pregnant women at risk of having offspring with the mutation (when fetus is female) in order to prevent virilization in girls. This treatment is still controversial due to potential adverse effects.

With proper treatment patients may have a normal life expectancy. However, uncontrolled CAH may be associated with life-threatening acute adrenal insufficiency and a higher risk for comorbidities (metabolic, cardiovascular, subfertility).

Last update: February 2022 - Expert reviewer(s): Pr Juliane LEGER | Endo-ERN*

* European Reference Network