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Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is an inherited endocrine disorder caused by a steroidogenic enzyme deficiency that is characterized by adrenal insufficiency and variable degrees of hyper or hypo androgeny manifestations, depending of the type and the severity of the disease.
ORPHA:418Classification level: Group of disorders
The estimated prevalence is 1/10,000 and annual incidence ranges from 1/5,000 to 1/15,000.
The most frequent form of CAH is classical CAH due to a 21-hydroxylase deficiency which can further be divided into simple virilizing, salt wasting or non-classical types (see these terms). Girls present at birth with ambiguous genitalia and variable levels of virilization. They have a normal uterus but abnormal vaginal development. The external genitalia in boys are normal. Salt wasting forms of CAH lead to symptoms of dehydration 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 and accelerated skeletal maturation (leading to short stature in adulthood). 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 and fertility problems. Other rare forms can present with arterial hypertension, craniofacial malformations and sexual ambiguity 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 (see these terms).
Diagnosis of girls with classical CAH is usually at birth when ambiguous 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 National systematic 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. Polycystic ovarian syndrome (PCOS) is another differential diagnosis.
Antenatal diagnosis is possible by screening for a disease causing gene by amniocentesis or chorionic villus sampling.
CAH is an autosomal recessive disorder and genetic counselling can be offered to parents with CAH. 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.
Management and treatment
Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels. It is essential in allowing 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 and 9 alpha-fludrocortisone acetate for mineralocorticoid replacement. Regular follow-up by a specialist is important so that dosage is monitored and modified if needed. Vaginoplasty can be performed in the first year of life. Psychological support is often needed. Methods of hair removal treat hirsutism. Menstrual cycles can sometimes be regulated with oral contraceptives.
With proper treatment patients may have a normal life expectancy.