Congenital adrenal hyperplasia

Congenital adrenal hyperplasia is the most common cause of adrenal dysfunction in children, typically presenting with features of androgen excess. It is a genetic condition that causes deficiency of an enzyme essential in the biosynthesis of cortisol and aldosterone; the enzyme most commonly affected is 21-hydroxylase. While this results in cortisol and aldosterone deficiency, androgen excess also occurs because the low cortisol concentration leads to excess release of adrenocorticotrophic hormone (ACTH) from the pituitary gland (due to lack of negative feedback), causing increased synthesis of adrenal precursor hormones. These precursor hormones, which would normally be converted to cortisol, aldosterone and androgens, are converted primarily to androgens.

Congenital adrenal hyperplasia is usually diagnosed in infancy or early childhood. Females usually present as neonates with virilisation of their genitalia. Infants of either sex can present with failure to thrive. They can also present with vomiting and dehydration as part of a life-threatening, salt-losing crisis, which is an endocrine emergency; seek urgent specialist advice.

Milder deficiencies of the enzymes responsible for cortisol and aldosterone biosynthesis can present in later childhood or adulthood, also with symptoms of androgen excess.

At diagnosis, screening of all siblings is recommended. Antenatal diagnosis is available if the genetic mutation for the family is known.

Lifelong glucocorticoid and mineralocorticoid therapy is required for congenital adrenal hyperplasia.

Dosing of glucocorticoid therapy for congenital adrenal hyperplasia in children is difficult—specialist management is required. A higher maintenance dose is often required than for primary adrenal insufficiency, because the aim is to achieve adrenal suppression rather than just cortisol replacement. If the glucocorticoid dosage is insufficient, androgenic effects continue, including growth acceleration (with bone age advancement and potential for premature growth plate closure and short stature), acne and advanced puberty. Excessive glucocorticoid dosage can cause slow growth, Cushingoid features and maturational delay.

Mineralocorticoid replacement allows use of a lower glucocorticoid dose, minimising the impact of glucocorticoid therapy on growth.

For a child or a prepubertal teenager, usual maintenance doses to achieve adrenal suppression in congenital adrenal hyperplasia are:

Infants may need a higher fludrocortisone dose in the first few months of life.

Prednisolone (or prednisone) and dexamethasone have a greater propensity to inhibit growth than hydrocortisone and cortisone acetate. They are occasionally used under specialist guidance if other drugs have not been effective. If prednisolone (or prednisone) is used, it may need to be given in divided doses.

Monitoring of congenital adrenal hyperplasia treatment is highly specialised, involving measurement of 17-hydroxyprogesterone concentration and either plasma renin concentration or plasma renin activity. Monitoring growth can help to identify over-suppression.

During intercurrent illness or surgery, a temporary increase in glucocorticoid therapy is necessary, as for primary adrenal insufficiency. See Glucocorticoid replacement during intercurrent illness and surgery for details.

Nonclassical congenital adrenal hyperplasia is caused by a partial deficiency of the 21-hydroxylase enzyme, leading to androgen excess without symptoms of glucocorticoid deficiency. In females, it usually presents as hirsutism and menstrual irregularity, and may be clinically indistinguishable from polycystic ovary syndrome. Nonclassical congenital adrenal hyperplasia can be asymptomatic and can go undiagnosed, particularly in men, in whom symptoms of androgen excess can be less obvious.

Treatment is a combined estrogen and progestin preparation, with or without an antiandrogen. Glucocorticoids are not used for routine maintenance therapy, but are sometimes used to suppress adrenal androgen production if fertility is desired. Specialist management is required.