Clinical characteristics: 21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.

Diagnosis/testing: The diagnosis of classic 21-OHD CAH is established in newborns with characteristic clinical features, elevated serum 17-OHP, and elevated adrenal androgens. The diagnosis of non-classic 21-OHD is established by comparison of baseline serum 17-OHP and ACTH-stimulated serum 17-OHP or early morning elevated 17-OHP. Identification of biallelic pathogenic variants in CYP21A2 confirms the clinical diagnosis and allows for family studies.

Management: Treatment of manifestations: Classic 21-OHD CAH: glucocorticoid replacement therapy, which needs to be increased during periods of stress. Salt-wasting form: mineralocorticoid 9α-fludrohydrocortisone therapy and often sodium chloride. Females who are virilized at birth may require feminizing genitoplasty and/or vaginal dilation. Symptomatic individuals with non-classic 21-OHD CAH may require treatment.

Prevention of primary manifestations: Newborn screening programs aim to identify infants with classic 21-OHD CAH in order to initiate glucocorticoid and mineralocorticoid treatment prior to a potentially life-threatening salt-wasting crisis.

Surveillance: Monitor:

1. Efficacy of glucocorticoid and mineralocorticoid replacement therapy every three to four months while children are actively growing, and less often thereafter;

2. For testicular adrenal rest tumors in males every three to five years after onset of puberty;

3. Weight, bone mineral density, fertility, cardiovascular and metabolic risks in adults.

Evaluation of relatives at risk: It is appropriate to measure 17-hydroxyprogesterone (17-OHP) of at-risk sibs to facilitate early diagnosis and treatment.

Genetic counseling: 21-OHD CAH is inherited in an autosomal recessive manner. Most parents are heterozygous for a pathogenic variant. Approximately 1% of pathogenic variants are de novo; thus, 1% of probands have only one parent who is heterozygous. In some instances during evaluation of a proband, a parent not previously known to be affected may be found to have biallelic pathogenic variants and the non-classic form of 21-OHD CAH. At conception, if the parents of a proband are both known to be heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.