11β-Hydroxylase catalyzes the conversion of deoxycorticosterone (DOC) to corticosterone (compound B) in the mineralocorticoid pathway of the ZG and 11-deoxycortisol (compound S) to cortisol in the glucocorticoid pathway of the ZF (Figure 1). Deficiency of the enzyme with resultant low plasma cortisol leads to chronic elevation of ACTH, with subsequent increased synthesis and secretion of steroid intermediates proximal to the 11β-hydroxylase block and their non-11β-hydroxylated products. Accumulation of these precursors produces the typical phenotype that characterizes this disorder. Excessive production of DOC and compound S exerts a net mineralocorticoid effect, leading to sodium retention and volume expansion. Hypertension occurs in about two-thirds of untreated patients, appears infrequently in infancy and is variable in childhood. Hypokalemia is variable, developing concomitantly with sodium retention. Renin production is suppressed secondary to sodium retention and volume expansion. Aldosterone production is low secondary to low plasma renin activity and low serum potassium concentrations. However, an unusual presentation of neonatal salt wasting has been reported. (2)

The precursors that accumulate in the glucocorticoid pathway are channeled into the androgen pathway and result in prenatal virilization, with varying degrees of genital ambiguity in the affected newborn female. Males and females may manifest signs of androgen excess at any phase of postnatal development, with progressive virilization, including precocious pubic hair, advanced somatic and epiphyseal development, and central precocious puberty later in childhood.

It is an autosomal recessive disorder, caused by mutations in the CYP11B1 gene mapped to chromosome 8.21. More than 45 mutations have been identified. (3), the majority being point mutations. Although the enzyme defect is found in about 1 in 100 000 live births, the disease frequency is significantly higher in consanguineous Jewish families of North African origin where it occurs 1 in 5000 - 7000 live births. (4, 5)

Treatment consists of glucocorticoid replacement. It is an effective approach because (a) it fulfills systemic steroid (glucocorticoid) requirements, and (b) by providing feedback inhibition of ACTH release, it reduces the drive on the adrenal for the synthesis and secretion of precursor steroids. Therapeutic control is achieved by careful clinical monitoring, particularly in children when the dosage is continually adjusted, with particular avoidance of suppression of linear growth from overdosing.

Identification of the CYP11B1 mutations has permitted prenatal diagnosis and subsequent treatment of the affected female fetus. (6) This is achieved by the administration of dexamethasone to the pregnant mother before 10 weeks gestation to suppress excess adrenal androgen secretion, thereby preventing virilization should the fetus be an affected female. Karyotyping and diagnosis by genetic analysis requires chorionic villus sampling in the 9th to 11th weeks, or later by amniocentesis in the second trimester. If the fetus is determined to be male or an unaffected female, treatment is discontinued. Otherwise treatment continues to term.