Congenital adrenal hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is a family of disorders produced by enzymatic deficiencies of adrenal steroidogenesis. Oversecretion of ACTH secondary to impairment of cortisol synthesis stimulates excessive synthesis of the precursors of the enzyme defect and accumulation of the products of those adrenal hormones whose synthesis is unimpaired by the enzyme deficiency. The most frequent enzyme deficiency is that of 21-hydroxylation. Deficiencies of the enzymes 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase, and cholesterol desmolase has also been reported. Ambiguous genitalia presenting at birth is the most important clinical feature of CAH due to 21-hydroxylase and 11β-hydroxylase deficiencies in genetic females as a result of excessive secretion of adrenal androgens prenatally. In 3β-HSD, 17β-hydroxylase, and cholesterol desmotase deficiency, androgen synthesis is impaired and thus cirilization of the genitalia in genetic males is incomplete. Salt-wasting is associated with those forms of CAH with deficient mineralocorticoid production; in other forms, hypertension may result from accumulation of steroid precursors with salt-retaining properties. Defects of 18-hydroxylase, and 18- dehydrogenase cause a defect in atdosterone synthesis, while 17-hydroxysteroid reductase, and 17–20 lyase deficiencies cause androgen deficiency without interrupting cortisol synthesis. With respect to regulation and secretion, a recent concept is that the adrenal zona fasciculata and zona glomerulosa function as two separate glands: the fasciculata is primarily regulated by ACTII and the glomerulosa by the reninangiotensin system. It has been documented that in CAH due to the 11β-hydroxylase deficiency there is a defect in 11- and 18-hydroxylation in the fasciculata while the enzymatic activity of these enzymes in the glomerulosa is normal. The concept that the fasciculata and glomerulosa function as two separate glands has been applied to CAH due to 21-hydroxylase deficiency. A new hypothesis to explain the presence or absence of salt-wasting signs in CAH due to 21-hydroxylase deficiency is as follows: i) in both simple virilizers and saltwasters there is a fasciculata defect of 21-hydroxylation in both the 17-hydroxy and 17-desoxy pathways, and ii) in saltwasters there is a 21-hydroxylase defect in the glomerulosa as well, while in simple virilizers the glomerulosa is spared this defect. The ability of simple virilizers, but not saltwasters, to respond to renin-angiolensin stimulation with an increase in aldosterone secretion supports this hypothesis. Close genetic linkage between HLA and 21-hydroxylase deficiency has been recently demonstrated, and the 21-hydroxylase deficiency gene has been mapped in close proximity to the HLA-B genetic locus. HLA genotyping, in addition to hormonal testing, is useful for the detection of heterozygote carriers for 21-hydroxylase deficiency and prenatal diagnosis in families with an affected index case. Two non-classical, FILA-linked forms of 21-hydroxylase deficiency are described: the late onset form and the asymptomatic “cryptic” form. Hormonal standards are presented for genotyping 21-hydroxylase deficiency, demonstrating a spectrum in the degree of enzymatic deficiency ranging from a severe deficiency in the classical form to a milder deficiency in the late onset and cryptic disorders, to a still milder deficiency detectable only with ACTII stimulation in heterozygotes for all three forms. It is also proposed that the cryptic disorder represents a genetic compound of the classical and mild 21-hydroxylase deficiency alleles. Studies of genetic linkage disequilibrium suggest that some late onset patients may also be genetic compounds, possessing both a mild and a classical 21-hydroxylase deficiency allele. A microfiller paper method for measuring 17-OHP for the neonatal diagnosis of 21-hydroxylase deficiency is described. The results of a pilot newborn screening program for CAH using the 17-OHP microfilter paper method demonstrates that screening for this disorder is feasible. Further 21-hydroxylase deficiency occurs with sufficient frequency to warrant screening. Measurement of 17-OHP and Δ4 in amniotic fluid make possible the prenatal diagnosis of 21-hydroxylase deficiency. The fundamental aim of therapy in CAH is to provide replacement of the deficient hormones. Glucocorticoid administration both replaces the deficient cortisol and suppresses ACTH production, resulting in a decrease in adrenal androgens which produce virilization and ultimate short stature. Mineralocortocoid supplement is required in the salt-wasting disorders. Mineralocorlicoid administration is also recommended for patients with elevated plasma renin activity but no evident symptoms of salt-wasting, to improve the control of androgen oversecretion. Recognition of this disorder is important in the sex assignment of newborns with ambiguous genitalia.