Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess

Abstract

Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1/27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11beta-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension.

Figure 1

Pathways of steroid biosynthesis.

Figure 2

Clinical spectrum of steroid 21-OHD. There is a wide spectrum of clinical presentations ranging from prenatal virilization with labial fusion to precocious adrenarche to pubertal or postpubertal virilization. [Reproduced with permission from ref. (copyright 1983, McGraw–Hill)].

Figure 3

17-OHP nomogram for the diagnosis of steroid 21-OHD (60-min cortrosyn stimulation test). The data for this nomogram was collected between 1982 and 1991 at the Department of Pediatrics. The New York Hospital–Cornell Medical Center, New York, NY 10021.

Figure 4

Algorithm depicting prenatal management of pregnancy in families at risk for a fetus with 21-OHD. hCG, human chorionic gonadotropin [Reproduced with permission from ref. (Copyright 1995, the Endocrine Society)].

Figure 5

Timetable of prenatal sexual differentiation.

Figure 6

Genitalia of prenatally untreated (A) and treated (B) sisters with salt-wasting 21-OHD. The untreated newborn girl exhibits ambiguous genitalia with an enlarged clitoris and scrotalization of the labia majora (Prader IV). The sib treated prenatally with dexamethasone was born with normal genitalia, and surgical recession will not be necessary.

Figure 7

Mutations in the gene for 11β-hydroxysteroid dehydrogenase type 2 in patients with AME who were investigated by our group. The HSD11B2 gene has five exons, is 6.2 kb long, and has been mapped to chromosome 16q22. All mutations found in affected patients are homozygous except for one patient, who is a compound heterozygote (D244N/L250R).

Figure 8

Pedigree of Mennonite family showing consanguinity (114).