Hormonal reference data, in the form of nomograms relating baseline and stimulated levels of adrenal hormones, provide a means of genotyping steroid 21-hydroxylase (21-OH) deficiency in congenital adrenal hyperplasia. Data from both 360- and 60-min ACTH stimulation tests are given. The serum hormone concentrations that have proven most useful in classifying 21-OH deficiency are 17-hydroxyprogesterone and delta 4-androstenedione. These nomograms clearly distinguish the patient with classical 21-OH deficiency from those with the milder symptomatic and asymptomatic nonclassical forms of 21-OH deficiency (previously referred to as late onset and cryptic forms) as well as heterozygotes for all of the forms and those subjects predicted by HLA genotyping to be unaffected. The nomograms also can identify individuals heterozygous for 21-OH deficiency in the general population who have a characteristic heterozygote response. These nomograms provide a powerful tool by which to assign the 21-OH deficiency genotype. Patients whose hormonal values fall on the regression line within a defined group are assigned to that group. In view of the strong correlation between the 60- and 360-min ACTH stimulation tests, the less cumbersome and shorter 60-min test can be used with the same confidence as the longer test.

Hormonal studies and human leukocyte antigen (HLA) genotyping were performed in 5 males and 13 females who were demonstrated to have 21-hydroxylase deficiency. The enzymatic deficiency of steroidogenesis was detected by family studies of 10 females who presented with varying symptoms of androgen excess. The 10 index cases had normal genitalia at birth, but virilized to varying degrees postnatally. The additional 8 affected family members had not sought medical care, but some were found to have signs of virilization on physical examination, while others were normal. Thus both late-onset (symptomatic) and cryptic asymptomatic) 21-hydroxylase deficiency occurred in the same pedigree. The hormonal and genetic linkage studies indicate that the late-onset (symptomatic) form of 21-hydroxylase deficiency, like the cryptic (asymptomatic) and classical forms of 21-hydroxylase deficiency, is transmitted by an autosomal recessive gene which is linked to HLA-B. Furthermore, the classical form of 21-hydroxylase deficiency associated with prenatal virilization is transmitted by an allelic variant for steroid 21-hydroxylase different from that of the nonclassical forms, late-onset (symptomatic) and cryptic (asymptomatic) 21-hydroxylase deficiency. Although these latter 2 disorders have different clinical manifestations, they demonstrate a similar degree of steroid 21-hydroxylase deficiency that is less severe than that observed in classical 21-hydroxylase deficiency. The hormonal and genetic linkage data indicate that cryptic (asymptomatic) and late-onset (symptomatic) 21-hydroxylase deficiency result from the same allelic variant at the steroid 21-hydroxylase locus. A glossary of terms is presented to describe the various allelic forms of 21-hydroxylase deficiency with consistency.