GENOTYPE-PHENOTYPE ANALYSIS IN LATE-ONSET 21-HYDROXYLASE DEFICIENCY IN COMPARISON TO THE CLASSICAL FORMS

OBJECTIVE To establish the type and frequency of mutations causing lat e onset 21-hydroxylase deficiency and associated clinical and biochemi cal phenotypes and to compare these findings to those from heterozygot es and homozygotes for classical 21-hydroxylase deficiency. DESIGN Ana lysis of the 21-hydroxylase genes by DNA amplification and mutation de tection. Measurement of serum 17-hydroxyprogesterone following stimula tion with adrenocorticotrophic hormone. PATIENTS Fifteen patients with late onset congenital adrenal hyperplasia, 18 obligate heterozygotes for classical congenital adrenal hyperplasia, 95 patients with classic al 21-hydroxylase deficiency. MEASUREMENTS 17-hydroxyprogesterone foll owing adrenal stimulation with adrenocorticotrophic hormone; frequency of 10 common mutations in the 21-hydroxylase gene. RESULTS Of alleles from patients with late onset CAH 46% carried V281L and 10% P30L muta tions compared to 2.6% and 1.1% respectively of alleles from patients with the classical disease where the most common mutations are a splic e site mutation in intron 2 (34%), deletions (25%) and I172N (15%). Se rum 17-hydroxyprogesterone following Synacthen stimulation reliably di fferentiated the late onset patients from carriers for the classical d isease, whereas there was overlap of the basal 17-hydroxyprogesterone concentration between these two conditions. CONCLUSIONS Normal basal s erum 17-hydroxyprogesterone levels cannot exclude late onset CAH, alth ough response to adrenocorticotrophic stimulation clearly distinguishe d this disorder from carriers of the classical disease. The frequency of mutations causing less severe enzyme deficiency was higher in the l ate onset patients than in a group of classical patients, although oth er genes or environmental pressures may determine the age of onset of disease.