ACTH-stimulated 17-hydroprogesterone (17-OHP) concentrations in the heterozygote range (400-1000 ng/dl) were observed in 8/42 patients with premature pubarche (PP) or functional ovarian hyperandrogenism (HA). To determine if the hormonal phenotype of heterozygote responses correlated with molecular genotype, we assessed for CYP21 mutations in 48 patients and 79 healthy adult controls using RFLP, SSCP, and ASOH analyses. Eleven of 31(35%) PP patients and 6 of 17(35%) HA patients were determined to be heterozygotic carriers of CYP21 mutations. Mutations in the PP+ group were V281L(n=4), I172N(2), del/conv(2), P30L(1), intron 2 splicing(1), and Q318X(1). Mutations in the HA+ were V281L(4), I172N(1), and del/conv(1). Five of 79 healthy adult controls were heterozygous carriers: Q318X(3), V281L(1), and intron 2 splicing(1).Frequency of heterozygosity for 21-hydroxylase deficiency was significantly greater in the patient groups (1/3) than in the healthy controls(1/16), p<0.001. Table indicates mean±SD for 17-OHP(ng/dl), chronologic age (CA), bone age (BA), and body mass index(BMI;kg/m2).

Table 1
Full size table

Mean 30 minute 17-OHP(ng/dl) was significantly greater in PP+ than PP-, p<0.005. Mean 30 minute 17-OHP was significantly greater in HA+ than HA-, p<0.05.

Thus, 35% of our hyperandrogenic patients appear to be manifesting heterozygotes. The increased frequency of heterozygotic carriers in our patient population in comparison to that of healthy controls suggests a functional relationship between heterozygosity for 21-hydroxylase deficiency and hyperandrogenic symptoms. Sequential evaluation of patients in conjunction with molecular genetic analysis may elucidate the other factors which trigger manifesting heterozygosity in some individuals.