EXAGGERATED 17-HYDROXYPROGESTERONE RESPONSE TO SHORT-TERM ADRENAL STIMULATION AND EVIDENCE FOR CYP21B GENE POINT MUTATIONS IN TRUE PRECOCIOUS PUBERTY

OBJECTIVE Following the observation of two patients affected by true p recocious puberty who went on to develop polycystic ovary syndrome (PC OS) and who were found to be heterozygotes (carriers) for 21-hydroxyla se deficiency (21-OHD), we decided to evaluate the frequency of hetero zygosity for adrenal 21-OHD in patients with true precocious puberty. STUDY DESIGN We investigated 32 girls affected by true precocious pube rty, by the single-dose ACTH stimulation test, HLA typing and the mole cular analysis of the CYP21B gene encoding for the 21-OH enzyme, in or der to detect gene deletions or point mutations. Twenty-eight cases we re on LHRH analogue treatment and the remaining four, untreated owing to parental refusal, were investigated 0.5-1.5 years after spontaneous menarche. RESULTS After ACTH testing, 13 out of the 32 (41%) cases di splayed higher 17-hydroxyprogesterone (17-OHP) levels than normal but less than those found in patients affected by nonclassical adrenal hyp erplasia (CAH); these levels were similar to those observed in obligat e heterozygotes for CAH due to 21-hydroxylase deficiency (21-OHD). HLA typing showed a significantly increased frequency of the HLA alleles A28 and B14 which are peculiar to the HLA haplotypes of nonclassical C AN due to 21-OHD. Molecular analysis of the CYP21B gene showed that in four out of the 10 tested patients with an exaggerated 17-OHP respons e there were heterozygous point mutations of the CYP21B gene. In contr ast, no CYP21B gene abnormalities were detected in the eight tested pa tients with normal 17-OHP. No differences were found between carriers and non-carriers of the 21-OHD with regard to age at onset of precocio us puberty, clinical features, bone age acceleration and gonadal suppr ession induced by LH-RH analogue treatment. Two out of the four untrea ted patients who were investigated after menarche were found to be car riers of the 21-OHD; these girls showed signs of androgen excess, irre gular menses and polycystic ovaries. CONCLUSIONS A high frequency of h eterozygosity for adrenal steroid 21-OHD was found in our patients wit h true precocious puberty. This adrenal defect does not seem to influe nce the pattern of central precocious puberty, but these patients requ ire longterm follow-up as they might go on to develop polycystic ovary syndrome (PCOS). Whether or not heterozygosity of the 21-OHD may be r elated to the premature activation of the hypothalamo-pituitary-gonoda l axis remains to be defined.