SPONTANEOUS PUBERTY IN 46,XX SUBJECTS WITH CONGENITAL LIPOID ADRENAL-HYPERPLASIA - OVARIAN STEROIDOGENESIS IS SPARED TO SOME EXTENT DESPITEINACTIVATING MUTATIONS IN THE STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR) GENE

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrino logical, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous pub erty. Phenotypic female infants with 46,XX karyotypes were diagnosed w ith lipoid CAH as newborns based on a clinical history of failure to t hrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal va lues of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ket osteroid. These patients responded to treatment with glucocorticoid an d 9 alpha-fludrocortisone. Spontaneous thelarche occurred in associati on with increased serum estradiol levels at the age of 10 and 11 yr, r espectively. Pubic hair developed at the age of 12 yr 11 mo in one sub ject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polyc ystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mu tation and a single A deletion at codon 238 in the other allele causin g a frame-shift, which renders the StAR protein nonfunctional. These f indings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This i s in marked contrast to the early onset of severe defects in testicula r and adrenocortical steroidogenesis which are characteristics of this disease.