title: Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.
abstract: 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, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9alpha-fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic 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 mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan. ken-fuji@med.hokudai.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Fujieda
authors.forename: T
authors.initials: T
authors.lastname: Tajima
authors.forename: J
authors.initials: J
authors.lastname: Nakae
authors.forename: S
authors.initials: S
authors.lastname: Sageshima
authors.forename: K
authors.initials: K
authors.lastname: Tachibana
authors.forename: S
authors.initials: S
authors.lastname: Suwa
authors.forename: T
authors.initials: T
authors.lastname: Sugawara
authors.forename: J F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000503:physiopathology*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010053:Ovary / Q000378:metabolism / Q000503:physiopathology*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D011627:Puberty; D017422:Sequence Analysis, DNA; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D002786:Cholesterol Side-Chain Cleavage Enzyme