Clinical, Endocrinological, and Epigenetic Features of the 46,XX Male Syndrome, Compared with 47,XXY Klinefelter Patients

The Journal of Clinical Endocrinology & Metabolism Clinical, Endocrinological, and Epigenetic Features of the 46,XX Male Syndrome, Compared with 47,XXY Klinefelter Patients Elena Vorona 0 1 Michael Zitzmann 0 1 J o¨rg Gromoll 0 1 Andreas N. Sch u¨ring 0 1 Eberhard Nieschlag 0 1 0 First Published Online 1 Institute of Reproductive Medicine (E.V. , M.Z., J.G. , E.N.) and Department of Obstetrics and Gynecology (A.N.S.), University Clinics of Mu ̈ nster , D-48129 Mu ̈ nster , Germany Context: The 46,XX male syndrome represents a rare, poorly characterized form of male hypogonadism. Objective: The objective of the study was to distinguish the 46,XX male syndrome from the more frequent 47,XXY-Klinefelter syndrome in regard to clinical, hormonal, and epigenetic features. Design: This was a case-control study. Setting: The study was conducted at a university-based reproductive medicine and andrology institution. Patients: Eleven SRY-positive 46,XX males were compared with age-matched controls: 101 47,XXY Klinefelter patients, 78 healthy men, and 157 healthy women [latter all heterozygous for androgen receptor (AR) alleles]. Interventions: There were no interventions. Main Outcome Measures: There was a comparison of phenotype, endocrine profiles, and X-chromosomal inactivation patterns of AR alleles. - T HE XX MALE syndrome, first described by de la Chapelle et al. ( 1 ) in 1964, occurs in about one in 20,000 newborn males ( 2 ). Phenotypically there are three groups of sex-reversed 46,XX individuals. The first classical group includes phenotypically normal XX males, the second group consists of males with genital ambiguities, and the third group describes true hermaphrodites ( 3 ). According to a proposed revised nomenclature (the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology, 2006) ( 4 ), the diagnosis of XX male or XX sex reversal is renamed as 46,XX testicular disorder of sex development. Worldwide, 150 patients with classical XX male syndrome were reported up to 1996 ( 5 ). We estimate that more than 100 cases have been described between 1996 and 2006 in the world literature, mostly as individual cases. Ninety percent of these patients have Y chromosomal material including the SRY gene. Y sequences are usually located on the distal tip of the short arm of the paternal X chromosome JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. Results: The 46,XX males were significantly smaller than Klinefelter patients or healthy men, resembling female controls in height and weight. The incidence of maldescended testes was significantly higher than that in Klinefelter patients and controls. Gynecomastia was more frequent in comparison with controls, whereas there was a nonsignificant trend in comparison with Klinefelter patients. All XX males were infertile and most were hypogonadal. The inactivation patterns of AR alleles in XX males were significantly more skewed than in Klinefelter patients and women. Seven of 10 heterozygous XX male patients displayed an extreme skewing of more than 80% with no preference toward the shorter or longer AR allele. The length of the AR CAG repeat polymorphism was positively related to traits of hypogonadism. Conclusions: XX males are distinctly different from Klinefelter patients in terms of clinical and epigenetic features. Nonrandom X chromosome inactivation ratios are common in XX males, possibly due to the translocated SRY gene. The existence of a Y-chromosomal, growth-related gene is discussed. (J Clin Endocrinol Metab 92: 3458 –3465, 2007) ( 6 ). Earlier it was suggested that an unequal Y-to-X interchange occurs during paternal meiosis ( 7 ), which was corroborated by more recent studies ( 2, 8 –10 ). Ten percent of XX males are SRY negative with different degrees of masculinization. Two major mechanisms of this phenomenon are discussed. A dominant autosomal or X-chromosomal inheritance of XX maleness has been described in several cases (11). It is suggested that a mutation in these unknown genes can trigger testis determination ( 12 ). As a second mechanism, a mosaicism with a prevalent XX-lineage and a hidden or scarce lineage containing a Y chromosome is discussed ( 12 ). A relationship between XX male prevalence and paternal age has not been observed ( 2 ). To date, it remains unclear how this genetic and clinical entity has to be distinguished from the other, far more frequent disorder of males with two X chromosomes, the 47,XXY Klinefelter syndrome ( 2, 3, 13–18 ). To this end, we present a comprehensive and systematic clinical, endocrinological, and (epi)genetic approach to the 46,XX male syndrome in a case-control setting involving large cohorts of age-matched 47,XXY Klinefelter patients, normal men, and healthy women. Patients and Methods Patients We evaluated 11 hitherto untreated XX male p (...truncated)