The role of the sex-determining region Y gene in the etiology of 46,XX maleness

Abstract

The condition of 46,XX maleness is characterized by testicular development in subjects who have two X chromosomes but who lack a normal Y chromosome. Several etiologies have been proposed to explain 46,XX maleness: 1) translocation of the testis-determining factor from the Y to the X chromosome, 2) mutation in an autosomal or X chromosome gene which permits testicular determination in the absence of TDF, and 3) undetected mosaicism with a Y-bearing cell line. We evaluated 10 affected subjects who were ascertained for different reasons and who had several distinct phenotypes. Six subjects had inherited sequences from the short arm of the Y chromosome including the sex-determining region Y gene (SRY). Five of the subjects were pubertal at the time of evaluation and had a phenotype similar to that of Klinefelter syndrome with evidence of Sertoli cell and Leydig cell dysfunction. One subject had evidence from Southern blot analysis and in situ hybridization for the presence of an intact Y chromosome in approximately 1% of cells. Three subjects lacked Y sequences by Southern blot analysis and by polymerase chain reaction amplification of SRY. These subjects were ascertained in the newborn period because of congenital anomalies. One had multiple anomalies including cardiac abnormalities; one had cardiac anomalies alone; and one had ambiguous genitalia. Our data confirm the genetic heterogeneity of 46,XX maleness, in which some subjects have SRY while other subjects lack it. In addition, there is phenotypic heterogeneity among subjects who lack SRY suggesting that there is also genetic heterogeneity within this subgroup.

Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports

“…Molecular genetics analyses have demonstrated that approximately 90 % of these patients carry a variable amount of Y material due to a Y-to-X interchange caused by an illegitimate recombination during paternal meiosis [13][14][15]. There was a report of an XX male caused by a translocation of an SRY gene fragment from the Y chromosome to an autosome [16].…”

Localization of the Sex-Determining Region-Y Gene in Xx Males

“…However, the great majority of the XX males with genital ambiguity are SRY negative [4,6]. Testing new Y-chromosome markers in XX males will make it possible to detect the breakpoints further in each individual and to establish correlations with the clinical features, identifying the Y regions implicated in the phenotypic definition.…”

46,XX Male - Testicular Disorder of Sexual Differentiation (DSD): hormonal, molecular and cytogenetic studies

“…On basis of the analysis and detection of SRY gene, 46, XX male patients can be clinically divided into SRY-positive and the SRY-negative groups (6,7). SRYpositive individuals usually have normal male genitalia, small azoospermic testes and hypergonadotropic hypogonadism (8), and most carry the SRY gene translocated to the X chromosome during paternal meiosis (7,9); however, SRY autosomal translocations have also been reported in some XX males (10)(11)(12). The diagnosis of SRY-positive patients is usually achieved in adulthood during infertility investigation (3).…”