Clinical, Hormonal and Cytogenetic Evaluation of 46,XX Males and Review of the Literature

Abstract

The main factor influencing the sex determination of an embryo is the genetic sex determined by the presence or absence of the Y chromosome. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46,XX maleness is a rare sex reversal syndrome affecting 1 in 20,000 newborn males. Molecular analysis of sex-reversed patients led to the discovery of the SRY gene (sex-determining region on Y). The presence of SRY causes the bipotential gonad to develop into a testis. The majority of 46, SRY-positive XX males have normal genitalia; in contrast SRY-negative XX males usually have genital ambiguity. A small number of SRY-positive XX males also present with ambiguous genitalia. Phenotypic variability observed in 46,XX sex reversed patients cannot be explained only by the presence or absence of SRY despite the fact that SRY is considered to be the major regulatory factor for testis determination. There must be some other genes either in the Y or other autosomal chromosomes involved in the definition of phenotype. In this article, we evaluate four patients with 46,XX male syndrome with various phenotypes. Two of these cases are among the first reported to be diagnosed prenatally.

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

“…Therefore the mechanism generating this syndrome in SRY carriers involves mainly a mistake in the cross-over between pseudoautosomal regions of sexual chromosomes during the paternal meiosis (10,18). However, 10% of the patients are SRY-negative (1,3). Molecular analysis in our patient showed absence of SRY, which is an unusual form of the XX male syndrome.…”

“…In most cases this gene is translocated to the short arm-end of the paternal X chromosome (1,3). Therefore the mechanism generating this syndrome in SRY carriers involves mainly a mistake in the cross-over between pseudoautosomal regions of sexual chromosomes during the paternal meiosis (10,18).…”

“…During puberty, testosterone levels are normal evolving, in adulthood, to hypergonadotrophic hypogonadism (6,7,10,15,18). Some authors evidenced a deficient testosterone production after β-hCG stimulation test; whereas, others reported a normal testosterone production by the Leydig cells, although not ruling out the possibility of a testosterone deficiency during adulthood (3,10).…”

“…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). The group of SRYnegative (OMIM ID 278850) includes patients with Ovotesticular-DSD, which is characterized by the presence of both testicular and ovarian tissue in the gonads of the same individual (13,14), and Testicular-DSD characterized by a full development of both gonads as testes without any evidence of ovarian tissue (2).…”

Report of Fertility in a Woman with a Predominantly 46,XY Karyotype in a Family with Multiple Disorders of Sexual Development

“…Normal sexual differentiation in 46,XY individuals relies on a complex cascade of numerous genes, many of which have yet to be identified (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Defects in these genes can cause disorders of sexual development of varying severity.…”