Hormonal and molecular genetic findings in 46,XX subjects with sexual ambiguity and testicular differentiation

Abstract

Ten patients were studied who had sexual ambiguity having in common a 46.XX karyotype and testicular tissue. They were aged from one month to 23 years; some of them were followed through puberty. Eight cases were sporadic and two familial. They were divided into two groups according to finding of surgery and histology: 46, XX males with sexual ambiguity and 46 XX true hermaphrodites (TH). They were no differences in phenotypes (except uterus and ovotestis in TH). The endocrinological data were identical in the two groups: testosterone levels were in the normal range during puberty, then decreased in adulthood. Gonadotrophins were above the normal range at mid-puberty. Gonadal biopsies, regardless of the ovarian part of the ovotestis, were identical in two groups, i.e., normal in the youngest patients, then spermatogonia disappeared afterwards and dysgenesis became obvious. In one case, the ovarian zone of the ovotestis was only detected on serial cuts after gonadectomy. Southern blots displayed the presence of Y specific material in tow cases (PABY-SRY-PO.9). Otherwise, in all other patients, there was the lack of any Y sequences without any differences between the two groups. These data suggests that 46, XX males with sexual ambiguity and 46 XX true hermaphrodites may be alternative expressions of two genetic defects: one, a minimal interchange between Yp and Xp, another, a mutation of an autosomal testis determining factor for the patients without Y detectable material.

Sex Chromosome Mosaicism in the Gonads of DSD Patients: A Karyotype/Phenotype Correlation

“…Alves et al [2010] suggested that negative XX testicular DSD may result due to gain-of-function mutations in one or more genes downstream to the SRY gene pathway or due to a loss of function in some genes associated with the inhibition of male development. It has been postulated that Y-negative XX testicular DSD and XX OT-DSD have a common origin [Toublanc et al, 1993;Kolon et al, 1998], which is supported by many reports of sibship among XX males and XX OT-DSD [Abbas et al, 1990;Ramos et al, 1996;Slaney et al, 1998;Maciel-Guerra et al, 2008].…”

Familial disorder of sex determination in seven individuals from three related sibships

“…The literature contains several reports of familial cases of true hermaphrodites [2,11,12,18,20,30], familial cases of XX males [1,9,21,23,24,26,35,39] and the two conditions co-existing in the same family [3, 15, 17, 19, 25, 27±29, 32, 33, 38]. Whenever molecular studies were done in families in the last category, most subjects were negative for the presence of Y chromosome material and most of them had genital ambiguity.…”

SRY protein is expressed in ovotestis and streak gonads from human sex-reversal

“…This condition reflects dysfunction at the level of sexual differentiation hormones, after testis or ovary formation (Smith and Sinclair, 1999). The histology of testicular tissue shows normal spermatogonia in the youngest patients and dysgenic tissue after 5 or 8 years of age (Toublanc et al, 1993). Ferguson-Smith (1966) hypothesized that the presence of testis and ovarian tissue in the gonads of 46,XX true hermaphrodites is caused by a mosaicism expression of TDF (SRY) related to X-chromosome inactivation.…”