46,xx Sex Reversal 1

A number sign (#) is used with this entry because of evidence that 46,XX sex reversal and 46,XX true hermaphroditism are caused by translocation of a segment of the Y chromosome containing the SRY gene (480000; Yp11.3) to the X chromosome.

Description

A disorder of sex development (DSD) is a 'congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XX DSD is a disorder of gonadal (ovarian) development, which may be complete or partial (Lee et al., 2006). Sex-reversed 46,XX individuals can present as phenotypically normal males, as men with genital ambiguities, or as true hermaphrodites (Ahmad et al., 2012).

46,XX male sex reversal is a condition in which a phenotypically normal male has a female genotype. A 'true hermaphrodite' must have both mature ovarian and mature testicular tissue with histologic evidence of follicles and tubules, respectively (van Niekerk and Retief, 1981). It is a genetically heterogeneous condition.

Genetic Heterogeneity of 46,XX Sex Reversal

Another form of 46,XX sex reversal (SRXX2; 278850) is caused by duplication or triplication in a regulatory region upstream of the SOX9 gene (608160) on chromosome 17q24. SRXX3 (300833) is caused by duplications or deletions in the SOX3 (313430) regulatory region on chromosome Xq26.

Nomenclature

As a result of discussions at the International Consensus Conference on Intersex, Lee et al. (2006) proposed the term 'disorder(s) of sex development' (DSD) to replace the previously used terms 'pseudohermaphroditism,' 'intersex,' and 'sex reversal.'

Clinical Features

Van Niekerk and Retief (1981) found that the ovotestis was the most common gonad of the true hermaphrodite, found in 44.3% of 406 cases. The genotype of most affected individuals was 46,XX, but many had 46,XY (see 400044) or a mosaic of 46,XX/46,XY. Of 106 cases, 60% were considered to have a male phenotype and 40% a female phenotype, which did not correlate with presence or absence of the Y chromosome, although the presence of a Y chromosome tended to be associated with a male phenotype. Krob et al. (1994) determined that approximately 60% of affected individuals are 46,XX, 33% are mosaic 46,XX/46,XY, and 7% are 46,XY.

Armendares et al. (1975) and Gallegos et al. (1976) reported a family with 3 affected sibs. The proband had a male phenotype and gender role, bilateral scrotal ovotestes with palpable nodules, and absence of mullerian structures. The karyotype was 46,XX in peripheral blood lymphocytes and gonadal fibroblasts.

Vorona et al. (2007) compared the 46,XX male syndrome and the more frequent 47,XXY-Klinefelter syndrome in regard to clinical, hormonal, and epigenetic features. 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 androgen receptor (AR; 313700) 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. Vorona et al. (2007) concluded that nonrandom X-chromosome inactivation ratios are common in XX males, possibly due to the translocated SRY gene.

Aksglaede et al. (2008) evaluated the role of abnormal chromosome constitution for longitudinal growth in relation to reproductive hormones, IGF1 (147440), and IGFBP3 (146732) in eighty-six 47,XXY males, fourteen 46,XX males, and nine 47,XYY. They found accelerated growth in early childhood in boys with 47,XXY and 47,XYY karyotypes, whereas 46,XX males were shorter than controls. These abnormal growth patterns were not reflected in circulating levels of IGF1 and IGFBP3. The boys with 46,XX and 47,XXY karyotypes developed hypogonadism in puberty, but androgen secretion in 47,XYY boys remained normal. Aksglaede et al. (2008) suggested that the abnormal stature of these patients may be a result of abnormal gene expression due to the underlying chromosome aberration resulting in excessive expression of growth-related genes.

Ahmad et al. (2012) reported a 19-year-old 46,XX Middle Eastern man, born of consanguineous parents, who presented with bilateral gynecomastia, sparse facial hair, and low libido. He had normal axillary and pubic hair, and external genitalia were male, with normal penile length but small soft atrophic testes. Testosterone was low, whereas follicle-stimulating hormone (FSH; see 136530) and luteinizing hormone (LH; see 152780) were both markedly elevated. Pelvic MRI did not show any Mullerian structures, and the urinary system appeared normal. Semen analysis revealed azoospermia, with a normal-volume (3 mL) fructose-positive ejaculate.

Mapping

Using a Y-specific DNA clone for in situ hybridization studies, Andersson et al. (1986) demonstrated transfer of Y-material to the end of Xp in 3 XX males. By study of XX males with translocation of material from Yp onto Xp, and by study of XY females with deletion of part of the short arm of the Y chromosome, Simpson et al. (1987) were able to separate the genetic loci for the H-Y antigen (426000) and for testis-determining factor (TDF), or SRY. H-Y antigen maps to the centromeric region or the proximal part of the long arm of the Y chromosome, whereas SRY maps more distally on the short arm of the Y chromosome.

Cytogenetics

Nieto et al. (2004) reported a 12-year-old phenotypic male who was evaluated for ambiguous genitalia, small phallus, labioscrotal folds, and a urogenital sinus. He had low levels of serum testosterone. Exploratory surgery demonstrated a right fallopian tube, hypoplastic uterus, a left ovary, and a right ovotestis. Conventional karyotype showed 46,XX, but DNA from peripheral blood leukocytes and ovotestis demonstrated a second cell line with presence of Ycen and Yqh and absence of all Yp sequences (delYp). FISH analysis confirmed absence of the SRY gene. Further analysis showed that most of the cells were 46,XX, but some cells were XX,delYp. In addition, there were 45,X and 47,XXX cell lines. Nieto et al. (2004) concluded that the different cell lines in this patient derived from early embryogenesis and that the phenotype could not be attributed to the SRY gene. They suggested that X polysomy may also be involved in gonadal development.

Molecular Genetics

Approximately 10% of 46,XX true hermaphrodites have the SRY gene (Nieto et al., 2004).

The mechanism of masculinization in occasional persons with an apparently normal female chromosome complement (and a Klinefelter phenotype) had been thought to be due to reciprocal X-Y interchange at paternal meiosis (Ferguson-Smith, 1966).

Inoue et al. (1998) reported a 46,XX true hermaphrodite born with ambiguous genitalia who was found to have a testis on the right side and an ovotestis on the left side. No SRY was detected in DNA from peripheral blood leukocytes, but SRY was found in tissue from the ovotestis, indicating mosaicism.

Margarit et al. (2000) studied a 46,XX true hermaphrodite and found that Yp-specific sequences, including the SRY gene, had been transferred to the long arm of one of the X chromosomes at the Xq28 level. The derivative X chromosome of the patient lacked q-telomeric sequences. The authors suggested that this was the first report of a Yp/Xq translocation. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences were missing.

In a 46,XX Middle Eastern man, Ahmad et al. (2012) performed FISH analysis that indicated the presence of the SRY region on 1 of the X chromosomes, consistent with a diagnosis of 46,XX(SRY+).

History

In Finland, de la Chapelle et al. (1978) observed three XX males in one pedigree consistent with autosomal recessive inheritance. All three XX males and their mothers were found to have H-Y antigen (426000) and their fathers appeared to have excess H-Y antigen. The data were interpreted as indicating that the H-Y structural loci constitute a family of testis-determining genes and that either dominant or recessive modes of XX sex reversal can be produced by Y-autosome (or Y-X) translocations, depending upon the particular portion of H-Y genes transferred. Cytogenetic evidence of structural abnormality of Xp was presented by Evans et al. (1979) but could not be corroborated by de la Chapelle et al. (1979).

Fraccaro et al. (1979) found H-Y positivity in 2 46,XX sibs, one of female and one of male gender but both with ambiguous external genitalia and ovotestis. The mother was H-Y negative. They assumed that the underlying mutation was transmitted by the father as an autosomal dominant.