46,xy Sex Reversal 7

A number sign (#) is used with this entry because this form of 46,XY sex reversal can be caused by a mutation in the desert hedgehog gene (DHH; 605423) on chromosome 12q13.

For a discussion of genetic heterogeneity of 46,XY sex reversal, see SRXY1 (400044).

Clinical Features

Canto et al. (2004) studied 6 unrelated phenotypic females of Mexican-Mestizo origin with 46,XY complete gonadal dysgenesis. All 6 had bilateral streaks, infantile uterus, and bilateral fallopian tubes, 1 had a left epididymis, and 2 had bilateral epididymis. Two had bilateral gonadoblastoma and 1 had bilateral dysgerminoma.

Molecular Genetics

Canto et al. (2004) sequenced the DHH gene using genomic DNA from paraffin-embedded gonadal tissue from 6 patients with complete 46,XY pure gonadal dysgenesis. They identified in 1 patient a homozygous mutation in exon 2 (L162P; 605423.0002) and in 2 patients a homozygous 1086delG in exon 3 (605423.0003). The patients with DHH mutations displayed 46,XY complete gonadal dysgenesis, differentiating from the only previously described patient with a homozygous DHH mutation, who exhibited 46,XY partial gonadal dysgenesis with polyneuropathy (607080), suggesting that localization of mutations influence phenotypic expression.

Heterogeneity

Fuqua et al. (1996) used linkage and sequence analyses to test the role of X-linked and various autosomal genes in the etiology of 46,XY partial gonadal dysgenesis in a 2-generation family with 4 affected members, previously reported by Fechner et al. (1993). No linkage was detected between the trait and 29 markers on the X chromosome. Linkage analysis using a polymorphism within the 3-prime untranslated region of the WT1 gene (607102) excluded the involvement of autosomal loci. Similarly, linkage to 4 microsatellites on the distal short arm of chromosome 9 was excluded. Also, linkage analysis of a locus close to the SOX9 gene (608160) as well as analysis of the coding region of the SOX9 gene suggested that this gene was not associated with the trait.

History

Wachtel et al. (1980) concluded that the XY female type of gonadal dysgenesis may arise through any of 4 ways: loss of the H-Y structural genes from the Y through mutation or deletion; loss of the function of an X-chromosomal regulator of H-Y; loss of an H-Y receptor; or XY-XO mosaicism. The third of these mechanisms was thought to be involved in an autosomal recessive form of XY gonadal dysgenesis. These individuals are H-Y positive (Wachtel et al. (1980) reported 5 such cases), but the H-Y antigen is ineffectual because of lack of receptor on target cells. One model of the H-Y antigen generating system suggested the requirement of at least 3 genes: an H-Y inducer gene (I) on the Y chromosome, one or more repressor genes (R) on the X, and the structural gene (S) on an autosome. The testis-determining function of the ubiquitously distributed H-Y antigen relies on a specific embryonic gonadal somatic cell receptor. The X-Y molecule may have two parts: one responsible for its organogenetic function, and one determining its antigenic activity.

Moreira-Filho et al. (1982) reported an H-Y negative case of XY gonadal dysgenesis in an offspring of first-cousin parents. They suggested that the patient may be homozygous for a 'S' locus mutation affecting both parts of the H-Y molecule. An alternative designation they used for this condition was familial testicular agenesis syndrome (FTAS). They pointed to the cases of Haseltine and Ohno (1981) and Ghosh et al. (1978) as likewise representing S mutations. Cases of H-Y antigen-positive XY gonadal dysgenesis differ from the cases just mentioned by the findings in the gonads which show testicular primordia; hence the term familial testicular dysgenesis syndrome (FTDS) suggested by Moreira-Filho et al. (1979). Parental consanguinity (Nazareth et al., 1979) and familial occurrence (Moltz et al., 1981) support an autosomal mutation, which may alter the H-Y antigen receptor or a regulator function involved in normal testicular organogenesis. Alternatively, it was suggested that mutation at the 'S' locus might alter organogenetic function without destroying antigenic activity. Gonadal tumors occur frequently in FTDS but apparently not in FTAS. Thus, the H-Y antigen status can be used as a practical guide as to whether extirpation of the streak gonads is necessary.