46,xy Sex Reversal 4

A number sign (#) is used with this entry because 9p24.3 deletions have been observed in patients with 46,XY sex reversal without other features of the chromosome 9p deletion syndrome (158170).

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

Clinical Features

Hoo et al. (1989) described 4 patients with 46,XY complete gonadal dysgenesis and a chromosome 9p deletion. All showed female external genitalia and uterus. Histologic studies of the gonads in 2 showed immature testicular tissue containing Sertoli cells but no germinal cells. The gonads appeared to produce androgens in normal amounts and responded to stimulation by HCG (see 118850).

Muroya et al. (2000) reported clinical and molecular findings in 5 karyotypic males (cases 1-5) and 1 karyotypic female (case 6) with distal 9p monosomy. Cases 1-3 and 6 had female external genitalia, case 4 showed ambiguous external genitalia, and case 5 exhibited male external genitalia with left cryptorchidism and right intrascrotal testis. Gonadal explorations at gonadectomy in case 3 and 4 revealed that case 3 had left streak gonad and right agonadism, and case 4 had bilateral hypoplastic testes. Endocrine studies in cases 1-4 and 6 showed that cases 1, 3, and 6 had definite primary hypogonadism, with basal follicle stimulating hormone levels of 54, 39, and 41 IU/L, respectively, whereas case 2 with severe malnutrition was unremarkable for the baseline values, and case 4 had fairly good testicular function.

Cytogenetics

Pointing out that 4 cases of total sex reversal in association with a de novo translocation involving 9p had been described, Hoo et al. (1989) suggested that 9p24 (the shortest region of overlap) carries a gene important for testis development. Since in most 9p deletion cases (158170) sex reversal is not observed, Hoo et al. (1989) postulated that there might be a recessive gene on 9p24 that codes for a gene product, probably an enzyme, important in the early development of the testes. Lack of this gene product would cause delayed and incomplete testicular formation. The 4 cases of sex reversal may have occurred in individuals who carried a defective gene on their normal chromosome 9 and concurrent deletion of the healthy allele on the other chromosome 9.

Bennett et al. (1993) reported the case of a female infant with a de novo deletion of distal 9p, sex reversal (the karyotype was 46,XY), and an apparently intact SRY gene. They reviewed 5 other reports of deletions of the distal short arm of chromosome 9 in association with sex reversal. Four of these involved a familial translocation. The translocation was derived from the mother in 2 cases and from the father in 2 cases, thus making imprinting unlikely.

Ion et al. (1998) described a patient with failure of testicular development and a chromosomal rearrangement involving 9p24.1, in a region proximal to the SNF2 gene (600014). They quoted Huret et al. (1988) as finding that two-thirds of males with a 9p deletion present with hypospadias or abnormal external genitalia.

Flejter et al. (1998) presented the cytogenetic and molecular analyses of 4 sex-reversed XY females, each with gonadal dysgenesis and other variable malformations, and with terminal deletions of distal chromosome 9p, resulting from unbalanced autosomal translocations. PCR amplification and DNA sequence analysis of SRY revealed no mutations in the high mobility group domain (i.e., HMG box) in any of the 4 patients. Conventional and molecular cytogenetic analyses of metaphase chromosomes from each patient suggested that the smallest region of overlap (SRO) of deletions involved a very small region of distal band 9p24. Loss of heterozygosity (LOH) studies using 17 highly polymorphic microsatellite markers, as well as fluorescence in situ hybridization using YAC clones corresponding to the most distal markers on 9p, showed that the SRO lies distal to marker D9S1779. Thus, the region occupied by the putative sex-determining gene was narrowed to the very terminal region of 9p. Previously Guioli et al. (1998) performed a molecular analysis of 9p deletions associated with XY sex reversal, thereby refining the localization of a sex-determining gene to the tip of the chromosome.

Veitia et al. (1998) reported studies of 2 patients with 46,XY complete or partial gonadal dysgenesis associated with 9p deletions but without the rest of the features of monosomy 9p syndrome.

Mapping

Shan et al. (2000) reviewed the accumulating evidence that haploinsufficiency of a dosage-sensitive gene(s) on 9p24.3 is responsible for the failure of testicular development and feminization in XY patients with monosomy for 9p. They used molecular cytogenetic methods to characterize the sex-reversing 9p deletions in 2 XY females. FISH with YACs from the critical 9p region containing the DMRT1 gene (602424) proved to be a fast and reliable assay for patient screening.

By FISH and microsatellite analyses, Muroya et al. (2000) determined that 6 patients with gonadal dysgenesis (see CLINICAL FEATURES section) had hemizygosity of the 9p sex-determining region distal to D9S1779, with loss of the DMRT1 and DMRT2 (602425) genes from the abnormal chromosome 9. Sequence analysis in patients 1-4 and 6 showed that they had normal sequences of each exon of DMRT1 and the DM domain of DMRT2 on the normal chromosome 9, and that patients 1-4 had normal SRY sequences. The authors concluded that the results provide further support for the presence of a sex-determining gene(s) on distal 9p and favor the possibility of DMRT1 and/or DMRT2 being the sex-determining gene(s). They inferred that haploinsufficiency of the 9p sex-determining gene(s) primarily hinders the formation of indifferent gonad, leading to various degrees of defective testis formation in karyotypic males and impaired ovary function in karyotypic females.

Barbaro et al. (2009) noted that separate regions of deletion on chromosome 9 had been identified for 46,XY gonadal dysgenesis and monosomy 9p deletion syndrome: 9p24.3, extending from the DMRT genes to the telomere for the former, and 9p23-p22.3 for the latter.

History

By in situ hybridization, Affara et al. (1989) identified a ZFY (490000)-related DNA sequence that mapped to 9pter-p22. ZFY was at that time thought to be a testis-determining factor.