46,xy Sex Reversal 10

A number sign (#) is used with this entry because of evidence that 46,XY sex reversal-10 (SRXY10) is caused by heterozygous deletion of a 32.5-kb regulatory region (XYSR) -640 to -607 kb upstream of the SOX9 gene (608160) on chromosome 17q24.

Description

46,XY females with gonadal dysgenesis have streak gonads but look like normal females at birth. They do not develop secondary sexual characteristics at puberty and do not menstruate. They are chromatin-negative and are usually of normal stature, without the somatic stigmata of Turner syndrome (see 163950) (summary by Mann et al., 1983).

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

Clinical Features

German et al. (1978) reported a family in which 2 sisters, a maternal aunt, and a female cousin were 46,XY phenotypic females who in adulthood were found to have gonadal streaks or gonadoblastoma. At birth and throughout childhood, each had appeared to be a normal girl, in whom axillary and pubic hair developed at puberty; breast development and menarche failed to occur but were inducible by hormone administration. Examination revealed unambiguously female genitalia, and each had a normally developed uterus and fallopian tubes of prepubertal size. Endocrine analysis in the 2 sisters showed greatly elevated levels of follicle-stimulating hormone (FSH; see 136530) and luteinizing hormone (LH; see 152780), with a plasma testosterone level of 0.028 ug/100 mL in 1 sister. Pelvic surgery was performed in all 4 patients between the ages of 19 years and 29 years. The 2 sisters had bilateral streak ovaries that were grossly and histologically similar to those seen in 45,X gonadal dysgenesis (Turner syndrome); their affected cousin had gonads resembling the streaks grossly, but histopathology revealed bilateral gonadoblastoma. Surgical records for the affected maternal aunt were unavailable, but a 'purplish, probably calcified abdominal tumor' was known to have been removed.

Mann et al. (1983) described a family in which 3 sisters, a maternal aunt, and a cousin's child were 46,XY phenotypic females. All had gonadal germ cell tumors. The proband was evaluated at 13 years of age for short stature, at which time she was found to have a 46,XY chromosome constitution. She was of dull intelligence (reading age 10 years), with height and weight just below the 3rd centile, and had no breast development and only scant pubic hair. At 14.5 years of age, she developed a large pelvic mass; at laparotomy the unresectable tumor was biopsied, and histology showed a malignant yolk sac tumor with an epithelial appearance, some papillary areas, Schiller-Duval bodies, and much necrosis. After chemotherapy, subtotal excision was performed, histologic examination of which showed necrotic tumor with some viable areas consisting of yolk sac tumor and small areas of well-differentiated teratoma containing respiratory epithelium, plain muscle, and glial tissue. The patient underwent postoperative chemotherapy and radiotherapy, but she eventually refused further treatment and died of tumor recurrence within 2 years. Examination of all available family members revealed that both of the proband's younger sisters and a cousin's child also had 46,XY gonadal dysgenesis; their gonads were removed prophylactically and histologic examination showed gonadoblastoma, dysgerminoma, and/or dysgenesis in all tissue. A maternal aunt who had been treated for bilateral 'ovarian' dysgerminomas was also found to be 46,XY. Family history revealed 4 phenotypic females from previous generations who were said to have been infertile, but all were deceased and could not be evaluated.

Benko et al. (2011) reported two 46,XY cousins (family DSD4) with gonadal dysgenesis. In the first patient, a severe disorder of sex development (DSD) was apparent at birth, with asymmetric external genitalia consisting of a urogenital sinus with a 2-cm phallus, right hemiscrotum with palpable gonad, and left labioscrotal fold with nonpalpable gonad. At day 45, hormonal data resembled that of classic minipuberty observed in normal 46,XY males, with normal LH, FSH, and serum testosterone concentrations. Anti-mullerian hormone (AMH; 600957) was low, indicating testicular dysgenesis. As the decision was made to rear the neonate as a girl, feminizing genitoplasty and bilateral gonadectomy were performed at age 4 months. Microscopic examination revealed that the right gonad was a small testis with normal architecture and spermatogonia in seminiferous tubules, whereas the left gonad was a streak gonad associated with a fallopian tube and hemi-uterus. The proband's cousin, who had a normal external female phenotype, presented with dispersed pubic hair at age 8 years and was found to have elevated urinary FSH, which prompted karyotyping that showed the patient to be 46,XY. Ultrasonography revealed the presence of a uterus with 'ovaries.' Hormonal evaluation at age 9 years showed low AMH and high FSH, suggestive of gonadal dysgenesis. Bilateral gonadectomy was performed; the left gonad was compatible with an ovary, whereas the right gonad was a streak gonad with gonadoblastoma. The well-limited gonadoblastoma contained calcifications as well as 2 types of cells: germ cells expressing placental-like alkaline phosphatase and CD117 (KIT; 164920), and sex cord cells expressing inhibin (INHA; 147380) and WT1 (607102). Examination of the index cases and their parents excluded any bone or craniofacial abnormalities reminiscent of campomelic dysplasia (114290).

Molecular Genetics

In a cohort of patients with 46,XY DSD, including 29 with complete female phenotype and 118 with undermasculinized external genitalia, Benko et al. (2011) used MLPA and quantitative PCR to screen for copy number variation (CNV) in the SOX9 (608160) proximal gene desert. They identified two 46,XY cousins, 1 with a normal external female phenotype and the other with severe ambiguous and asymmetric external genitalia; both were heterozygous for an approximately 240-kb deletion (608160.0018) between 405 and 645 kb upstream of the SOX9 transcription start site. The affected cousins were negative for mutation in 6 known 46,XY DSD-associated genes. Their unaffected mothers were sisters and carried the same deletion, which was not found in the Database of Genomic Variants. Benko et al. (2011) stated that the region of overlap between the deletion in this 46,XY DSD family and duplications in 3 other families with 46,XX DSD reveals a minimal noncoding 78-kb sex-determining region (RevSex) located in a gene desert approximately 517 to 595 kb upstream of the SOX9 promoter.

By performing CNV analysis in 100 patients with SRY-positive 46,XY nonsyndromic partial or complete gonadal dysgenesis, Kim et al. (2015) identified 4 unrelated individuals with heterozygous deletions upstream of the SOX9 gene, including a patient from the family originally reported by German et al. (1978) (608160.0019) and a patient from the family studied by Mann et al. (1983) (608160.0020). Both of the latter deletions segregated with disease in the respective families. Together, the 4 deletions defined a 32.5-kb interval, which Kim et al. (2015) designated XYSR for 'XY sex-reversal region,' noting that it overlapped with previously described SOX9 upstream deletions but not with the RevSex region. The authors also defined a distinct 68-kb XX sex-reversal region (XXSR) upstream of the SOX9 gene, based on 46,XX patients with duplications (see 278850), which was largely identical to the RevSex region. Kim et al. (2015) stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element.

Animal Model

Using in vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing, Gonen et al. (2018) detected several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer-13 (Enh13), a 557-basepair element located 565 kilobases 5-prime from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Gonen et al. (2018) concluded that their data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within the 32.5-kilobase SR XY region, whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.