MON-056 Rare X Chromosome Pericentric Inversion Associated with Ovotesticular Disorder of Sex Development

Abstract

Ovotesticular disorder of sex development (OT-DSD) is a rare condition characterized by coexistence of ovarian and testicular parenchyma, in separate gonads or in the same gonad (ovotestis), in individuals with variable degrees of genital ambiguity. Karyotype may be 46,XX (60%), 46,XY (10%), or there may be sex chromosomes abnormalities, including mosaicism, chimerism and structural anomalies (30%). A genetic origin may be identified in some subjects with normal XX or XY karyotype, but most cases are of unknown origin. Apparently balanced chromosome rearrangements (translocations, insertions and inversions) may cause truncation, deletion, inactivation or over-expression of specific genes. We report on a case of OT-DSD associated with an X chromosome inversion. Case report: A 3-month old girl was referred due to atypical genitalia. She was born at term to a 42 years old G3P2A1 mother and her 45 years old unrelated husband with normal weight, length and head circumference. She had normal development, no associated health problems, and family history was unremarkable. Physical examination revealed a 3.1-cm phallus with chordee, scrotal hypospadias, partial penoscrotal inversion and a 0.5 cm3 right gonad palpable in the inguinal region; there were no associated dysmorphic features. At 1.5 months there were normal levels of FSH (3.09 IU/L) and LH (3.67 IU/L), and testosterone (155 ng/dL) was in the normal male range. Ultrasound revealed normal uterus and gonads were in the inguinal regions. Urethra-cystoscopy and vaginoscopy at 9 months revealed a urogenital sinus with high vaginal confluence. Laparoscopy and gonadal biopsies were also performed; the left gonad was an ovotestis with multiple ovarian follicles, while the right gonad was a testis. In both gonads the seminiferous tubules had only Sertoli cells. Karyotype revealed a pericentric X chromosome inversion, 46,X,inv(X)(p22.1q26)dn[20]. FISH on peripheral blood and cultured cells from the right gonad with probes for X (DXZ1) and Y (DYZ3) centromeres and SRY (Yp11.3 - 122 Kb) showed only two X chromosome signals. Array GH analysis (Cytoscan 750K, Affymetrix) showed a 1.3 Mb deletion distal to the short arm breakpoint (Xp22.31), which was reported as VOUS, and a 9 Mb region of LOH on chromosome 9. Discussion: Several cases of X pericentric inversion with different breakpoints have been reported; though phenotypes of female heterozygotes are often normal, early menopause, irregular menses, gonadal dysgenesis or sterility have been described. In this case, it is plausible that the genomic rearrangement could have affected long-range regulation of SOX3 (located in Xq27.1) resulting in ectopic expression of this gene in the bipotential gonad. In addition, the features detected in array GH may have a role in the phenotype. Different methods to determine the exact chromosomal breakpoints and copy number variations in this region will be required.