Background: A portion of 160 kb on Xp21.2 is defined as dosage sensitive sex reversal, including NR0B1, which is considered the most likely candidate gene involved in XY gonadal dysgenesis if overexpressed. The excess of NR0B1 gene product seems to disturb testicular development by down regulating NR5A1, WT1, and SOX9. Xp duplication causes insufficient SRY expression leading to testis development failure. However, NR0B1 single duplication associated with XY gonadal dysgenesis is still to be demonstrated as an evidence of its direct involvement in this condition.
Objective and hypotheses: To describe the duplication of ≈277 kb at Xp21.2 excluding NR0B1, in a girl with 46,XY partial gonadal dysgenesis. The patient was referred in the first month of life due to genital ambiguity. She was the first child of unrelated parents, and pregnancy was uneventful. She had a 0.5-cm phallus, a single perineal opening, partially fused labioscrotal folds and nonpalpable gonads (EMS=4). Karyotype was 46,XY and FISH showed no 45,X cell line. Histopathological analysis of gonads revealed no gonadal tissue with mullerian and wolffian derivatives on the left and dysgenetic testis on the right. Mutations on SRY, WT1, DMRT1, NR5A1 and SOX9 were not identified.
Method: MLPA and aGH (Affymetrix® 750K) assays were performed.
Results: MLPA revealed the duplication of CXorf21 probes at Xp21.2 [30,595,621-30,615,321] (arr[hg19]), but signals for NR0B1 were normal. aGH showed ≈277 kb duplication at Xp21.2 (arr[hg19] Xp21.2(30,580,693-30,857,187)x2), thereby GK gene is present in an extra dose and TAB3 and CXorf21 are partially duplicated.
Conclusion: To our knowledge this is the first description of Xp21.2 duplication resulting in gonadal dysgenesis with normal NR0B1. This study questions the well-accepted theory that NR0B1 is responsible for sex reversal in DSS region. Further studies are required to understand the roles of GK, CXorf21 and TAB3 on sex reversal.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology