Disorders of Sex Development in Wolf-Hirschhorn Syndrome: A Genotype-phenotype Correlation and MSX1 as Candidate Gene

Abstract Background: Wolf-Hirschhorn (WHS) is a set of congenital physical anomalies and mental retardation associated with a partial deletion of the short arm of chromosome 4.To establish a genotype-phenotype correlation; we carried out a molecular cytogenetic analysis on two Tunisian WHS patients. Patient 1was a boy of one-year-old presented typical WHS phenotype while patient 2, is a boy of two days presented an hypospadias, a micropenis and cryptorchidie in addition to the typical WHS phenotype. Both the comparative genomic hybridization (CGH array) and Fluorescence in Situ Hybridization (FISH) techniques were used.Results: Results of the analysis showed that patient 2 had a greater deletion size (4,8Mb) of chromosome 4 than patient 1 (3, 4 Mb). Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. If we analyze the uncommon deleted region between patient1 and patient 2 we found that the Muscle Segment Homeobox (MSX1) gene is included in this region. MSX1 is a critical transcriptional repressor factor, expressed in the ventral side of the developing anterior pituitary and implicated in gonadotrope differentiation. Msx acts as a negative regulatory pituitary development by repressing the gonadotropin releasing hormone (GnRH) genes during embryogenesis. We hypothesized that the deletion of MSX1 in our patient may deregulate the androgen synthesis. Conclusion: Based on the MSX1 gene function, its absence might be indirectly responsible for the hypospadias phenotype by contributing to the spatiotemporal regulation of GnRH transcription during development.