Abstract
BackgroundWolf–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 1 was a boy of 1-year-old, presented a typical WHS phenotype while patient 2, is a boy of 2 days presented an hypospadias, a micropenis and a cryptorchidie in addition to the typical WHS phenotype. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used.ResultsResults of the analysis showed that patient 2 had a greater deletion size (4.8 Mb) 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. Msx1 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.ConclusionBased 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.
Highlights
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
Array Array comparative genomic hybridization (CGH) analysis revealed partial 4p deletion encompassing at least 3.4 Mb ranging from nucleotides 72,447 to 3,519,927 according to the Human reference genome hg18,46,XY. arr[hg18]4p16.3 (72,447_3,519,927) ×1 dn (Fig. 2a)
Array CGH characterized this deletion encompassing at least 4.8 Mb extending from nucleotides 62,447 to 19,065,971, according to the Human reference genome hg18,46,XY.arr[hg18] 4p16.3(62,447–19,065,971) ×1 dn (Fig. 2b)
Summary
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. Patient 1 was a boy of 1-year-old, presented a typical WHS phenotype while patient 2, is a boy of 2 days presented an hypospadias, a micropenis and a cryptorchidie in addition to the typical WHS phenotype. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used. Several literature reports point to the great variability of the WHS phenotype, depending mostly on the variability of the underlying genomic defect based on different size deletions [5, 6]. By reviewing the literature, we emphasize Disorders of sex Development (DSD) traits in the phenotype and suggest a candidate gene
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