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 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. Results 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. 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.

中文翻译：

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Wolf-Hirschhorn综合征的性发育障碍：基因型-表型相关性和MSX1作为候选基因

Wolf-Hirschhorn（WHS）是一组先天性生理异常和智力低下，与4号染色体短臂的部分缺失有关。我们对两名突尼斯WHS患者进行了分子细胞遗传学分析。患者1是1岁的男孩，表现出典型的WHS表型，而患者2，是2天的男孩，除了典型的WHS表型外，还表现出尿道下裂，微阴茎和隐睾。使用了阵列比较基因组杂交和荧光原位杂交技术。分析结果表明，患者2具有比患者1（3.4 Mb）更大的4号染色体缺失大小（4.8 Mb）。在这里，我们注意到缺失越大，可能涉及的基因越多，并且表型可能越严重。如果我们分析患者1和患者2之间的罕见缺失区域，我们会发现该区域包括肌肉节同形盒（MSX1）基因。MSX1是一个关键的转录抑制因子，在发育中的垂体前叶的腹侧表达，并牵涉性腺激素的分化。Msx1通过抑制胚胎发生过程中促性腺激素释放激素（GnRH）基因抑制垂体腺发育。我们假设患者中MSX1的缺失可能使雄激素合成失控。基于MSX1基因的功能，它的缺失可能通过促进发育过程中GnRH转录的时空调节而间接导致尿道下裂表型。