Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype-phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.2, including ALX4. We explored the correlations between skull defect size and age, gene, and mutation type, and reviewed additional phenotypic manifestations. Four PFM cases had mutations in either ALX4 or MSX2; including previous families, we have identified six ALX4 and six MSX2 mutations, accounting for 11/13 familial, but only 1/6 sporadic cases. The deletion family confirms the delineation of a mental retardation locus to within 1.1 Mb region of 11p11.2. Overall, no significant size difference was found between ALX4- and MSX2-related skull defects, but the ALX4 mutation p.R218Q tends to result in persistent CB and is associated with anatomical abnormalities of the posterior fossa. We conclude that PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable. Mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.

中文翻译：

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同源盒基因ALX4和MSX2突变引起的顶壁孔洞扩大：从基因型到表型。

同源框基因ALX4和MSX2的杂合突变会引起颅骨缺损，称为顶壁孔扩大（PFM）和颅骨裂开（CB）。一个独特的颅突神经病（CRS）家族中已记录了单个MSX2突变。但是，这些基因对PFM / CB和CRS的相对突变贡献尚不清楚，并且有关基因型-表型相关性的信息还不完整。我们分析了11个与PFM / CB无关的新病例或家族，181例CRS和分离亚显微缺失11p11.2的单个家族的ALX4和MSX2，包括ALX4。我们探讨了颅骨缺损的大小与年龄，基因和突变类型之间的相关性，并审查了其他表型表现。4例PFM病例的ALX4或MSX2发生了突变。包括以前的家族在内，我们已经确定了六个ALX4和六个MSX2突变，占家族性的11/13，但只有零星的案例1/6。该缺失家族证实了智力低下基因座的轮廓在11p11.2的1.1Mb区域内。总体而言，ALX4和MSX2相关的颅骨缺损之间没有发现明显的大小差异，但ALX4突变p.R218Q倾向于导致持续的CB，并与后颅窝的解剖学异常有关。我们得出的结论是，由ALX4和MSX2中的突变引起的PFM具有相似的患病率，通常在临床上无法区分。突变筛查在PFM中具有较高的拾取率，尤其是在家族性病例中，但在CRS中没有显示。在ALX4和MSX2相关的颅骨缺损之间没有发现明显的大小差异，但是ALX4突变p.R218Q倾向于导致持续的CB，并且与后颅窝的解剖学异常有关。我们得出的结论是，由ALX4和MSX2中的突变引起的PFM具有相似的患病率，通常在临床上无法区分。突变筛查在PFM中具有较高的拾取率，尤其是在家族性病例中，但在CRS中没有显示。在ALX4和MSX2相关的颅骨缺损之间没有发现明显的大小差异，但是ALX4突变p.R218Q倾向于导致持续的CB，并且与后颅窝的解剖学异常有关。我们得出的结论是，由ALX4和MSX2中的突变引起的PFM具有相似的患病率，通常在临床上无法区分。突变筛查在PFM中具有较高的拾取率，尤其是在家族性病例中，但在CRS中没有显示。