Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype

Abstract

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.

Enlarged parietal foramina: a review of genetics, prognosis, radiology, and treatment

“…EPF is caused by a heterozygous mutation in the homeobox genes ALX4 and MSX2 located at 5q34-35 and 11p11, respectively [6]. EPF associated with either ALX4 or MSX2 mutations have a similar prevalence and are usually clinically indistinguishable [16]. Homeobox ALX4 and MSX2 genes encode a homeodomain, a protein structural domain that binds DNA or RNA, in transcription factors involved in skeletal development.…”

“…Molecular genetic testing is performed using sequence analysis and deletion/duplication analysis looking for sequence variants or whole gene/exon deletions, respectively [25]. On sequence analysis 6 ALX4 and 6 MSX2 mutations are identified in about 85 % of familial, but only 16 % of sporadic cases [16]. Except for multiple exostoses the frequency of mutation detection is generally lower if additional clinical abnormalities are present [25].…”

“…Most people with EPF have a positive family history as the condition is inherited in an autosomal dominant fashion with high, but incomplete penetrance [25]. Mutations of either MSX2 or ALX4 genes are associated with enlarged parietal foramina and molecular genetic testing is clinically available [16,25].…”

Differential Impact of Msx1 and Msx2 Homeogenes on Mouse Maxillofacial Skeleton

“…Mutations in the human Msx2 gene cause abnormalities in cranial sutures. Msx2 haploinsufficiency has been shown to lead to enlarged parietal foramina [Wilkie et al, 2000], whereas gain-of-function mutations in this gene result in the premature fusion of calvarial bones in Boston-type craniosynostosis [for review, see Mavrogiannis et al, 2006]. Enamel defects associated with impaired tooth eruption have also recently been reported for 1 mutation of the human Msx2 gene [Suda et al, 2006].…”

Enlarged parietal foramina: a rare forensic autopsy finding

“…Furthermore, two out of these 13 individuals had cleft lip and cleft palate [14]. Mavrogiannis et al [16] state that heterozygous mutations of the homeobox genes ALX4 and MSX2 are at their origin. Greig [17,15] who has been one of the principal authors on the subject of enlarged parietal foramina has stated that the condition is so rare that every case should be recorded, and this is one of the reasons why we think this case is worth publication.…”