ALX4 – Parietal Foramina 2

Autosomal dominant parietal foramina type 2 (PFM2) is characterised by persistent bilateral defects of the parietal bones often accompanied by cortical and vascular anomalies. A multigenerational pedigree demonstrated co-segregation of an ALX4 homeobox mutation with PFM2 in a 4-year-old boy, his mother, aunt and grandfather (3 affected relatives) ([PMID:15569759]).

Genetic evidence includes heterozygous ALX4 loss-of-function mutations detected by FISH in two unrelated patients with the 11p11.2-contiguous gene deletion syndrome, in which biparietal foramina are a hallmark feature ([PMID:11017806]). The segregation of ALX4 alterations in four individuals and independent deletion events support a dosage-sensitive mechanism.

Functional studies show bone‐restricted expression of ALX4 with absence in other tissues, consistent with the parietal bone–specific phenotype. Murine Alx4 haploinsufficiency phenocopies parietal foramina, confirming the requirement for two functional ALX4 alleles for normal skull vault development.

No conflicting reports have been documented. The concordance of human segregation, cytogenetic deletion data, bone-specific expression and mouse genetics provides strong support for haploinsufficiency as the pathogenic mechanism.

Key Take-home: Heterozygous ALX4 mutations cause autosomal dominant PFM2 via haploinsufficiency, informing molecular diagnosis and genetic counselling.

References

• American Journal of Neuroradiology • 2004 • Malformation of cortical and vascular development in one family with parietal foramina determined by an ALX4 homeobox gene mutation. PMID:15569759
• American Journal of Human Genetics • 2000 • Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. PMID:11017806

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