MSX2

At least 10 mutations in the MSX2 gene have been identified in people with enlarged parietal foramina type 1. This condition is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. Openings in the parietal bones are normal during fetal development, but they usually close before birth. In people with this condition, the parietal foramina remain open throughout life.

The mutations that cause enlarged parietal foramina result in the production of an MSX2 protein that cannot bind to DNA, which alters the regulation of multiple genes. As a result, several cell processes are disrupted, including proliferation, differentiation, and survival. In early development, the skull seems to be particularly sensitive to changes in MSX2 protein activity and changes in cell function. Specifically, cells in the skull that are involved in bone formation (ossification) cannot function normally, leading to a lack of bone in areas of the skull and enlarged parietal foramina.

At least two mutations in the MSX2 gene cause a condition called craniosynostosis type 2 (also known as Boston type craniosynostosis). Craniosynostosis involves premature closure of the bones of the skull, leading to a misshapen head. People with craniosynostosis type 2 can have skull malformations including a protruding forehead (frontal bossing), a short wide head that is pointed at the top (turribrachycephaly), or a cloverleaf-shaped skull (Kleeblattschaedel deformity). Most affected people have vision problems, and a few have experienced seizures. Intelligence is typically normal.

It is unclear how changes in the MSX2 gene can cause premature closure of the skull bones in craniosynostosis type 2 and impaired bone formation in enlarged parietal foramina (described above).