MSX2 – Parietal foramina with cleidocranial dysplasia

Parietal foramina with cleidocranial dysplasia is an autosomal dominant skull ossification defect characterized by enlarged parietal bone defects coupled with clavicular hypoplasia. MSX2 encodes a homeodomain transcription factor critical for calvarial osteogenesis. Heterozygous loss-of-function variants in MSX2 disrupt DNA binding and lead to deficient ossification around the parietal notch, resulting in characteristic parietal foramina and clavicular abnormalities.

Genetic evidence for MSX2 in this phenotype includes three unrelated families with segregating heterozygous MSX2 variants. In a third pedigree comprising four affected individuals across three generations, a tetranucleotide duplication, c.505_508dup (p.Ala170fs), segregates perfectly with disease status (PMID:14571277). Earlier, three unrelated PFM families harbored MSX2 deletions or intragenic homeodomain mutations (RK159-160del, R172H) leading to >85% reduction in DNA binding, confirming haploinsufficiency as the disease mechanism (PMID:10742103).

Variant spectrum in PFMCCD is dominated by frameshift and homeodomain-altering alleles: c.254del (p.Gly85fs), c.475_480del (p.Arg159_Lys160del), c.505_508dup (p.Ala170fs) and c.515G>A (p.Arg172His). All variants are heterozygous, consistent with autosomal dominant inheritance and manifest with both parietal bone and clavicular defects.

Functional assays demonstrate that MSX2 homeodomain mutations significantly reduce DNA-binding affinity and transcriptional repression of osteogenic targets, establishing haploinsufficiency as the pathogenic mechanism. Mouse and in vitro binding studies show >85% loss of binding for RK159-160del and R172H variants, correlating with human phenotype severity.

No conflicting reports dispute the MSX2–PFMCCD association. The concordance of segregation data in three pedigrees with functional loss-of-function assays provides robust evidence for a moderate to strong clinical validity classification.

Key take-home: Heterozygous loss-of-function MSX2 variants cause parietal foramina with cleidocranial dysplasia via haploinsufficiency, warranting MSX2 screening in patients with skull ossification defects.

References

• European journal of human genetics • 2003 • Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2. PMID:14571277
• Nature genetics • 2000 • Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. PMID:10742103

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