Parietal Foramina 1

A number sign (#) is used with this entry because parietal foramina-1 (PFM1) is caused by heterozygous mutation in the MSX2 gene (123101) on chromosome 5q35.

Description

Parietal foramina are symmetric, oval defects in the parietal bone situated on each side of the sagittal suture and separated from each other by a narrow bridge of bone. The size of the openings decrease with age and considerable intrafamilial variability is observed (summary by Spruijt et al., 2005).

Genetic Heterogeneity of Parietal Foramina

See also PFM2 (609597) and the 11p11.2 deletion syndrome (601224), in which parietal foramina are caused by haploinsufficiency of the ALX4 gene (605420) on chromosome 11p.

A third locus for PFM (PFM3; 609566) has been mapped to chromosome 4q21-q23.

Clinical Features

Goldsmith (1922) called this condition 'Catlin marks' because he observed 16 instances in 5 generations of the Catlin family. This, like Hartnup disease, Cowden syndrome, Lutheran trait, and Hageman factor, is one of the few examples of hereditary traits named for the family in which it was first observed. Lother (1959) described 5 cases in 2 generations. Many of the affected persons in Goldsmith's family had circumscribed aplasia of the scalp and the same was true of Lother's family (see 107600). Kite (1961) observed association with seizures. The possibility of confusion with aboriginal trephination was pointed out by Powell (1970). Clefts of the lip and/or palate were present in cases reported by Hollender (1967), Irvine and Taylor (1936), and others.

Little et al. (1990) suggested that hereditary cranium bifidum is the same entity as symmetric parietal foramina. They described a family with serial radiographs that documented the development of parietal foramina in late childhood and adulthood from apparent cranium bifidum and parietal foramina during infancy and early childhood. They concluded that the 2 manifestations are merely a function of age. Murphy and Gooding (1970) demonstrated, in a single patient, progression from apparent cranium bifidum during early childhood to parietal foramina during mid-childhood and adulthood. Normally, components of the calvaria (frontal and parietal bones), which are formed by intramembranous ossification, grow and migrate toward each other to eventually enclose the brain during fetal development. A wide opening between these bones, a fontanel, normally occurs superiorly in term infants, posteriorly and anteriorly, and persists into adulthood only rarely. Cranium bifidum, literally 'cleft skull,' is characterized by the persistence of wide fontanel, bilaterally or in the midline, posteriorly or anteriorly, into childhood. During mid-childhood, these areas usually close, leaving only symmetric openings (foramina) in the frontal or parietal regions. Terrafranca and Zellis (1953) described mother and 2 children with cranium bifidum. In one of the children a medial defect in the frontal bone was accompanied by symmetrical parietal lacunae like those in parietal foramina, as well as cervical (C5-C7) and lumbosacral (L5-S1) spina bifida occulta. The other offspring had an identical frontal defect but less conspicuous parietal foramina and no spina bifida. The mother had a U-shaped frontal defect astride the metopic suture. Little et al. (1990) reviewed other families.

Chrzanowska et al. (1998) reported a patient with a 'new' branchial syndrome that included the features of parietal foramina; Rauch et al. (1998) considered the patient to represent a case of the FG syndrome (305450).

Spruijt et al. (2005) reported a girl born with a large skull defect, who at 2 months of age had a 5 by 3 cm posterior cranial skull defect. At 10 months of age, the skull defect was much smaller due to a midsagittal bony bridge in the middle of the defect, resulting in bilateral symmetrical foramina of approximately 2 cm in diameter each. The patient's clavicles were normal both on physical and radiographic examination. On CT scan, the father was found to have bilateral skull defects of 1.5 cm in diameter separated by a bony bridge in the same posterior position of the skull as the proband; he had no clavicular defects, and he recalled being told that he had late milk tooth eruption, although he had normal permanent dentition. The grandparents were not available for examination, but neither had a history of a skull defect as a child.

Molecular Genetics

In affected members of 3 unrelated families with PFM1, Wilkie et al. (2000) identified 3 different heterozygous mutations in the MSX2 gene (123101.0002-123101.0004). One was a deletion of approximately 206 kb including the entire gene, and the others were intragenic mutations of the DNA-binding homeodomain that predicted disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal MSX2 DNA-binding site. These findings contrasted with the previously described MSX2 homeodomain mutation (P148H; 123101.0001), associated with craniosynostosis, which binds with enhanced affinity to the same target.

In the affected father of a child with parietal foramina, Spruijt et al. (2005) identified an 8-bp deletion in the MSX2 gene (123101.0008). DNA analysis was refused for the proband and her grandparents.

Among 5 unrelated families and 6 sporadic cases with parietal foramina, Mavrogiannis et al. (2006) identified 2 different heterozygous mutations in the MSX2 gene in 2 families and 2 different heterozygous mutations in the ALX4 gene (605420.0006; 605420.0007) in 1 family and 1 sporadic case, respectively. Combined with previous reports, mutations in the ALX4 or MSX2 genes had been identified in 11 of 13 familial PFM cases and 1 of 6 sporadic PFM cases. There were no significant genotype/phenotype correlations. Mavrogiannis et al. (2006) concluded that PFM caused by ALX4 and MSX2 have a similar prevalence and are clinically indistinguishable.