ORPHA: 60015; DO: 0060285;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p11.2 | Parietal foramina 2 | 609597 | Autosomal dominant | 3 | ALX4 | 605420 |
A number sign (#) is used with this entry because parietal foramina-2 (PFM2) is caused by heterozygous mutation in the ALX4 gene (605420) on chromosome 11p11.
Parietal foramina also occur as part of the Potocki-Shaffer syndrome (601224), a contiguous gene syndrome caused by a deletion on chromosome 11p11.2 that includes the ALX4 gene.
Biallelic ALX4 mutations cause frontonasal dysplasia-2 (FND2; 613451), which is also associated with parietal foramina but has more severe frontonasal defects.
Parietal foramina-2 (PFM2) is an autosomal dominant disorder characterized by bilateral parietal foramina in the skull. Some patients with PFM2 may also have mild features of frontonasal dysplasia, including hypertelorism or nose abnormalities (summary by Altunoglu et al., 2014).
For a phenotypic description and a discussion of genetic heterogeneity of parietal foramina, see PFM1 (168500).
Bertola et al. (2013) reported a 10-year-old boy with abnormal craniofacial features, including hypertelorism, lack of formation of the nasal tip, and broad and elongated columella. He also had frontal alopecia, sparse eyebrows, bilateral cryptorchidism, and broad thumbs. Cranial imaging showed parietal foramina. The patient's mother showed a similar pattern of facial features and parietal foramina.
Altunoglu et al. (2014) reported a consanguineous Turkish family with autosomal dominant transmission of minute PFM and mild frontonasal defects spanning 3 generations. The proband was a 12-year-old girl with brachycephaly, an additional hair whorl on the frontal hairline, mild hypertelorism, upslanting palpebral fissures, wide nasal ridge, broad, depressed nasal tip, low-inserted and broad columella, and cleft alae nasi. She also had diastema of the upper incisors, narrow palate, and horizontal crease on the chin. She had a history of delayed anterior fontanel closure and a nasal skin tag. Her mother, sister, and maternal grandmother all had minute PFM, broad nasal tip, and some mild dysmorphic facial features similar to those observed in the proband.
The transmission pattern of PFM2 and mild nasal defects in the family reported by Altunoglu et al. (2014) was consistent with autosomal dominant inheritance.
Using FISH, Wu et al. (2000) found a heterozygous deletion of a region corresponding to a BAC clone containing ALX4 on chromosome 11p in 2 patients with the Potocki-Shaffer syndrome. The authors stated that the involvement of Alx4 in murine skull development (Qu et al., 1997), its bone-specific expression pattern, the finding that Alx4 is a dosage-sensitive gene in the mouse, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, supported the contention that ALX4 is a candidate gene for PFM in the Potocki-Shaffer syndrome.
In affected members of 2 unrelated families with PFM2, Wuyts et al. (2000) identified 2 different heterozygous mutations in the ALX4 gene (605420.0004-605420.0005).
Mavrogiannis et al. (2001) identified 3 distinct heterozygous mutations in the ALX4 gene (605420.0001-605420.0003) in 19 affected individuals from 4 unrelated families with PFM2. Two families demonstrated linkage to chromosome 11p.
Among 5 unrelated families and 6 sporadic patients with parietal foramina, Mavrogiannis et al. (2006) identified 2 different heterozygous mutations in the ALX4 gene (605420.0006; 605420.0007) in 1 family and 1 sporadic case, respectively, and 2 different heterozygous mutations in the MSX2 gene in 2 additional families. Combined with previous reports, mutations in the ALX4 or MSX2 (123101) 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.
In a son and his mother with PFM2 and frontonasal abnormalities, Bertola et al. (2013) identified a heterozygous truncating mutation in the ALX4 gene (605420.0012). Bertola et al. (2013) noted that this was the first report of features of frontonasal dysplasia associated with a heterozygous ALX4 mutation. The authors postulated that the mutation would escape nonsense-mediated mRNA decay and might interfere with the normal ALX4 allele in a dominant-negative manner. The findings expanded the phenotype associated with heterozygous ALX4 mutations to include mild features of frontonasal dysplasia.
In 4 members of a consanguineous Turkish family with PFM2 and frontonasal abnormalities, Altunoglu et al. (2014) identified a heterozygous missense mutation in the ALX4 gene (R216G; 605420.0013). Functional studies were not performed.
Altunoglu, U., Satkin, B., Uyguner, Z. O., Kayserili, H. Mild nasal clefting may be predictive for ALX4 heterozygotes. Am. J. Med. Genet. 164A: 2054-2058, 2014. [PubMed: 24764194] [Full Text: https://doi.org/10.1002/ajmg.a.36578]
Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R. Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation. Am. J. Med. Genet. 161A: 600-604, 2013. [PubMed: 23401352] [Full Text: https://doi.org/10.1002/ajmg.a.35762]
Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M. Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nature Genet. 27: 17-18, 2001. [PubMed: 11137991] [Full Text: https://doi.org/10.1038/83703]
Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M. Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype. Europ. J. Hum. Genet. 14: 151-158, 2006. [PubMed: 16319823] [Full Text: https://doi.org/10.1038/sj.ejhg.5201526]
Qu, S., Niswender, K. D., Ji, Q., van der Meer, R., Keeney, D., Magnuson, M. A., Wisdom, R. Polydactyly and ectopic ZPA formation in Alx-4 mutant mice. Development 124: 3999-4008, 1997. [PubMed: 9374397] [Full Text: https://doi.org/10.1242/dev.124.20.3999]
Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G. Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Am. J. Hum. Genet. 67: 1327-1332, 2000. [PubMed: 11017806] [Full Text: https://doi.org/10.1016/S0002-9297(07)62963-2]
Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J. Med. Genet. 37: 916-920, 2000. [PubMed: 11106354] [Full Text: https://doi.org/10.1136/jmg.37.12.916]