DiagnosisClinical DiagnosisRadiographic findings. Enlarged parietal foramina are characteristic symmetric, paired radiolucencies of the parietal bones, located close to the intersection of the sagittal and lambdoid sutures, caused by deficient ossification around the parietal notch, which is normally obliterated by the fifth month during fetal development [Currarino 1976]. Typically oval or round, they resemble a ‘pair of spectacles’ on postero-anterior skull radiographs. They may be less apparent on lateral skull radiographs because the lucencies are projected obliquely through normal bone. 3D CT scan. In young children, the disorder may present as a persistently enlarged posterior fontanelle caused by a single large central parietal bone defect (cranium bifidum). This tends to give a less characteristic appearance on plain skull radiography, especially in neonates, but 3D CT scanning using bone windows clearly reveals the defect. MRΙ scan. Although less satisfactory than CT scanning for visualizing the bone defect, cranial MRI is superior for demonstrating localized and often subtle changes in the meningeal, vascular, and cortical structures.Clinical examination. A flattened region behind the apex of the skull is apparent. The defects are often palpable. Molecular Genetic TestingGenes. Mutations in two genes are currently known to cause isolated (nonsyndromic) enlarged parietal foramina: MSX2 (parietal foramina 1)ALX4 (parietal foramina 2) Evidence for locus heterogeneity. Very limited evidence for additional genetic heterogeneity exists (OMIM 609566) [Chen et al 2003]. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Enlarged Parietal ForaminaView in own windowGene SymbolProportion of Enlarged Parietal Foramina Attributed to Mutations in This Gene ^{1Test MethodMutations DetectedMutation Detection Frequency 2 Test AvailabilityFamily HistoryPositiveNegative or UnknownMSX2 ~40%Sequence analysisSequence variants 3, 416/20 (~80%)7/23 (~30%) Clinical Deletion / duplication analysis 5Exonic or whole-gene deletions 6ALX4 ~60%Sequence analysisSequence variants 3, 4Clinical Deletion / duplication analysis 5Exonic or whole-gene deletions 61. Only cases/families with identified mutations are considered.2. The mutation detection rate is significantly higher in confirmed familial cases [Mavrogiannis et al 2006; T Lester & H Lord, unpublished data]. 3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Excluding syndromic cases, sequence changes comprise the vast majority of mutations [Wilkie et al 2000; Wuyts et al 2000a; Wuyts et al 2000b; Mavrogiannis et al 2001; Spruijt et al 2005; Ghassibé et al 2006; Mavrogiannis et al 2006; T Lester & H Lord, unpublished data].5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Excluding syndromic cases, deletions appear to account for a very small fraction of the mutation spectrum [T Lester & H Lord, unpublished data].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandStandard karyotyping and/or chromosomal microarray (CMA) are indicated to exclude the following, especially if a contiguous gene rearrangement is suspected (see Contiguous Gene Rearrangements) or an underlying syndrome; see Differential Diagnosis.Gross structural changes involving MSX2 on chromosome 5q35.2 [Aftimos et al 2010] Large deletions involving ALX4 on chromosome 11p11.2 [Wuyts et al 2004, Swarr et al 2010]Other concurrent chromosomal abnormalities [Gentile et al 2004]In nonsyndromic cases, molecular genetic testing of MSX2 and ALX4 by sequencing is the appropriate first step, followed by deletion/duplication analysis of both genes if no mutation is identified by sequencing.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Contiguous Gene RearrangementsProximal 11p deletion syndrome (P11pDS) (Potocki-Shaffer syndrome [PSS]) is a rare contiguous gene deletion syndrome with enlarged parietal foramina and multiple exostoses as defining clinical features; intellectual disability and craniofacial dysmorphism are also frequently present (OMIM 601224) [Wuyts et al 2004, Swarr et al 2010, Kim et al 2012]. Deletion events invariably remove ALX4 and the adjacent gene, EXT2 (see Hereditary Multiple Exostoses); PHF21A, which is variably deleted, is highly likely to account for the intellectual disability and facial dysmorphism.Genetically Related (Allelic) DisordersALX4-related frontonasal dysplasia is caused by biallelic loss-of-function mutations in ALX4. Reported in consanguineous families with probands who are autozygous for nonsense or missense mutations, it features median facial malformations of the frontonasal dysplasia spectrum with enlarged parietal foramina. Severity appears to correlate with the type of mutation and the clinical presentation extends to craniosynostosis, total alopecia, cryptorchidism, brain abnormalities, and intellectual disability (OMIM 613451) [Kayserili et al 2009, Kayserili et al 2012]. MSX2-related craniosynostosis has been identified in a single family with a unique MSX2 point mutation (OMIM 604757) [Jabs et al 1993, Warman et al 1993] and also in individuals with an additional copy of MSX2 as a result of gross structural abnormalities [Kariminejad et al 2009].MSX2-related cleidocranial dysplasia includes both a cleidocranial dysplasia variant, parietal foramina with cleidocranial dysplasia (OMIM 168550), which has been associated with an MSX2 mutation in a single family [Garcia-Minaur et al 2003] and in individuals with classic cleidocranial dysplasia with microduplications in non-coding regions upstream of MSX2 and no identified mutation in RUNX2 [Ott et al 2012].}

Natural HistoryIsolated enlarged parietal caused by ALX4 or MSX2 mutations are primary osseous defects and are usually asymptomatic. Enlarged parietal foramina/cranium bifidum may present as an unexpected finding on prenatal ultrasound examination, as a large posterior fontanelle in infancy, or as a coincidental finding on skull radiography in children or adults. Cranium bifidum tends to resolve into distinct enlarged parietal foramina over the first few years of life through the midline ossification of a central bridge of bone bisecting the defect [Pang & Lin 1982, Little et al 1990]. A minor suture, perpendicular to the sagittal suture, often connects the two foramina, which tend to decrease in size with age but may persist throughout life.Meningeal, cortical, and vascular malformations of the posterior fossa occasionally accompany the bone defects and may predispose to epilepsy [Preis et al 1995, Wuyts et al 2000b, Mavrogiannis et al 2001, Valente et al 2004, Valente & Valente 2004]. In a minority of individuals, headaches, vomiting, or intense local pain are sometimes associated with the defects, especially on application of mild pressure to the unprotected cerebral cortex [Pang & Lin 1982, Ghassibé et al 2006]. Scalp defects have been reported [Preis et al 1995, Wuyts et al 2000b]. Thumb/hallux broadening has been described in association with ALX4 [Mavrogiannis et al 2006] mutations. A risk from direct trauma exists and skull fracture has been reported [Edwards et al 2012].

Genotype-Phenotype CorrelationsWith respect to the skull defects, no significant phenotypic differences exist between parietal foramina 1 and parietal foramina 2. Enlarged parietal foramina caused by MSX2 and ALX4 mutations are usually of similar size and clinically indistinguishable [Mavrogiannis et al 2006]. For MSX2, two apparent genotype-phenotype correlations exist. Loss-of-function mutations cause enlarged parietal foramina [Wilkie et al 2000, Wuyts et al 2000b]. The peculiar craniosynostosis-related p.Pro148His mutation has been reported to enhance DNA binding affinity [Ma et al 1996] while making the protein more prone to degradation [Yoon et al 2008]; its precise mechanism of action is unclear, but intricate gain-of-function and/or dominant-negative effects are likely. No obvious genotype-phenotype correlation exists between different loss-of-function mutations in MSX2. However, unique mutations in single families have been associated with aplasia cutis congenita [Preis et al 1995, Wuyts et al 2000b] and clavicular hypoplasia [Garcia-Minaur et al 2003], possibly suggesting subtle dominant-negative effects.For ALX4, no prominent genotype-phenotype correlations have been described. The missense mutation p.Arg218Gln tends to cause particularly large calvarial defects [Mavrogiannis et al 2006] and a different mutation at the same codon, p.Arg218Trp, has been associated with sparse hair and delayed loss of primary dentition [A Fryer & T Lester, unpublished observations]. These more severe phenotypes may result from a dominant-negative effect.

Differential DiagnosisIsolated enlarged parietal foramina need to be distinguished from other causes of defective skull ossification including meningoencephalocele, ventricular, or arachnoid cyst; ectopic glial tissue; tumors; scalp defects; craniolacunae; osteoporosis; local inflammation; injury; and infections [Lodge 1975, Currarino 1976, Pang & Lin 1982]. Additionally, isolated enlarged parietal foramina need to be distinguished from unequivocal syndromic associations including the following:Proximal 11p deletion or Potocki-Shaffer syndrome (OMIM 601224) (see Contiguous Gene Rearrangements)ALX4-related frontonasal dysplasia (OMIM 613451) (see Genetically Related Disorders)Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by coronal synostosis, facial asymmetry, ptosis, and a distinctive appearance of the ear. Syndactyly of digits two and three of the hand is variably present and several other less common manifestations have been observed, including enlarged parietal foramina. Saethre-Chotzen syndrome is caused by mutations in TWIST1 and inheritance is autosomal dominant. Cleidocranial dysplasia, characterized by a severe midline ossification defect of the skull vault associated with frontal bossing, absent or hypoplastic clavicles, and dental abnormalities. Enlarged parietal foramina are not observed in the classic form of the disorder, which is caused predominantly by mutations in RUNX2. MSX2 is likely to be a minor gene for cleidocranial dysplasia (see Genetically Related Disorders). Inheritance is autosomal dominant. Craniofacial dysplasia with genitourinary and skin abnormalities (OMIM 603116). Consensus features of this rare syndrome are coronal synostosis, wide fontanelles and enlarged parietal foramina, hypoplasia of the clavicles, imperforate anus, and skin eruptions. The respective locus has been mapped to chromosome 22q. Inheritance is autosomal recessive.Acromelic frontonasal dysostosis (OMIM 603671) is characterized by severe frontonasal dysplasia, preaxial polydactyly, cranium bifidum/enlarged parietal foramina, and cryptorchidism in males. Both autosomal dominant and recessive inheritance have been proposed.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Enlarged parietal foramina 1Enlarged parietal foramina 2

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with enlarged parietal foramina/cranium bifidum, the following evaluations are recommended:Plain skull radiography3D CT scan of the head with bone windowsBrain imaging using CT or MRI scanning, if appropriateMedical genetics consultationTreatment of ManifestationsThe management of enlarged parietal foramina is generally conservative. Although surgical closure of parietal bone defects has been advocated and performed [Kortesis et al 2003], its role is controversial. The procedure is not likely to be routinely clinically indicated, given the benign natural history of the skull defects, their tendency to reduce in size with age, and uncertainty as to whether symptoms such as headaches are improved. However, persistent cranium bifidum may warrant operative closure [Perlyn et al 2005]. Associated headaches or seizures should be treated symptomatically.Agents/Circumstances to AvoidThe risk of penetrating injury to the brain is small but may cause anxiety. Education of parents, teachers, and the affected child to avoid risky behaviors suffices in most circumstances. Contact sports should be avoided if a midline bony defect persists.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementWhen large skull defects are identified prenatally, consideration should be given to delivery planning (e.g., indications to use scalp electrodes, forceps, or vacuum extraction could be reviewed). Elective Caesarian section may theoretically reduce the risk of traumatic birth injury.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Enlarged Parietal Foramina: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMSX25q35​.2Homeobox protein MSX-2MSX2 homepage - Mendelian genesMSX2ALX411p11​.2Homeobox protein aristaless-like 4ALX4 homepage - Mendelian genesALX4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Enlarged Parietal Foramina (View All in OMIM) View in own window 123101MUSCLE SEGMENT HOMEOBOX, DROSOPHILA, HOMOLOG OF, 2; MSX2 168500PARIETAL FORAMINA; PFM 605420ARISTALESS-LIKE 4, MOUSE, HOMOLOG OF; ALX4 609597PARIETAL FORAMINA 2; PFM2MSX2 Normal allelic variants. MSX2 comprises two exons (reference sequence: NM_002449.4). Established polymorphisms (in northern Europeans) are: c.-17C>G, c.379+59G>A, and c.386T>C (p.Met129Thr) [Verdyck et al 2003, Mavrogiannis et al 2006]. These variants have no known disease association. Pathologic allelic variants. Whole-gene deletions, frameshift or nonsense mutations anywhere in the coding region, and most missense mutations within the homeodomain are likely to result predominantly in loss of function and to cause enlarged parietal foramina. The mutation p.Pro148His (NM_002449.4:c.443C>A) is associated with craniosynostosis (see Genotype-Phenotype Correlations). Normal gene product. MSX2 encodes a member of the Msx family of homeodomain proteins required for diverse developmental processes. In humans, the skull appears to be particularly sensitive to its dosage.Abnormal gene product. The likely consequence of most missense mutations is loss of DNA binding, which was demonstrated biochemically in two cases [Wilkie et al 2000]. The mechanism of action of the p.Pro148His mutation is not fully understood [Ma et al 1996, Yoon et al 2008]. ALX4 Normal allelic variants. ALX4 comprises four exons (reference sequence: NM_021926.3). Known, relatively common polymorphisms (in northern Europeans) include: c.104G>C (p.Arg35Thr), c.304C>T (p.Pro102Ser), c.594C>A, c.729G>A, c.879C>T, c.1074C>T, and c.*228C>T [Verdyck et al 2003, Mavrogiannis et al 2006]. None is known to have any pathologic effect. Ambiguous allelic variants. The rare variants c.19G>T (p.Val7Phe), c.314_325del (p.Pro105_Gln108del), c.605T>G (p.Leu202Trp), c.631A>G (p.Lys211Glu), and c.917C>T (p.Pro306Leu) were encountered during screens of individuals with craniosynostosis [Mavrogiannis et al 2006, Yagnik et al 2012]. Their clinical significance is uncertain, although conferring a predisposition for craniosynostosis is a possibility.Pathologic allelic variants. Complete gene deletions, frameshift or nonsense mutations anywhere in the coding region, and missense mutations within the homeodomain are likely to result predominantly in loss of function and to cause enlarged parietal foramina. Normal gene product. ALX4 encodes a member of the Alx family of homeodomain proteins. Apart from the paired-type homeodomain, a poly(Pro/Gln) tract and an aristaless/OAR domain are evident. As with MSX2, the ALX4 gene product is required for many developmental processes. In humans, the skull appears to be particularly sensitive to a moderate reduction of its dosage; in its absence, median facial development, hair follicle growth, and genital development are also affected. Abnormal gene product. The likely consequence of most missense mutations is loss of DNA binding, which was demonstrated biochemically in one case [Qu et al 1998]. A weak dominant-negative effect may account for the particularly severe skull defects associated with the p.Arg218Gln mutation and the cutaneous manifestations of the p.Arg218Trp mutation (see Genotype-Phenotype Correlations). The ambiguous variants in craniosynostosis may have gain-of-function properties [Yagnik et al 2012].