Clinical Diagnosis

Radiographic 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 that 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.

Testing

Standard karyotyping and/or array comparative genomic hybridization (array CGH) are indicated to exclude the following, especially in syndromic cases:

• Gross structural changes affecting MSX2 on 5q35.2 [Aftimos et al 2010]

• Large deletions involving ALX4 on 11p11.2 [Wuyts et al 2004, Wakui et al 2005]

• Other concurrent chromosomal abnormalities [Gentile et al 2004]

Molecular Genetic Testing

Genes. Two genes are currently known to be associated with enlarged parietal foramina/cranium bifidum:

• MSX2 (parietal foramina 1)

• ALX4 (parietal foramina 2)

MSX2 and ALX4 account for approximately equal numbers of cases of the disorder.

Other loci. Limited evidence for further genetic heterogeneity with a possible third locus at 4q21-q23 exists (OMIM 609566) [Chen et al 2003].

Clinical testing

• Sequence analysis. Sequencing of the coding regions of MSX2 and ALX4 identifies mutations in more than 80% of affected individuals with isolated enlarged parietal foramina/cranium bifidum and a positive family history [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].
  
  The mutation detection frequency is lower when the phenotype is associated with additional clinical abnormalities (except for multiple exostoses; see Genetically Related Disorders).

• Deletion/duplication analysis. Although the relative frequency of submicroscopic deletions of ALX4 or MSX2 in isolated enlarged parietal foramina/cranium bifidum is low (~10% based on unpublished data from a molecular diagnostic service [T Lester, Oxford Genetics Laboratories, personal communication]), targeted dosage analysis by a suitable method (e.g., multiplex ligation-dependent probe amplification; MLPA) is recommended.

Table 1. Summary of Molecular Genetic Testing Used in Enlarged Parietal Foramina/Cranium Bifidum

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1		Test Availability
			Positive Family History	Negative Family History
MSX2	Sequence analysis	Sequence variants	11/13 (~85%)	1/6 (~16%)	Clinical
	Deletion / duplication analysis 2	Exonic or whole-gene deletions
ALX4	Sequence analysis	Sequence variants			Clinical
	Deletion / duplication analysis 2	Exonic or whole-gene deletions

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Mutations were detected in 11/13 familial but only 1/6 simplex cases (i.e., single occurrence in a family) [Mavrogiannis et al 2006].

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array CGH (gene/segment-specific) may be used. A full array CGH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• Cytogenetic analysis

• Molecular genetic testing of MSX2 and ALX4

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Proximal 11p deletion syndrome (P11pDS) or Potocki-Shaffer syndrome is a rare contiguous gene deletion syndrome with enlarged parietal foramina/cranium bifidum and multiple exostoses as defining clinical features (OMIM 601224) [Wuyts et al 2004, Wakui et al 2005]. Deletion events invariably remove ALX4 and the adjacent EXT2 (see Hereditary Multiple Exostoses).

ALX4-related frontonasal dysplasia is caused by biallelic loss-of-function mutations in ALX4. Reported in consanguineous families with probands autozygous for a nonsense mutation, it features median facial malformations of the frontonasal dysplasia spectrum, also with cranium bifidum and coronal craniosynostosis, as well as total alopecia and cryptorchidism [Kayserili et al 2009].

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 persons with an additional copy of MSX2 as a result of gross structural abnormalities [Bernardini et al 2007, Wang et al 2007, Kariminejad et al 2009].

Parietal foramina with cleidocranial dysplasia (OMIM 168550) was associated with MSX2 mutation in a single family with mild clavicular dysplasia [Garcia-Minaur et al 2003].

Natural History

Isolated enlarged parietal foramina 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.

Associated neural or cutaneous abnormalities, if any, tend to be limited and mild. However in a single family segregating an ALX4 mutation, sparse hair and delayed loss of primary dentition were consistently present (see Genotype-Phenotype Correlations).

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].

Scalp defects have been reported [Preis et al 1995, Wuyts et al 2000b].

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].

In single families, mild clavicular hypoplasia (a combination known as parietal foramina with cleidocranial dysplasia; (OMIM 168550) and thumb/hallux broadening, have been described in association with MSX2 [Garcia-Minaur et al 2003] and ALX4 [Mavrogiannis et al 2006] mutations, respectively.

Although a theoretical risk from direct trauma exists, it has not been reported.

Genotype-Phenotype Correlations

With 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 major genotype-phenotype correlations exist: loss-of-function mutations cause enlarged parietal foramina [Wilkie et al 2000, Wuyts et al 2000a]; and the craniosynostosis-related p.Pro148His mutation has been shown to enhance DNA binding affinity [Ma et al 1996].

No obvious genotype-phenotype correlation exists between different loss-of-function MSX2 mutations; 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 genotype-phenotype correlation has been described, with the possible exception of the missense mutation c.653G>A (p.Arg218Gln), which tends to cause particularly large calvarial defects [Mavrogiannis et al 2006]. A different mutation at the same codon c.652C>T (p.Arg218Trp) was associated in addition with sparse hair and delayed loss of primary dentition [A Fryer & T Lester, unpublished observation]. These more severe phenotypes may result from a dominant-negative effect.

Penetrance

Penetrance is approximately 90% overall for either MSX2 or ALX4 mutations. Several individuals with a documented disease-causing mutation have had no radiographic evidence of enlarged parietal foramina [Wilkie et al 2000, Mavrogiannis et al 2001, Mavrogiannis et al 2006].

Presence of enlarged parietal foramina, assessed radiologically, is age-related since the relative width of the defects decreases with age [Mavrogiannis et al 2006].

Anticipation

Anticipation is not observed in this disorder.

Nomenclature

Enlarged parietal foramina have been referred to using the obsolete eponymous label 'Catlin mark.' Other terms that may be encountered are foramina parietalia permagna, fenestrae parietales symmetricae, and giant parietal foramina.

Prevalence

The prevalence of enlarged parietal foramina is in the range of one in 15,000 to one in 50,000 according to old surveys [Moore 1949, Lodge 1975].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with enlarged parietal foramina/cranium bifidum, the following evaluations are recommended:

• Plain skull radiography

• 3D CT scan of head with bone windows

• Brain imaging using CT or MRI scanning, if appropriate.

Treatment of Manifestations

The management of enlarged parietal foramina/cranium bifidum 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 Avoid

The 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.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Enlarged parietal foramina/cranium bifidum is inherited in an autosomal dominant manner with high, but not complete, penetrance.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with enlarged parietal foramina/cranium bifidum have an affected parent.

• A proband with enlarged parietal foramina/cranium bifidum may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations appears to be small.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination, skull radiography, and molecular genetic testing if the mutation has been identified in the proband.

Note: Although most individuals diagnosed with enlarged parietal foramina/cranium bifidum have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected or has an MSX2 or ALX4 mutation, the risk to the sibs is 50%.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of the either parent, the risk to sibs is low, but greater than that of the general population because although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with enlarged parietal foramina/cranium bifidum has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent either is affected or has the disease-causing mutation identified in the proband, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder and this is corroborated on molecular genetic testing, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound examination.

Fetal imaging. Careful fetal ultrasound examination at 18 to 20 weeks' gestation usually detects enlarged parietal foramina/cranium bifidum in a fetus at 50% prior risk [Salamanca et al 1994, Fink & Maixner 2006]. This information may be useful for delivery planning (e.g., indications to use scalp electrodes, forceps, or vacuum extraction could be reviewed).

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 30 March 2010 (me) Comprehensive update posted live

• 25 May 2006 (me) Comprehensive update posted to live Web site

• 26 May 2004 (aw) Revision: prenatal testing availability

• 30 March 2004 (ca/me) Review posted to live Web site

• 13 January 2004 (aw) Original submission