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, 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 Testing

Genes. 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 testing

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

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Gene Symbol	Proportion of Enlarged Parietal Foramina Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Mutation Detection Frequency 2		Test Availability
				Family History
				Positive	Negative or Unknown
MSX2	~40%	Sequence analysis	Sequence variants 3, 4	16/20 (~80%)	7/23 (~30%)	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions 6
ALX4	~60%	Sequence analysis	Sequence variants 3, 4			Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions 6

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. 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. See CMA.

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 proband

• Standard 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any 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).

Contiguous Gene Rearrangements

Proximal 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) Disorders

ALX4-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 2011].

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 History

Isolated 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 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 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.

Penetrance

Penetrance is approximately 90% overall for either MSX2 or ALX4 mutations. Several individuals with a documented disease-causing mutation showed 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 the head with bone windows
• Brain imaging using CT or MRI scanning, if appropriate
• Medical genetics consultation

Treatment of Manifestations

The 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 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.

Evaluation of Relatives at Risk

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

Pregnancy Management

When 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 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.

Mode of Inheritance

Enlarged parietal foramina are 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 have an affected parent.
• A proband with enlarged parietal foramina 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 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 of the possibility of germline mosaicism. No instances of germline mutation have been reported to date.

Offspring of a proband. Each child of an individual with enlarged parietal foramina 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 is either affected or has the disease-causing mutation identified in the proband, his or her family members are at risk.

Related Genetic Counseling Issues

When enlarged parietal foramina are ascertained in families with a background of consanguinity or endogamy, the risk for severe multiple malformations from homozygous ALX4 (and theoretically MSX2) mutations should be considered (see Genetically Related Disorders).

Considerations in families with an apparent de novo mutation. If molecular genetic testing confirms that neither parent of a proband with an autosomal dominant condition has the disorder, 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.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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 this service.

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 approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 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 in a fetus at 50% prior risk; fetal MRI is also an option [Salamanca et al 1994, Fink & Maixner 2006, Chung et al 2010]. This information may be useful for delivery planning.

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 in GeneReviews™ chapters any 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).

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Acknowledgments

We are grateful to Tracy Lester and Helen Lord at the Oxford Medical Genetics Laboratories for collating and providing clinical testing service data.

Revision History

• 8 November 2012 (me) Comprehensive update posted live
• 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