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Enlarged Parietal Foramina

Synonym: Symmetric Parietal Foramina. Includes: Parietal Foramina 1, Parietal Foramina 2

, MA, DM, FRCP and , MSc, DPhil.

Author Information
, MA, DM, FRCP
University of Oxford
Oxford, UK
, MSc, DPhil
DNA Laboratory
St James University Hospital
Leeds, United Kingdom

Initial Posting: ; Last Update: November 8, 2012.

Summary

Disease characteristics. 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 of fetal development. Enlarged parietal foramina are usually asymptomatic. Meningeal, cortical, and vascular malformations of the posterior fossa occasionally accompany the bone defects and may predispose to epilepsy. 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.

Diagnosis/testing. Typically oval or round, enlarged parietal foramina 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. In young children, the disorder may present as a persistently enlarged posterior fontanelle caused by a single large central parietal bone defect (cranium bifidum). 3D CT scanning using bone windows clearly reveals the defect. MRI is useful in defining associated intracranial anatomic changes. MSX2 and ALX4 are the two genes in which mutations are known to cause enlarged parietal foramina.

Management. Treatment of manifestations: Treatment is generally conservative. Persistent cranium bifidum may warrant operative closure. Associated headaches or seizures should be treated appropriately. The risk for penetrating injury to the brain is small but may cause anxiety; education of parents, teachers, and the affected child to avoid risky behaviors that could result in injury suffices in most circumstances.

Agents/circumstances to avoid: Contact sports should be avoided if a midline bony defect persists.

Genetic counseling. Enlarged parietal foramina are inherited in an autosomal dominant manner with high, but not complete, penetrance. Most individuals diagnosed with enlarged parietal foramina have an affected parent. The proportion of cases caused by de novo mutations appears to be small. Each child of an individual with enlarged parietal foramina has a 50% chance of inheriting the mutation. Careful fetal ultrasound examination at 18 to 20 weeks' gestation can usually detect the defects in a fetus at risk. Fetal MRI is also an option. Prenatal diagnosis using molecular genetic testing is possible for families in which the disease-causing mutation has been identified in an affected family member.

Diagnosis

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

Gene SymbolProportion of Enlarged Parietal Foramina Attributed to Mutations in This Gene 1Test MethodMutations DetectedMutation Detection Frequency 2
Family History
PositiveNegative or Unknown
MSX2 ~40%Sequence analysisSequence variants 3, 416/20 (~80%)7/23 (~30%)
Deletion / duplication analysis 5Exonic or whole-gene deletions 6
ALX4 ~60%Sequence analysisSequence variants 3, 4
Deletion / duplication analysis 5Exonic or whole-gene deletions 6

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.

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

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

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.

Clinical Description

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].

Differential Diagnosis

Isolated 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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:

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com

Molecular Genetics

Information 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 Databases

Data 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)

123101MUSCLE SEGMENT HOMEOBOX, DROSOPHILA, HOMOLOG OF, 2; MSX2
168500PARIETAL FORAMINA; PFM
605420ARISTALESS-LIKE 4, MOUSE, HOMOLOG OF; ALX4
609597PARIETAL FORAMINA 2; PFM2

MSX2

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].

References

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Chapter Notes

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
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