Clinical 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. Heterozygous pathogenic variants in either ALX4 or MSX2 are established causes.

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 in those with a persistent midline bony defect.

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 pathogenic variants appears to be small. Each child of an individual with enlarged parietal foramina has a 50% chance of inheriting the pathogenic variant. Detailed 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. When the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Enlarged parietal foramina should be suspected in individuals with the following clinical and imaging findings.

Establishing the Diagnosis

The diagnosis of enlarged parietal foramina is established in a proband with compatible clinical and imaging findings, and on identification of a heterozygous pathogenic variant in ALX4 or MSX2 by molecular genetic testing (see Table 1), which can assist with identification of disorders that are either allelic (see Table 2) or in the differential diagnosis (Table 4).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) (Option 1) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) (Option 2). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

Clinical Description

Isolated enlarged parietal foramina caused by a heterozygous ALX4 or MSX2 pathogenic variant are primary osseous defects that 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].

A risk from direct trauma exists and skull fracture has been reported [Edwards et al 2012].

Features of the frontonasal dysplasia spectrum, ranging from almost inconspicuous to mild, may manifest in individuals with heterozygous ALX4 pathogenic variants [Bertola et al 2013, Altunoglu et al 2014].

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 pathogenic variants are usually of similar size and clinically indistinguishable [Mavrogiannis et al 2006].

MSX2. No prominent genotype-phenotype correlation exists between different MSX2 pathogenic loss-of-function variants causing enlarged parietal foramina. However, unique pathogenic variants in single families have been associated with aplasia cutis congenita [Preis et al 1995, Wuyts et al 2000b] and clavicular hypoplasia [Garcia-Miñaur et al 2003], possibly suggesting subtle dominant-negative effects.

ALX4. Heterozygous missense variants that tend to affect residues of the homeodomain or other complex pathogenic variants with potential for dominant-negative effects have been associated with clinical features in addition to parietal foramina, such as hypertelorism, nasal clefting and broad columella, sparse hair, thumb/hallux broadening, and genital abnormalities [Bertola et al 2013; Altunoglu et al 2014; A Fryer & T Lester, unpublished observations]. Although secondary and only documented in a few reports, these abnormalities suggest genuine overlap with ALX4-related frontonasal dysplasia, which is typically caused by biallelic pathogenic variants.

Penetrance

Penetrance for either an MSX2 or ALX4 heterozygous pathogenic variant is age related (as the relative width of the defects decreases with age) and high, but reduced (several individuals with a documented pathogenic variant showed no radiographic evidence of enlarged parietal foramina [Wilkie et al 2000, Mavrogiannis et al 2001, Mavrogiannis et al 2006]).

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 1:15,000 to 1:50,000 according to old surveys [Moore 1949, Lodge 1975].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with enlarged parietal foramina / cranium bifidum, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Plain skull radiography
• 3D CT scan of the head with bone windows
• Brain imaging using CT or MRI scanning, if appropriate
• Consultation with a clinical geneticist and/or genetic counselor

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.

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.

Agents/Circumstances to Avoid

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 the planning of the delivery (e.g., review of indications to use scalp electrodes, forceps, and/or vacuum extraction). Elective cesarean section may reduce the theoretic risk for traumatic birth injury.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Isolated enlarged parietal foramina are inherited in an autosomal dominant manner.

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 de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants appears to be small.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include physical examination, skull radiography, and molecular genetic testing if an MSX2 or ALX4 variant has been identified in the proband.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. While theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with enlarged parietal foramina may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and molecular genetic testing have been performed on the parents of the proband.

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

• If a parent of the proband is affected and/or is known to have the MSX2 or ALX4 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known MSX2 or ALX4 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the MSX2 or ALX4 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for enlarged parietal foramina because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with enlarged parietal foramina has a 50% chance of inheriting the enlarged parietal foramina-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is either affected or has the pathogenic variant identified in the proband, other members of the parent's family 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) pathogenic variants should be considered (see Genetically Related Disorders).

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the enlarged parietal foramina-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. However, given the usually benign prognosis, such requests are expected to be very infrequent.

Fetal imaging. Detailed 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 [Chung et al 2010, Saraç Sivrikoz et al 2016]. This information may be useful for delivery planning (see Pregnancy Management).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ALX4 and MSX2 encode members of the Alx and Msx homeodomain protein families required for diverse developmental processes. In humans, the skull appears to be particularly sensitive to their dosage. In the absence of ALX4, median facial development, hair follicle growth, and genital development are also affected.

Mechanism of disease causation. For both ALX4 and MSX2, heterozygous whole-gene deletions, frameshift or nonsense variants anywhere in the coding region, and, to a degree, missense variants within the homeodomain are likely to result predominantly in loss of function and cause enlarged parietal foramina because of haploinsufficiency. Certain missense variants within the homeodomain or other complex changes, particularly in ALX4, may also have dominant-negative effects that could explain the broader phenotypes in heterozygosity (see Genetically Related Disorders). The MSX2 missense variants in craniosynostosis involve a particular homeodomain residue; there is evidence that these stabilize DNA binding [Ma et al 1996].

Laboratory-specific technical considerations: MSX2. A processed pseudogene of MSX2, MSX2P1, resides on human chromosome 17q22, within an intron of the gene OR4D1.

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

• 27 November 2019 (bp) Comprehensive update posted live
• 8 November 2012 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 25 May 2006 (me) Comprehensive update posted live
• 26 May 2004 (aw) Revision: prenatal testing availability
• 30 March 2004 (ca/me) Review posted live
• 13 January 2004 (aw) Original submission

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