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PubMed This is a summary of 12 peer-reviewed journal articles Updated

When EPF is Part of a Syndrome

At a Glance

Enlarged Parietal Foramina (EPF) is typically an isolated skull variation, but it can sometimes signal a genetic condition like Potocki-Shaffer Syndrome. Specialists recommend genetic testing if a child with EPF also shows developmental delays, unusual facial features, or bony growths.

While Enlarged Parietal Foramina (EPF) is usually a stand-alone anatomical “quirk,” it can sometimes be a clue to a more complex genetic situation. When EPF occurs alongside other physical or developmental findings, doctors look for specific syndromes that involve the same “construction” genes used to build the skull.

Potocki-Shaffer Syndrome (PSS)

The most well-known syndrome associated with EPF is Potocki-Shaffer Syndrome [1]. This condition is caused by a “contiguous gene deletion” on chromosome 11 (specifically the 11p11.2 region) [2]. Instead of a single small mutation, a chunk of genetic material is missing, taking several important genes with it:

  • ALX4: As we’ve seen, the loss of this gene causes the parietal foramina (skull holes) [3].
  • EXT2: Missing this gene can lead to multiple osteochondromas—benign, cartilage-capped bony growths that usually appear on the long bones of the arms and legs [4][5].
  • PHF21A: The loss of this gene is linked to intellectual disability and certain facial features [6][2].

Children with PSS may have a combination of EPF, developmental delays, and unique facial features such as a tall, broad forehead, full cheeks, or a broad nasal tip [7][2].

Other Syndromic Connections

Less commonly, EPF can be seen in other conditions where skull development is affected:

  • Saethre-Chotzen Syndrome: This is a condition typically characterized by craniosynostosis (the skull bones fusing too early), but it can sometimes occur with EPF, leading to more complex skull shapes [8].
  • CDC42BPB-related Neurodevelopmental Disorder: Recent research has identified a link between EPF and rare genetic variants in the CDC42BPB gene, which may involve global developmental delay in addition to the parietal bone defects [9].

When to Seek Broader Genetic Testing

If your child has EPF but is otherwise healthy and hitting all their milestones, it is likely isolated EPF. However, specialists may recommend broader genetic tests—such as a Chromosomal Microarray (CMA) or Whole Exome Sequencing (WES)—if they notice certain “red flags” [10][11]:

  1. Developmental Delays: Significant delays in learning to walk, talk, or interact with others [10][9].
  2. Bony Growths: Feeling hard, painless lumps near the joints of the knees, shoulders, or wrists [5].
  3. Distinctive Facial Features: Physical traits that are noticeably different from other family members, such as the shape of the nose or forehead [7].
  4. Limb Abnormalities: Fingers that are unusually short, curved, or fused together [12].

Understanding whether EPF is isolated or syndromic is important because it helps your medical team provide the right support. While isolated EPF usually requires no action, a syndromic diagnosis allows for early interventions—like physical or speech therapy—that can significantly improve a child’s long-term outcomes [6].

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Common questions in this guide

Is Enlarged Parietal Foramina always part of a syndrome?
No, EPF is usually an isolated anatomical difference with no other health issues. However, if a child also has developmental delays, distinctive facial features, or abnormal bone growths, it may be part of a broader genetic syndrome.
What is Potocki-Shaffer Syndrome?
Potocki-Shaffer Syndrome is a rare genetic condition caused by missing genetic material on chromosome 11. It commonly involves EPF along with other physical signs like multiple bony growths and developmental or intellectual delays.
When should my child get genetic testing for EPF?
Specialists may recommend broader genetic testing, such as a Chromosomal Microarray, if your child with EPF shows red flags like developmental delays, unusual facial features, or abnormal limb development.
What are multiple osteochondromas?
Multiple osteochondromas are benign, cartilage-capped bony growths that usually form on the long bones of the arms and legs. When they occur alongside EPF, they can be a strong indicator of Potocki-Shaffer Syndrome.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Is my child's EPF 'isolated,' or are there other physical or developmental signs that suggest it might be part of a syndrome?
  2. 2.Given these findings, should we consult with a clinical geneticist for a deeper evaluation?
  3. 3.Should we perform a Chromosomal Microarray (CMA) to look specifically for the 11p11.2 deletion?
  4. 4.Are there any signs of multiple osteochondromas (bony growths) that we should be monitoring for?
  5. 5.Does my child's facial structure or limb development show any of the hallmark signs of Potocki-Shaffer or Saethre-Chotzen syndrome?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (12)
  1. 1

    A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.

    Labonne JD, Vogt J, Reali L, et al.

    American journal of medical genetics. Part A 2015; (167A(12)):3011-8 doi:10.1002/ajmg.a.37344.

    PMID: 26333423
  2. 2

    De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies.

    Hamanaka K, Sugawara Y, Shimoji T, et al.

    European journal of human genetics : EJHG 2019; (27(3)):378-383 doi:10.1038/s41431-018-0289-x.

    PMID: 30487643
  3. 3

    Bilateral Foramina Parietalia Permagna - A Calvarial Defect Caused by Haploinsufficiency of the Msh Homeobox 2 Gene: A Case Report and Current Literature Review.

    Kahl N, Lüsebrink N, Schubert-Bast S, et al.

    Neuropediatrics 2024; (55(3)):205-208 doi:10.1055/s-0044-1781465.

    PMID: 38447947
  4. 4

    Heparan sulfate deficiency leads to hypertrophic chondrocytes by increasing bone morphogenetic protein signaling.

    Kawashima K, Ogawa H, Komura S, et al.

    Osteoarthritis and cartilage 2020; (28(11)):1459-1470 doi:10.1016/j.joca.2020.08.003.

    PMID: 32818603
  5. 5

    Multiple Osteochondromas Comorbid With Enlarged Parietal Foramina, Elongated Styloid Processes, and Tibiofibular Synostosis.

    Baugher EC, Batarseh TR, Becker AK, et al.

    American journal of clinical pathology 2021; (156(4)):513-520 doi:10.1093/ajcp/aqaa282.

    PMID: 33769443
  6. 6

    New Insights into Potocki-Shaffer Syndrome: Report of Two Novel Cases and Literature Review.

    Trajkova S, Di Gregorio E, Ferrero GB, et al.

    Brain sciences 2020; (10(11)) doi:10.3390/brainsci10110788.

    PMID: 33126574
  7. 7

    The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients.

    Poole RL, Bijlsma EK, Houge G, et al.

    Clinical dysmorphology 2023; (32(2)):49-54 doi:10.1097/MCD.0000000000000455.

    PMID: 36876344
  8. 8

    Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1.

    Walters ME, Lacassie Y, Azamian M, et al.

    American journal of medical genetics. Part A 2021; (185(3)):916-922 doi:10.1002/ajmg.a.62036.

    PMID: 33369125
  9. 9

    AI-Based CT Image Recognition With Med-Gemini-3D in the Diagnosis of a Rare Craniofacial Condition: A Catlin Mark Skull.

    Hajebian HH, Friel MT

    The Journal of craniofacial surgery 2026; (37(3-4)):910-913 doi:10.1097/SCS.0000000000012413.

    PMID: 41543485
  10. 10

    Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

    Srivastava S, Love-Nichols JA, Dies KA, et al.

    Genetics in medicine : official journal of the American College of Medical Genetics 2019; (21(11)):2413-2421 doi:10.1038/s41436-019-0554-6.

    PMID: 31182824
  11. 11

    Diagnostic evaluation of patients with epileptic spasms in the era of next-generation sequencing.

    Mir A, AlQahtani M, Amer F, et al.

    Epileptic disorders : international epilepsy journal with videotape 2024; (26(5)):651-661 doi:10.1002/epd2.20259.

    PMID: 38949266
  12. 12

    Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism.

    Kim HG, Rosenfeld JA, Scott DA, et al.

    Molecular autism 2019; (10()):35 doi:10.1186/s13229-019-0286-0.

    PMID: 31649809

This page explains syndromic presentations of EPF for educational purposes only. It does not replace professional medical advice. Always consult a pediatrician or clinical geneticist to evaluate your child's specific symptoms.

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