Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical interest of molecular study in cases of isolated midline craniosynostosis

European Journal of Human Genetics volume 31, pages 621–628 (2023)Cite this article

Subjects

Abstract

In some cases of infants with apparently isolated single-suture synostosis, an underlying variant can be found. We aimed to determine the molecular substratum in isolated sagittal and metopic craniosynostosis. To this end, we included all infants who presented isolated midline synostosis (sagittal or metopic) and had undergone surgery at the craniosynostosis national reference center of Lyon University Hospital. All infants were examined by a multidisciplinary team including neurosurgeons, clinical geneticists and neuropsychologist. Among 101 infants tested, 13 carried a total of 13 variants; that is, 12.9% of the infants carried a variant in genes known to be involved in craniosynostosis. Seven infants carried SMAD6 variants, 2 in FGFR2, 1 in TWIST1, one in FREM1, one in ALX4 and one in TCF12. All variants were detected at the heterozygous level in genes associated with autosomal dominant craniosynostosis. Also, neurodevelopmental testing showed especially delayed acquisition of language in children with than without variants in SMAD6. In conclusion, a high percentage of young children with isolated midline craniosynostosis, especially in isolated trigonocephaly, carried SMAD6 variants. The interpretation of the pathogenicity of the genes must take into account incomplete penetrance, usually observed in craniosynostosis. Our results highlight the interest of molecular analysis in the context of isolated sagittal and/or metopic craniosynostosis to enhance an understanding of the pathophysiology of midline craniosynostosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Transcription analysis.
Fig. 2: Distribution of children with or without a variant according to their developmental level, below or under the 50th percentile.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Wilkie AOM, Johnson D, Wall SA. Clinical genetics of craniosynostosis. Curr Opin Pediatr. 2017;29:622–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cornelissen M, Ottelander B, den, Rizopoulos D, van der Hulst R, Mink van der Molen A, van der Horst C, et al. Increase of prevalence of craniosynostosis. J Cranio-Maxillofac Surg. 2016;44:1273–9.

    Article  Google Scholar 

  3. Di Rocco F, Arnaud E, Renier D. Evolution in the frequency of nonsyndromic craniosynostosis: clinical article. J Neurosurg: Pediatr. 2009;4:21–5.

    PubMed  Google Scholar 

  4. Mocquard C, Aillet S, Riffaud L. Recent advances in trigonocephaly. Neurochirurgie. 2019;65:246–51.

    Article  CAS  PubMed  Google Scholar 

  5. Vinchon M, Guerreschi P, Karnoub MA, Wolber A. Synostosis of the lambdoid suture: a spectrum. Child’s Nerv Syst. 2021;37:1991–2000.

    Article  Google Scholar 

  6. Calpena E, Cuellar A, Bala K, Swagemakers SMA, Koelling N, McGowan SJ, et al. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. Genet Med. 2020;22:1498–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Timberlake AT, Choi J, Zaidi S, Lu Q, Nelson-Williams C, Brooks ED, et al. Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles. Elife. 2016;5:e20125.

  8. McGillivray G, Savarirayan R, Cox TC, Stojkoski C, McNeil R, Bankier A, et al. Familial scaphocephaly syndrome caused by a novel mutation in the FGFR2 tyrosine kinase domain. J Med Genet. 2005;42:656–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sharma VP, Wall SA, Lord H, Lester T, Wilkie AOM. Atypical crouzon syndrome with a novel Cys62Arg mutation in FGFR2 presenting with sagittal synostosis. Cleft Palate-Cranio-fac J. 2012;49:373–7.

    Article  Google Scholar 

  10. Yilmaz E, Mihci E, Guzel Nur B, Alper OM. A novel AXIN2 gene mutation in sagittal synostosis. Am J Med Genet Part A. 2018;176:1976–80.

    Article  CAS  PubMed  Google Scholar 

  11. Foo R, Guo Y, McDonald-Mcginn DM, Zackai EH, Whitaker LA, Bartlett SP. The natural history of patients treated for TWIST1-confirmed Saethre-Chotzen syndrome. Plast Reconstr Surg. 2009;124:2085–95.

    Article  CAS  PubMed  Google Scholar 

  12. Vissers LELM, Cox TC, Maga AM, Short KM, Wiradjaja F, Janssen IM, et al. Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genet. 2011;7:e1002278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Timberlake AT, Persing JA. Genetics of nonsyndromic craniosynostosis. Plast Reconstr Surg. 2018;141:1508–16.

    Article  CAS  PubMed  Google Scholar 

  14. Duyme M, Zorman M, Tervo R, Capron C. French norms and validation of the Child Development Inventory (CDI): Inventaire du Développement de l’Enfant (IDE). Clin Pediatr. 2011;50:636–47.

    Article  Google Scholar 

  15. Yang Y, Zheng Y, Li W, Li L, Tu M, Zhao L, et al. SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. Genet Med. 2019;21:2577–85.

    Article  PubMed  Google Scholar 

  16. Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, et al. Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor. Front Physiol. 2017;8:400.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Roscioli Tony. Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients. Am J Med Genet Part C: Semin Med Genet. 2013;163:259–70.

    Article  CAS  Google Scholar 

  18. Lapunzina P, Fernández A, Sánchez Romero JM, Delicado A, De Pipaon MS, Pajares IL, et al. A novel insertion in the FGFR2 gene in a patient with Crouzon phenotype and sacrococcygeal tail. Birth Defects Res Part A - Clin Mol Teratol. 2005;73:61–4.

    Article  CAS  Google Scholar 

  19. Marie PJ, Kaabeche K, Guenou H. Roles of FGFR2 and twist in human craniosynostosis: insights from genetic mutations in cranial osteoblasts. Front Oral Biol. 2008;12:144–59.

    Article  PubMed  Google Scholar 

  20. Funato N, Twigg SRF, Higashihori N, Ohyama K, Wall SA, Wilkie AOM, et al. Functional analysis of natural mutations in two TWIST protein motifs. Hum Mutat. 2005;25:550–6.

    Article  CAS  PubMed  Google Scholar 

  21. Altunoglu U, Satkin B, Uyguner ZO, Kayserili H. Mild nasal clefting may be predictive for ALX4 heterozygotes. Am J Med Genet Part A. 2014;164:2054–8.

    Article  CAS  Google Scholar 

  22. Mavrogiannis LA, Taylor IB, Davies SJ, Ramos FJ, Olivares JL, Wilkie AOM. Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype. Eur J Hum Genet. 2006;14:151–8.

    Article  CAS  PubMed  Google Scholar 

  23. Yagnik G, Ghuman A, Kim S, Stevens CG, Kimonis V, Stoler J, et al. ALX4 gain-of-function mutations in nonsyndromic craniosynostosis. Hum Mutat. 2012;33:1626–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fonteles CS, Finnell RH, Lei Y, Zurita-Jimenez ME, Monteiro AJ, George TM, et al. De novo ALX4 variant detected in child with non-syndromic craniosynostosis. Braz J Med Biol Res. 2021;54:11396.

    Article  Google Scholar 

  25. Bertola DR, Rodrigues MG, Quaio CRDC, Kim CA, Passos-Bueno MR. Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation. Am J Med Genet Part A. 2013;161:600–4.

    Article  CAS  Google Scholar 

  26. Loebel DAF, O’Rourke MP, Steiner KA, Banyer J, Tam PPL. Isolation of differentially expressed genes from wild-type and Twist mutant mouse limb buds. Genesis. 2002;33:103–13.

    Article  CAS  PubMed  Google Scholar 

  27. García-Sanz P, Fernández-Pérez A, Vallejo M. Differential configurations involving binding of USF transcription factors and Twist1 regulate Alx3 promoter activity in mesenchymal and pancreatic cells. Biochem J. 2013;450:199–208.

    Article  PubMed  Google Scholar 

  28. Tønne E, Due-Tønnessen BJ, Wiig U, Stadheim BF, Meling TR, Helseth E, et al. Epidemiology of craniosynostosis in Norway. J Neurosurg: Pediatr. 2020;26:68–75.

    PubMed  Google Scholar 

  29. Timberlake AT, Wu R, Nelson-Williams C, Furey CG, Hildebrand KI, Elton SW, et al. Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis. Hum Genome Var. 2018;5:14.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yilmaz E, Mihci E, Nur B, Alper ÖM, Taçoy Ş. Recent advances in craniosynostosis. Pediatr Neurol. 2019;99:7–15.

    Article  PubMed  Google Scholar 

  31. Wu RT, Timberlake AT, Abraham PF, Gabrick KS, Lu X, Peck CJ, et al. SMAD6 genotype predicts neurodevelopment in nonsyndromic craniosynostosis. Plast Reconstr Surg. 2020;145:117e–25e.

    Article  CAS  PubMed  Google Scholar 

  32. Dawson AJ, Hovanes K, Liu J, Marles S, Greenberg C, Mhanni A, et al. Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly. Clin Dysmorphol. 2021;30:83–8.

    Article  PubMed  Google Scholar 

  33. Seto ML, Hing AV, Chang J, Hu M, Kapp-Simon KA, Patel PK, et al. Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet Part A. 2007;143:678–86.

    Article  Google Scholar 

  34. Antonopoulou I, Mavrogiannis LA, Wilkie AOM, Morriss-Kay GM. Alx4 and Msx2 play phenotypically similar and additive roles in skull vault differentiation. J Anat. 2004;204:487–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sewda A, White SR, Erazo M, Hao K, García-Fructuoso G, Fernández-Rodriguez I, et al. Nonsyndromic craniosynostosis: novel coding variants. Pediatr Res. 2019;85:463–8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yoon JG, Hahn HM, Choi S, Kim SJ, Aum S, Yu JW, et al. Molecular diagnosis of craniosynostosis using targeted next-generation sequencing. Neurosurgery. 2020;87:294–302.

    Article  PubMed  Google Scholar 

  37. Lee E, Le T, Zhu Y, Elakis G, Turner A, Lo W, et al. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations. Genet Med. 2018;20:1061–8.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang J, Kurgan L. Review and comparative assessment of sequence-based predictors of protein-binding residues. Brief Bioinform. 2018;19:821–37.

  39. Fan X, Waardenberg AJ, Demuth M, Osteil P, Sun JQJ, Loebel DAF, et al. TWIST1 homodimers and heterodimers orchestrate lineage-specific differentiation. Mol Cell Biol. 2020;40:e00663–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ms Stephanie Serre for her help in the preparation of the manuscript. We are grateful to the patients and their families who participated to this study.

Funding

No specific funding.

Author information

Authors and Affiliations

  1. Department of Pediatric Neurosurgery, French Referral Center for Craniosynostosis, Hôpital Femme Mère-Enfant Hospices Civils de Lyon, University of Lyon, INSERM 1033, Lyon, France

    Federico Di Rocco, Isabelle Verlut, Alexandru Szathmari, Pierre Aurélien Beuriat, Carmine Mottolese, Matthieu Vinchon & Sofia Guernouche

  2. Department of Genetics, Lyon University Hospitals, INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Lyon, France

    Massimiliano Rossi, Nicolas Chatron & Pauline Monin

  3. Department of Pediatric Cranio-Maxillo-Facial Surgery, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon 1, Lyon, France

    Julie Chauvel-Picard

  4. Department of Genetics, Robert Debré Hospital, Inserm 1132, Université de Paris Cité, Paris, France

    Corinne Collet

Authors
  1. Federico Di Rocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massimiliano Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabelle Verlut
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandru Szathmari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre Aurélien Beuriat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicolas Chatron
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julie Chauvel-Picard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carmine Mottolese
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pauline Monin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthieu Vinchon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sofia Guernouche
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Corinne Collet
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FDR: conception and design, acquisition of data (AD), analysis and interpretation of data and writing original draft. MR: AD, analysis and interpretation of data, manuscript revising, IV: AD, analysis and interpretation of data, manuscript revising. AS: AD, NC: AD, PAB: AD, JCP: AD, PM: AD, CM: AD, MV: AD, SG: AD, analysis and interpretation of data,manuscript revising, CC: AD, conception and design, analysis and interpretation of data and writing original draft.

Corresponding author

Correspondence to Corinne Collet.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

The molecular analysis was approved by the French ethics committee (no. IRB00011687; College de neurochirurgie IRB #1: 2022/05) and was performed after parents gave signed informed consent for genetic testing.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Di Rocco, F., Rossi, M., Verlut, I. et al. Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet 31, 621–628 (2023). https://doi.org/10.1038/s41431-023-01295-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41431-023-01295-y

This article is cited by

Search

Advanced search

Quick links