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Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis
Open accessAbstract
OBJECTIVES: We describe the first cohort-based analysis of the impact of genetic disorders in craniosynostosis. We aimed to refine the understanding of prognoses and pathogenesis and to provide rational criteria for clinical genetic testing. METHODS: We undertook targeted molecular genetic and cytogenetic testing for 326 children who required surgery because of craniosynostosis, were born in 1993–2002, presented to a single craniofacial unit, and were monitored until the end of 2007. RESULTS: Eighty-four children (and 64 relatives) had pathologic genetic alterations (86% single-gene mutations and 14% chromosomal abnormalities). The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and were associated with increased rates of many complications. Children with an initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to have a causative mutation if the synostoses were unicoronal or bicoronal (10 of 48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003). Repeat craniofacial surgery was required for 58% of children with single-gene mutations but only 17% of those with chromosomal abnormalities (P = .01). CONCLUSIONS: Clinical genetic assessment is critical for the treatment of children with craniosynostosis. Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses. Single-gene disorders that disrupt physiologic signaling in the cranial sutures often require reoperation, whereas chromosomal abnormalities follow a more-indolent course, which suggests a different, secondary origin of the associated craniosynostosis.
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“Results showed that 21% of all non-syndromic had a genetic cause, mainly single-gene mutations (86%) and fewer chromosomal abnormalities (14%) with the FGFR3 P250R mutation being the most common.”
From Developments in diagnostic and surgical techniques in children with sagittal suture craniosynostosis: a systematic review spanning the last 30 years (2025) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In contrast, sagittal craniosynostosis showed minimal genetic links, with only a small percentage linked to single-gene mutations and even fewer chromosomal abnormalities.”
From Developments in diagnostic and surgical techniques in children with sagittal suture craniosynostosis: a systematic review spanning the last 30 years (2025) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Unlike coronal synostosis, which has stronger genetic associations, sagittal cases likely involve environmental factors.”
From Developments in diagnostic and surgical techniques in children with sagittal suture craniosynostosis: a systematic review spanning the last 30 years (2025) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Wilkie et al. showed that sagittal craniosynostosis has minimal genetic links, reducing recurrence risk but complicating early diagnosis.”
From Developments in diagnostic and surgical techniques in children with sagittal suture craniosynostosis: a systematic review spanning the last 30 years (2025) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In a recent analysis of a 10-year prospective cohort of craniosynostosis presenting to our unit, a genetic diagnosis was achieved in 21% of cases, comprising 86% single gene disorders and 15% chromosome abnormalities (one patient had both).7”
From Craniosynostosis (2011) · cites this paper as [7]
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“Genes most commonly mutated in craniosynostosis are FGFR2, FGFR3, TWIST1 and EFNB1.”
From Craniosynostosis (2011) · cites this paper as [7]
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“Compared with single gene disorders, which often required reoperation (58% of cases), patients with chromosome abnormalities followed a less aggressive course (reoperation rate 17%) suggesting a different, secondary origin of the associated craniosynostosis.”
From Craniosynostosis (2011) · cites this paper as [7]
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“The genes most frequently mutated were FGFR2 (32% of all genetic cases), FGFR3 (25%), TWIST1 (19%) and EFNB1 (7%).”
From Craniosynostosis (2011) · cites this paper as [7]
The cited source says what the claim attributes to it.
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“Compared with single gene disorders, which often required reoperation (58% of cases), patients with chromosome abnormalities followed a less aggressive course (reoperation rate 17%) suggesting a different, secondary origin of the associated craniosynostosis.”
From Craniosynostosis (2011) · cites this paper as [7]
The cited source says what the claim attributes to it.
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“The Oxford study 7 showed a predominance (85%) of metopic or sagittal synostosis in patients with chromosome abnormalities.”
From Craniosynostosis (2011) · cites this paper as [7]
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“Muenke syndrome, defined by identification of the Pro250Arg substitution, is individually the most common genetic abnormality found in craniosynostosis, comprising B5% of all cases.7”
From Craniosynostosis (2011) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“In a recent analysis of a 10-year prospective cohort of craniosynostosis presenting to our unit, a genetic diagnosis was achieved in 21% of cases, comprising 86% single gene disorders and 15% chromosome abnormalities (one patient had both).7”
From Craniosynostosis (2011) · cites this paper as [7]
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In the citing paper
“Published studies of the prevalence of submicroscopic chromosomal abnormalities in syndromic craniosynostosis have ranged widely, from 6.7% 7 to 28% (ref.38).”
From Craniosynostosis (2011) · cites this paper as [7]
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Citations
Cites
Craniosynostosis: Diagnosis, Evaluation, and Management
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Self-citationMuenke, M., Gripp, K. W., McDonald‐McGinn, D. M., Gaudenz, K., Whitáker, L. A., Bartlett, S. P., Markowitz, R. I., Robin, N. H., Nwokoro, N., Mulvihill, J. J., et al. (1997) · PubMed · Cited by 382
Self-citationDigenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29884 · Cited by 379
Genetic study of nonsyndromic coronal craniosynostosis
Lajeunie, E., Merrer, M. L., Bonaïti‐Pellie, C., Marchac, D., & Renier, D. (1995) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320550422 · Cited by 374
A population‐based study of craniosynostosis in metropolitan Atlanta, 1989–2003
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Twigg, S. R. F., Kan, R., Babbs, C., Bochukova, E. G., Robertson, S. P., Wall, S. A., Morriss‐Kay, G. M., & Wilkie, A. O. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402819101 · Cited by 341
Self-citationBellus, G. A., Gaudenz, K., Zackai, E. H., Clarke, L. A., Szabo, J., Francomano, C. A., & Muenke, M. (1996) · Nature Genetics · doi:10.1038/ng1096-174 · Cited by 311
Nail patella syndrome: a review of the phenotype aided by developmental biology
Sweeney, E., Fryer, A., Mountford, R., Green, A., & McIntosh, I. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.3.153 · Cited by 282
Kan, S.-H., Elanko, N., Johnson, D., Cornejo-Roldan, L., Cook, J., Reich, E. W., Tomkins, S., Verloes, A., Twigg, S. R. F., Rannan-Eliya, S., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/338758 · Cited by 265
Self-citation
Research works printed but not linked: 1
- National Specialist Commissioning Advisory Group, National Health Service Executive, 1998, Current designated services: changes and clarifications: craniofacial surgery service
Cited by
Sorted by citations
Johnson, D., & Wilkie, A. O. M. (2011) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.235 · Cited by 499
Self-citationA Genetic-Pathophysiological Framework for Craniosynostosis
Twigg, S. R. F., & Wilkie, A. O. M. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.07.006 · Cited by 276
Self-citationHand in glove: brain and skull in development and dysmorphogenesis
Richtsmeier, J. T., & Flaherty, K. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1104-y · Cited by 264
Sharma, V., Fenwick, A. L., Brockop, M. S., McGowan, S. J., Goos, J. A. C., Hoogeboom, A. J. M., Brady, A. F., Jeelani, O., Lynch, S. A., Mulliken, J. B., et al. (2013) · Nature Genetics · doi:10.1038/ng.2531 · Cited by 226
Self-citationIncrease of prevalence of craniosynostosis
Cornelissen, M., Ottelander, B. D., Rizopoulos, D., van der Hulst, R., Mink van der Molen, A., van der Horst, C., Delye, H., van Veelen, M.-L., Bonsel, G., & Mathijssen, I. (2016) · Journal of Cranio-Maxillofacial Surgery · doi:10.1016/j.jcms.2016.07.007 · Cited by 226
Metadata
- Authors
- Wilkie, A. O. M., Byren, J. C., Hurst, J. A., Jayamohan, J., Johnson, D., Knight, S. J. L., Lester, T., Richards, P. G., Twigg, S. R. F., & Wall, S. A.
- Affiliations
- John Radcliffe Hospital (GB)
- Department of Clinical Genetics and
- Centre for Human Genetics (GB)
- National Health Service (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- ORCID
- Venue
- Pediatrics
- Publisher
- American Academy of Pediatrics (AAP)
- Published
- 2010-08-01
- Volume
- 126
- Issue
- 2
- Pages
- e391-e400
- ISSN
- 0031-4005 (ISSN-L)
- 1098-4275
- PMC
- PMC3535761
- OpenAlex
- W1989045574
- Cited by
- 297
- References
- 51
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 24 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 23 · 2019: 17 · 2018: 22 · 2017: 34 · 2016: 22 · 2015: 10 · 2014: 24 · 2013: 22 · 2012: 16
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- PEDIATRICS (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (078666, 075491)
- Topics
- Health Sciences › Medicine › Surgery › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Dentistry › General Dentistry › dental development and anomalies
- Keywords
- craniosynostosis, single-gene mutations, chromosomal abnormalities, genetic testing, nonsyndromic craniosynostosis, coronal synostosis, sagittal synostosis, metopic synostosis, pathogenesis
- MeSH terms
- Chromosome Aberrations, Craniosynostoses, Exons, Humans, Infant, Infant, Newborn, Molecular Biology, Signal Transduction, Prevalence, Point Mutation, Neurosurgical Procedures, Plastic Surgery Procedures, Cytogenetic Analysis, Genetic Diseases, Inborn, Receptor, Fibroblast Growth Factor, Type 3
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