Molecular Genetics of Craniosynostosis


Craniosynostosis (CS) is a relatively prevalent congenital malformation, due to the premature ossification of calvarial sutures that articulate skull bones, leading to a variable alteration of craniofacial landmarks and shape. CS is extremely heterogeneous in both clinical and a etiological aspects. It occurs as an isolated defect (i.e. nonsyndromic) in most cases, while it is syndromic in less than one fourth of cases. A genetic aetiology (i.e. mutations in FGFR, TWIST1, EFNB1, MSX, and ERF genes, among others) is known for most syndromes. Recent studies helped clarifying the genetic basis of new CS syndromes and nonsyndromic forms. The discovery of new genes (including RUNX2, ALX4, TCF12 and ZIC1) enabled deciphering the complex signalling network that orchestrates craniofacial development. In this light, the entire CS disease spectrum can be regarded as a nosological continuum, with variable degree of severity, in which a strong genetic component provides the background for environmental factors that contribute to the aetiopathogenesis of the birth defect.

Key Concepts

  • Craniosynostosis is a frequent congenital defect with a high degree of clinical and genetic heterogeneity.
  • Nonsyndromic forms are more frequent, although their aetiology is still poorly understood.
  • Many developmental syndromes include craniosynostosis in their phenotype.
  • Different closely interacting genes (FGFR, TWIST1, MSX2, ERF, TCF12, among others) are involved in the molecular genetics of the best characterised and more frequent syndromic craniosynostoses.
  • Most genes involved in the etiopathogenesis of craniosynostosis interact within a common gene network.

Keywords: craniosynostosis; sutures; FGFR; TWIST1; TCF12; ERF; MSX2; Eph‐ephrin; neural crest; craniofacial development

Figure 1. Craniosynostosis gene network. The diagram shows the network of known and predicted interactions among genes associated to CS phenotypes and syndromes (listed in Table ). The network was drawn using String (version 10.0) license‐free software (http://string‐ Colored nodes refer to gene/protein symbol included in the query; small nodes are for proteins with unknown 3D structure while large nodes are for those with known structures. Edges among nodes represent interactions: known interactions are in purple (experimental evidence) or light blue (data gathered from curated datasets); light green edges indicate interactions inferred from text‐mining in scientific literature. Functional annotations of the entire gene set, according to Gene Ontology (GO) consortium specifications, are provided in the table on the right.


Boyadjiev SA and International Craniosynostosis Consortium (2007) Genetic analysis of non‐syndromic craniosynostosis. Orthodontics & Craniofacial Research 10 (3): 129–137.

Brewer JR, Mazot P and Soriano P (2016) Genetic insights into the mechanisms of Fgf signaling. Genes and Development 30 (7): 751–771.

Chai Y and Maxson RE Jr (2006) Recent advances in craniofacial morphogenesis. Developmental Dynamics 235 (9): 2353–2375.

Chun K, Teebi AS, Jung JH, et al. (2002) Genetic analysis of patients with the Saethre‐Chotzen phenotype. American Journal of Medical Genetics 110: 136–143.

Cohen MM (2000) Craniosynostosis: Diagnosis, Evaluation, and Management. New York: Oxford University Press.

Cunningham ML, Horst JA, Rieder MJ, et al. (2011) IGF1R variants associated with isolated single suture craniosynostosis. American Journal of Medical Genetics. Part A 155A (1): 91–97.

Di Rocco F, Arnaud E, Meyer P, Sainte‐Rose C and Renier D (2009) Focus session on the changing “epidemiology” of craniosynostosis (comparing two quinquennia: 1985–1989 and 2003–2007) and its impact on the daily clinical practice: a review from Necker Enfants Malades. Child's Nervous System 25 (7): 807–811.

Di Rocco F, Baujat G, Arnaud G, et al. (2014) Clinical spectrum and outcomes in families with coronal synostosis and TCF12 mutations. Eur J Hum Genet 22: 1413–1416.

Dollfus H, Biswas P, Kumaramanickavel G, et al. (2002) Saethre‐Chotzen syndrome: notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation. American Journal of Medical Genetics 109: 218–225.

Florisson JM, Verkerk AJ, Huigh D, et al. (2013) Boston type craniosynostosis: report of a second mutation in MSX2. American Journal of Medical Genetics. Part A 161A (10): 2626–2633.

Greives MR, Odessey EA, Waggoner DJ, et al. (2013) RUNX2 quadruplication: additional evidence toward a new form of syndromic craniosynostosis. Journal of Craniofacial Surgery 24 (1): 126–129.

Hajihosseini MK (2008) Fibroblast growth factor signaling in cranial suture development and pathogenesis. Frontiers of Oral Biology 12: 160–177.

Hall J, Jheon AH, Ealba EL, et al. (2014) Evolution of a developmental mechanism: species‐specific regulation of the cell cycle and the timing of events during craniofacial osteogenesis. Developmental Biology 385 (2): 380–395.

Hornik C, Brand‐Saberi B, Rudloff S, Christ B and Füchtbauer EM (2004) Twist is an integrator of SHH, FGF, and BMP signaling. Anatomy and Embryology (Berlin) 209 (1): 31–39.

Hufnagel RB, Zimmerman SL, Krueger LA, et al. (2016) A new frontonasal dysplasia syndrome associated with deletion of the SIX2 gene. American Journal of Medical Genetics. Part A 170A (2): 487–491.

Jabs EW, Müller U, Li X, et al. (1993) A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75 (3): 443–450.

Janssen A, Hosen MJ, Jeannin P, et al. (2013) Second family with the Boston‐type craniosynostosis syndrome: novel mutation and expansion of the clinical spectrum. American Journal of Medical Genetics. Part A 161A (9): 2352–2357.

Johnson D and Wilkie AO (2011) Craniosynostosis. European Journal of Human Genetics 19 (4): 369–376.

Justice CM, Yagnik G, Kim Y, et al. (2012) A genome‐wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nature Genetics 44 (12): 1360–1364.

Kini U, Hurst JA, Byren JC, et al. (2010) Etiological heterogeneity and clinical characteristics of metopic synostosis: evidence from a tertiary craniofacial unit. American Journal of Medical Genetics. Part A 152A (6): 1383–1389.

Ko JM, Jeong SY, Yang JA, Park DH and Yoon SH (2012) Molecular genetic analysis of TWIST1 and FGFR3 genes in Korean patients with coronal synostosis: identification of three novel TWIST1 mutations. Plast Reconstr Surg 129 (5): 814e–821e.

Kress W, Petersen B, Collmann H and Grimm T (2000) An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non‐syndromic trigonocephaly. Cytogenetics and Cell Genetics 91 (1–4): 138–140.

Lajeunie E, Le Merrer M, Bonaïti‐Pellie C, Marchac D and Renier D (1995) Genetic study of nonsyndromic coronal craniosynostosis. American Journal of Medical Genetics 55 (4): 500–504.

Lajeunie E, Crimmins DW, Arnaud E and Renier D (2005) Genetic considerations in nonsyndromic midline craniosynostoses: a study of twins and their families. Journal of Neurosurgery 103 (4 Suppl): 353–356.

Lakin GE, Sinkin JC, Chen R, Koltz PF and Girotto JA (2012) Genetic and epigenetic influences of twins on the pathogenesis of craniosynostosis: a meta‐analysis. Plastic and Reconstructive Surgery 129 (4): 945–954.

Lattanzi W, Bukvic N, Barba M, et al. (2012) Genetic basis of single‐suture synostoses: genes, chromosomes and clinical implications. Child's Nervous System 28 (9): 1301–1310.

Lattanzi W, Barba M, Novegno F, et al. (2013) Lim mineralization protein is involved in the premature calvarial ossification in sporadic craniosynostoses. Bone 52 (1): 474–484.

McDonald‐McGinn DM, Feret H, Nah HD, et al. (2010) Metopic craniosynostosis due to mutations in GLI3: a novel association. American Journal of Medical Genetics. Part A 152A (7): 1654–1660.

McGillivray G, Savarirayan R, Cox TC, et al. (2005) Familial scaphocephaly syndrome caused by a novel mutation in the FGFR2 tyrosine kinase domain. Journal of Medical Genetics 42 (8): 656–662.

Mefford HC, Shafer N, Antonacci F, et al. (2010) Copy number variation analysis in single‐suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis. American Journal of Medical Genetics. Part A 152A (9): 2203–2210.

Merrill AE, Bochukova EG, Brugger SM, et al. (2006) Cell mixing at a neural crest‐mesoderm boundary and deficient ephrin‐Eph signaling in the pathogenesis of craniosynostosis. Hum Mol Genet 15 (8): 1319–1328.

Moloney DM, Wall SA, Ashworth GJ, et al. (1997) Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis. Lancet 349 (9058): 1059–1062.

Moosa S and Wollnik B (2016) Altered FGF signalling in congenital craniofacial and skeletal disorders. Seminars in Cell and Developmental Biology 53: 115–125.

Nieminen P, Morgan NV, Fenwick AL, et al. (2011) Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. American Journal of Human Genetics 89 (1): 67–81.

Passos‐Bueno MR, Serti Eacute AE, Jehee FS, Fanganiello R and Yeh E (2008) Genetics of craniosynostosis: genes, syndromes, mutations and genotype‐phenotype correlations. Frontiers of Oral Biology 12: 107–143.

Paznekas WA, Cunningham ML, Howard TD, et al. (1998) Genetic heterogeneity of Saethre‐Chotzen syndrome, due to TWIST and FGFR mutations. American Journal of Human Genetics 62: 1370–1380.

Perdomo‐Sabogal A, Kanton S, Walter MB and Nowick K (2014) The role of gene regulatory factors in the evolutionary history of humans. Current Opinion in Genetics and Development 29: 60–67.

Persing JA, Jane JA and Shaffrey M (1989) Virchow and the pathogenesis of craniosynostosis: a translation of his original work. Plastic and Reconstructive Surgery 83 (4): 738–742.

Reardon W, Wilkes D, Rutland P, et al. (1997) Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis. Journal of Medical Genetics 34 (8): 632–636.

Selber J, Reid RR, Chike‐Obi CJ, et al. (2008) The changing epidemiologic spectrum of single‐suture synostoses. Plastic and Reconstructive Surgery 122 (2): 527–533.

Sharma VP, Fenwick AL, Brockop MS, et al. (2013) Mutations in TCF12, encoding a basic helix‐loop‐helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nature Genetics 45 (3): 304–307.

Takenouchi T, Hida M, Sakamoto Y, et al. (2013) Severe congenital lipodystrophy and a progeroid appearance: mutation in the penultimate exon of FBN1 causing a recognizable phenotype. American Journal of Medical Genetics. Part A 161A (12): 3057–3062.

Twigg SR, Vorgia E, McGowan SJ, et al. (2013) Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat Genet 45 (3): 308–313.

Twigg SR, Forecki J, Goos JA, et al. (2015) Gain‐of‐Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability. Am J Hum Genet 97 (3): 378–388.

Ursitti F, Fadda T, Papetti L, et al. (2011) Evaluation and management of nonsyndromic craniosynostosis. Acta Paediatrica 100 (9): 1185–1194.

van der Meulen J, van der Hulst R, van Adrichem L, et al. (2009) The increase of metopic synostosis: a pan‐European observation. The Journal of Craniofacial Surgery 20 (2): 283–286.

Varvagiannis K, Stefanidou A, Gyftodimou Y, et al. (2013) Pure de novo partial trisomy 6p in a girl with craniosynostosis. Am J Med Genet A 161A: 343–351.

Wilkie AO, Bochukova EG, Hansen RM, et al. (2007) Clinical dividends from the molecular genetic diagnosis of craniosynostosis. American Journal of Medical Genetics. Part A 143A (16): 1941–1949.

Wilkie AO, Byren JC, Hurst JA, et al. (2010) Prevalence and complications of single‐gene and chromosomal disorders in craniosynostosis. Pediatrics 126 (2): e391–e400.

Yagnik G, Ghuman A, Kim S, et al. (2012) ALX4 gain‐of‐function mutations in nonsyndromic craniosynostosis. Human Mutation 33 (12): 1626–1629.

Ye X, Guilmatre A, Reva B, et al. (2016) Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis. Plastic and Reconstructive Surgery 137 (3): 952–961.

Further Reading

Heuzé Y, Holmes G, Peter I, Richtsmeier JT and Jabs EW (2014) Closing the gap: genetic and genomic continuum from syndromic to nonsyndromic craniosynostoses. Current Genetic Medicine Reports 2 (3): 135–145.

Twigg SR and Wilkie AO (2015a) A genetic‐pathophysiological framework for craniosynostosis. American Journal of Human Genetics 97 (3): 359–377. DOI: 10.1016/j.ajhg.2015.07.006.

Twigg SR and Wilkie AO (2015b) New insights into craniofacial malformations. Human Molecular Genetics 24 (R1): R50–R59. DOI: 10.1093/hmg/ddv228. Epub 2015 Jun 17.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lattanzi, Wanda(Nov 2016) Molecular Genetics of Craniosynostosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025186]