Abstract
Craniosynostosis (occurrence: 1/2500 live births) is a result of premature fusion of cranial sutures, leading to alterations of the pattern of cranial growth, resulting in abnormal shape of the head and dysmorphic facial features. In approximately 85% of cases, the disease is isolated and nonsyndromic and mainly involves only one suture. Syndromic craniosynostoses such as Crouzon, Apert, Pfeiffer, Muenke, and Saethre–Chotzen syndromes not only affect multiple sutures, but are also associated with the presence of additional clinical symptoms, including hand and feet malformations, skeletal and cardiac defects, developmental delay, and others. The etiology of craniosynostoses may involve genetic (also somatic mosaicism and regulatory mutations) and epigenetic factors, as well as environmental factors. According to the published data, chromosomal aberrations, mostly submicroscopic ones, account for about 6.7–40% of cases of syndromic craniosynostoses presenting with premature fusion of metopic or sagittal sutures. The best characterized is the deletion or translocation of the 7p21 region containing the TWIST1 gene. The deletions of 9p22 or 11q23-qter (Jacobsen syndrome) are both associated with trigonocephaly. The genes related to the pathogenesis of the craniosynostoses itself are those encoding transcription factors, e.g., TWIST1, MSX2, EN1, and ZIC1, and proteins involved in osteogenic proliferation, differentiation, and homeostasis, such as FGFR1, FGFR2, RUNX2, POR, and many others. In this review, we present the clinical and molecular features of selected craniosynostosis syndromes, genotype–phenotype correlation, family genetic counseling, and propose the most appropriate diagnostic algorithm.
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16 March 2018
In the original article, figures 1 and 2 were inadvertently interchanged initially. The correct figures are as shown below. The original article has been corrected.
References
Agochukwu NB, Solomon BD, Muenke M (2014) Hearing loss in syndromic craniosynostoses: introduction and consideration of mechanisms. Am J Audiol 23(2):135–141. https://doi.org/10.1044/2014_AJA-13-0036
Arnaud-López L, Fragoso R, Mantilla-Capacho J, Barros-Núñez P (2007) Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin Genet 72(5):405–410
Arts H, Knoers N (2013) Cranioectodermal dysplasia. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews® [Internet]. University of Washington, Seattle; 1993–2017. Available online at: https://www.ncbi.nlm.nih.gov/books/NBK154653
Bezniakow N, Gos M, Obersztyn E (2014) The RASopathies as an example of RAS/MAPK pathway disturbances—clinical presentation and molecular pathogenesis of selected syndromes. Dev Period Med 18(3):285–296
Boulet SL, Rasmussen SA, Honein MA (2008) A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet A 146A(8):984–991
Boyadjiev SA; International Craniosynostosis Consortium (2007) Genetic analysis of non-syndromic craniosynostosis. Orthod Craniofac Res 10(3):129–137
Brasil AS, Malaquias AC, Kim CA, Krieger JE, Jorge AA, Pereira AC, Bertola DR (2012) KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: report of another family with metopic craniosynostosis. Am J Med Genet A 158A(5):1178–1184. https://doi.org/10.1002/ajmg.a.35270
Busche A, Graul-Neumann LM, Zweier C, Rauch A, Klopocki E, Horn D (2011) Microdeletions of chromosome 7p21, including TWIST1, associated with significant microcephaly, facial dysmorphism, and short stature. Eur J Med Genet 54(3):256–261. https://doi.org/10.1016/j.ejmg.2011.02.002
Chaudhry A, Sabatini P, Han L, Ray PN, Forrest C, Bowdin S (2015) Heterozygous mutations in ERF cause syndromic craniosynostosis with multiple suture involvement. Am J Med Genet A 167(11):2544–2547
Chawla R, Alden TD, Bizhanova A, Kadakia R, Brickman W, Kopp PA (2015) Squamosal suture craniosynostosis due to hyperthyroidism caused by an activating thyrotropin receptor mutation (T632I). Thyroid 25(10):1167–1172
Chinen Y, Kaname T, Yanagi K, Saito N, Naritomi K, Ohta T (2006) Opitz trigonocephaly C syndrome in a boy with a de novo balanced reciprocal translocation t(3;18)(q13.13;q12.1). Am J Med Genet A 140(15):1655–1657
Cho E, Yang TH, Shin ES, Byeon JH, Kim GH, Eun BL (2013) Saethre–Chotzen syndrome with an atypical phenotype: identification of TWIST microdeletion by array CGH. Childs Nerv Syst 29(11):2101–2104
Chun K, Teebi AS, Jung JH, Kennedy S, Laframboise R, Meschino WS, Nakabayashi K, Scherer SW, Ray PN, Teshima I (2002) Genetic analysis of patients with the Saethre–Chotzen phenotype. Am J Med Genet A 110(2):136–143
Cinalli G, Renier D, Sebag G, Sainte-Rose C, Arnaud E, Pierre-Kahn A (1995) Chronic tonsillar herniation in Crouzon’s and Apert’s syndromes: the role of premature synostosis of the lambdoid suture. J Neurosurg 83(4):575–582
Cohen MM Jr (2000) Saethre–Chotzen syndrome. In: Cohen MM Jr, MacLean RE (eds) Craniosynostosis: diagnosis, evaluation, and management, 2nd edn. Oxford University Press, New York pp 374–376
Cohen MM Jr, Kreiborg S (1992) Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods. Clin Genet 41(1):12–15
Cohen MM Jr, Kreiborg S (1995) Cutaneous manifestations of Apert syndrome. Am J Med Genet 58(1):94–96
Connolly JP, Gruss J, Seto ML, Whelan MF, Ellenbogen R, Weiss A, Buchman SR, Cunningham ML (2004) Progressive postnatal craniosynostosis and increased intracranial pressure. Plast Reconstr Surg 113(5):1313–1323
de Ravel TJ, Taylor IB, Van Oostveldt AJ, Fryns JP, Wilkie AO (2005) A further mutation of the FGFR2 tyrosine kinase domain in mild Crouzon syndrome. Eur J Hum Genet 13(4):503–505
Fenwick AL, Kliszczak M, Cooper F, Murray J, Sanchez-Pulido L, Twigg SR, Goriely A, McGowan SJ, Miller KA, Taylor IB, et al (2016) Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis. Am J Hum Genet. 99(1):125–38. https://doi.org/10.1016/j.ajhg.2016.05.019
Fernandes MB, Maximino LP, Perosa GB, Abramides DV, Passos-Bueno MR, Yacubian-Fernandes A (2016) Apert and Crouzon syndromes—cognitive development, brain abnormalities, and molecular aspects. Am J Med Genet A 170(6):1532–1537. https://doi.org/10.1002/ajmg.a.37640
Gill SK, Broussard C, Devine O, Green RF, Rasmussen SA, Reefhuis J; National Birth Defects Prevention Study (2012) Association between maternal age and birth defects of unknown etiology—United States, 1997–2007. Birth Defects Res A Clin Mol Teratol 94(12):1010–1018. https://doi.org/10.1002/bdra.23049
Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, Johnson D, Walsh S, Oldridge M, Wall SA, Wilkie AO, Jabs EW (2000) Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet 66(3):768–777
Goriely A, Lord H, Lim J, Johnson D, Lester T, Firth HV, Wilkie AO (2000) Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: implications for genetic testing in “paternal age-effect” syndromes. Am J Med Genet A 152A:2067–2073
Gorlin R.et al. (1990) Syndromes of the head and neck. Oxford University Press. New York
Heuzé Y, Holmes G, Peter I, Richtsmeier JT, Jabs EW (2014) Closing the gap: genetic and genomic continuum from syndromic to nonsyndromic craniosynostoses. Curr Genet Med Rep 2(3):135–145
Higashino T, Hirabayashi S (2013) A secondary craniosynostosis associated with juvenile hyperthyroidism. J Plast Reconstr Aesthet Surg 66(10):e284–e286
Hoefkens MF, Vermeij-Keers C, Vaandrager JM (2004) Crouzon syndrome: phenotypic signs and symptoms of the postnatally expressed subtype. J Craniofac Surg 15(2):233–240; discussion 241–2
Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Flück CE, Miller WL (2005) Diversity and function of mutations in P450 oxidoreductase in patients with Antley–Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 76:729–749
Jabs EW, Müller U, Li X, Ma L, Luo W, Haworth IS, Klisak I, Sparkes R, Warman ML, Mulliken JB 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
Jehee FS, Krepischi-Santos AC, Rocha KM, Cavalcanti DP, Kim CA, Bertola DR, Alonso LG, D’Angelo CS, Mazzeu JF, Froyen G, Lugtenberg D, Vianna-Morgante AM, Rosenberg C, Passos-Bueno MR (2008) High frequency of submicroscopic chromosomal imbalances in patients with syndromic craniosynostosis detected by a combined approach of microsatellite segregation analysis, multiplex ligation-dependent probe amplification and array-based comparative genome hybridisation. J Med Genet 45(7):447–450. https://doi.org/10.1136/jmg.2007.057042
Johnson D, Wilkie AO (2011) Craniosynostosis. Eur J Hum Genet 19(4):369–376. https://doi.org/10.1038/ejhg.2010.235
Johnson D, Horsley SW, Moloney DM, Oldridge M, Twigg SR, Walsh S, Barrow M, Njølstad PR, Kunz J, Ashworth GJ, Wall SA, Kearney L, Wilkie AO (1998) A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1. Am J Hum Genet 63(5):1282–1293
Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AO, Stoler J, Richtsmeier JT, Heuzé Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA, Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C, Kim J, Wilson AF, Boyadjiev SA (2012) A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44(12):1360–1364. https://doi.org/10.1038/ng.2463
Justice CM, Kim J, Kim SD, Kim K, Yagnik G, Cuellar A, Carrington B, Lu CL, Sood R, Boyadjiev SA, Wilson AF (2017) A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element. Am J Med Genet A 173(11):2893–2897
Katsianou MA, Adamopoulos C, Vastardis H, Basdra EK (2016) Signaling mechanisms implicated in cranial sutures pathophysiology: craniosynostosis. BBA Clin 6:165–176
Kini U, Hurst JA, Byren JC, Wall SA, Johnson D, Wilkie AO (2010) Etiological heterogeneity and clinical characteristics of metopic synostosis: evidence from a tertiary craniofacial unit. Am J Med Genet A 152A(6):1383–1389. https://doi.org/10.1002/ajmg.a.33435
Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, Oudesluys-Murphy AM, Di Rocco C, Kloska SP, Tartaglia M, Zenker M (2009) Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. Am J Med Genet A 149A(5):1036–1040. https://doi.org/10.1002/ajmg.a.32786
Kreiborg S, Barr M Jr, Cohen MM Jr (1992) Cervical spine in the Apert syndrome. Am J Med Genet 43(4):704–708
Kress W, Schropp C, Lieb G, Petersen B, Büsse-Ratzka M, Kunz J, Reinhart E, Schäfer WD, Sold J, Hoppe F, Pahnke J, Trusen A, Sörensen N, Krauss J, Collmann H (2006) Saethre–Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet 14(1):39–48
Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D (1995) Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet. 55 (4):500–4
Lajeunie E, Bonaventure J, El Ghouzzi V, Catala M, Renier D (2000) Monozygotic twins with Crouzon syndrome: concordance for craniosynostosis and discordance for thumb duplication. Am J Med Genet 91(2):159–160
Lapunzina P, Fernández A, Sánchez Romero JM, Delicado A, Sáenz de Pipaon M, López Pajares I, Molano J (2005) A novel insertion in the FGFR2 gene in a patient with Crouzon phenotype and sacrococcygeal tail. Birth Defects Res A Clin Mol Teratol 73(1):61–64
Mantilla-Capacho JM, Arnaud L, Díaz-Rodriguez M, Barros-Núñez P (2005) Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene. Genet Couns 16(4):403–406
McGillivray G, Savarirayan R, Cox TC, Stojkoski C, McNeil R, Bankier A, Bateman JF, Roscioli T, Gardner RJ, Lamandé SR (2005) Familial scaphocephaly syndrome caused by a novel mutation in the FGFR2 tyrosine kinase domain. J Med Genet 42(8):656–662
Murdoch-Kinch CA, Ward RE (1997) Metacarpophalangeal analysis in Crouzon syndrome: additional evidence for phenotypic convergence with the acrocephalosyndactyly syndromes. Am J Med Genet 73(1):61–66
Pantke OA, Cohen MM Jr, Witkop CJ Jr, Feingold M, Schaumann B, Pantke HC, Gorlin RJ (1975) The Saethre–Chotzen syndrome. Birth Defects Orig Artic Ser 11(2):190–225
Passos-Bueno MR, Serti Eacute AE, Jehee FS, Fanganiello R, Yeh E (2008) Genetics of craniosynostosis: genes, syndromes, mutations and genotype–phenotype correlations. Front Oral Biol 12:107–143. https://doi.org/10.1159/000115035
Quintero-Rivera F, Robson CD, Reiss RE, Levine D, Benson CB, Mulliken JB, Kimonis VE (2006) Intracranial anomalies detected by imaging studies in 30 patients with Apert syndrome. Am J Med Genet A 140(12):1337–1338
Ranger A, Chaudhary N, Matic D (2010) Craniosynostosis involving the squamous temporal sutures: a rare and possibly underreported etiology for cranial vault asymmetry. J Craniofac Surg 21(5):1547–1550
Renier D, Arnaud E, Cinalli G, Sebag G, Zerah M, Marchac D (1996) Prognosis for mental function in Apert’s syndrome. J Neurosurg 85:66–72
Renier D, Lajeunie E, Arnaud E, Marchac D (2000) Management of craniosynostoses. Childs Nerv Syst 16(10–11):645–658
Roscioli T, Flanagan S, Kumar P, Masel J, Gattas M, Hyland VJ, Glass IA (2000) Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature. Am J Med Genet 93(1):22–28
Sharma VP, Fenwick AL, Brockop MS, McGowan SJ, Goos JA, Hoogeboom AJ, Brady AF, Jeelani NO, Lynch SA, Mulliken JB, Murray DJ, Phipps JM, Sweeney E, Tomkins SE, Wilson LC, Bennett S, Cornall RJ, Broxholme J, Kanapin A; 500 Whole-Genome Sequences (WGS500) Consortium, Johnson D, Wall SA, van der Spek PJ, Mathijssen IM, Maxson RE, Twigg SR, Wilkie AO (2013) Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nat Genet 45(3):304–307. https://doi.org/10.1038/ng.2531
Timberlake AT, Furey CG, Choi J, Nelson-Williams C; Yale Center for Genome Analysis, Loring E, Galm A, Kahle KT, Steinbacher DM, Larysz D, Persing JA, Lifton RP (2017) De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis. Proc Natl Acad Sci U S A 114(35):E7341–E7347
Twigg SR, Wilkie AO (2015) New insights into craniofacial malformations. Hum Mol Genet 24(R1):R50–R59. https://doi.org/10.1093/hmg/ddv228
Twigg SR, Versnel SL, Nürnberg G, Lees MM, Bhat M, Hammond P, Hennekam RC, Hoogeboom AJ, Hurst JA, Johnson D, Robinson AA, Scambler PJ, Gerrelli D, Nürnberg P, Mathijssen IM, Wilkie AO (2009) Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J Hum Genet 84(5):698–705. https://doi.org/10.1016/j.ajhg.2009.04.009
Twigg SR, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Sadighi Akha E, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK, Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO (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. https://doi.org/10.1038/ng.2539
Twigg SRF, Hufnagel RB, Miller KA, Zhou Y, McGowan SJ, Taylor J, Craft J, Taylor JC, Santoro SL, Huang T, Hopkin RJ, Brady AF, Clayton-Smith J, Clericuzio CL, Grange DK, Groesser L, Hafner C, Horn D, Temple IK, Dobyns WB, Curry CJ, Jones MC, Wilkie AOM (2016) A recurrent mosaic mutation in SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry–Jones syndrome. Am J Hum Genet 98(6):1256–1265. https://doi.org/10.1016/j.ajhg.2016.04.007
Ueda K, Yamada J, Takemoto O, Okamoto N (2015) Eight patients with Williams syndrome and craniosynostosis. Eur J Med Genet 58(6–7):355–357. https://doi.org/10.1016/j.ejmg.2015.05.002
Vissers LE, Cox TC, Maga AM, Short KM, Wiradjaja F, Janssen IM, Jehee F, Bertola D, Liu J, Yagnik G, Sekiguchi K, Kiyozumi D, van Bokhoven H, Marcelis C, Cunningham ML, Anderson PJ, Boyadjiev SA, Passos-Bueno MR, Veltman JA, Smyth I, Buckley MF, Roscioli T (2011) Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genet 7(9):e1002278. https://doi.org/10.1371/journal.pgen.1002278
von Gernet S, Golla A, Ehrenfels Y, Schuffenhauer S, Fairley JD (2000) Genotype–phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery. Clin Genet 57(2):137–139
Wilkie AO (2000) Epidemiology and genetics of craniosynostosis. Am J Med Genet 90(1):82–84
Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P et al (1995a) Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9(2):165–172
Wilkie AO, Yang SP, Summers D, Poole MD, Reardon W, Winter RM (1995b) Saethre–Chotzen syndrome associated with balanced translocations involving 7p21: three further families. J Med Genet 32(3):174–180
Wilkie AO, Oldridge M, Tang Z, Maxson RE Jr (2001) Craniosynostosis and related limb anomalies. Novartis Found Symp 232:122–133
Wilkie AO, Bochukova EG, Hansen RM, Taylor IB, Rannan-Eliya SV, Byren JC, Wall SA, Ramos L, Venâncio M, Hurst JA, O’rourke AW, Williams LJ, Seller A, Lester T (2007) Clinical dividends from the molecular genetic diagnosis of craniosynostosis. Am J Med Genet A 143A(16):1941–1949
Wilkie AO, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, Lester T, Richards PG, Twigg SR, Wall SA (2010) Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 126(2):e391–e400. https://doi.org/10.1542/peds.2009-3491
Wilkie AOM, Johnson D, Wall SA (2017) Clinical genetics of craniosynostosis. Curr Opin Pediatr 29(6):622–628. https://doi.org/10.1097/MOP.0000000000000542
Zhang W, Taylor SP, Nevarez L, Lachman RS, Nickerson DA, Bamshad M; University of Washington Center for Mendelian Genomics Consortium, Krakow D, Cohn DH (2016) IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome. Hum Mol Genet 25(18):4012–4020. https://doi.org/10.1093/hmg/ddw241
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We would like to thank the patients and their families for their agreement to participate in our studies and to publish their photos. The studies on craniosynostoses is possible thanks to the financial support from the intramural grant of the Institute of Mother and Child.
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Communicated by: Michal Witt
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The original version of this article was revised: In the original article, figures 1 and 2 were inadvertently interchanged initially.
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Kutkowska-Kaźmierczak, A., Gos, M. & Obersztyn, E. Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling. J Appl Genetics 59, 133–147 (2018). https://doi.org/10.1007/s13353-017-0423-4
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DOI: https://doi.org/10.1007/s13353-017-0423-4