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Genetics of Crouzon Syndrome

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
 
Updated: May 06, 2015
 

Background

In 1912, Crouzon described the hereditary syndrome of craniofacial dysostosis in a mother and son. He described the triad of calvarial deformities, facial anomalies, and exophthalmos.

Crouzon syndrome is an autosomal dominant disorder with complete penetrance and variable expressivity.[1] It is characterized by premature closure of calvarial and cranial base sutures as well as those of the orbit and maxillary complex (craniosynostosis).

Other clinical features include hypertelorism, exophthalmos, strabismus, beaked nose, short upper lip, hypoplastic maxilla, and relative mandibular prognathism. Unlike some other forms of autosomal dominant craniosynostosis, no digital abnormalities are present. See the image below.

Child with Crouzon syndrome. Note midfacial hypopl Child with Crouzon syndrome. Note midfacial hypoplasia, proptosis secondary to shallow orbits, and ocular hypertelorism.
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Pathophysiology

See the list below:

  • Crouzon syndrome is caused by mutations in the fibroblast growth factor receptor-2 ( FGFR2) gene but exhibits locus heterogeneity with causal mutations in FGFR2 (Crouzon syndrome) and FGFR3 (Crouzon syndrome with acanthosis nigricans) in different affected individuals.
  • Premature synostosis of the coronal, the sagittal, and, occasionally, the lambdoidal sutures begins in the first year of life and is completed by the second or third year. The order and rate of suture fusion determine the degree of deformity and disability. Once a suture becomes fused, growth perpendicular to that suture becomes restricted, and the fused bones act as a single bony structure. Compensatory growth occurs at the remaining open sutures to allow continued brain growth. However, multiple sutural synostoses frequently extend to premature fusion of the skull base sutures, causing midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, maxillary hypoplasia, and occasional upper airway obstruction.
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Epidemiology

Frequency

United States

  • Prevalence is 1 case per 60,000 (approximately 16.5 cases per million population) live births. [2]
  • Crouzon syndrome is responsible for approximately 4.8% of all cases of craniosynostosis.

Mortality/Morbidity

See the list below:

  • Upper airway obstruction can lead to acute respiratory distress.
  • Increased intracranial pressure and optic atrophy may occur.

Race

See the list below:

  • Crouzon syndrome has no race predilection.

Sex

See the list below:

  • Crouzon syndrome has no known sex predilection.

Age

See the list below:

  • The condition is detected in the newborn or infant period because of dysmorphic features.
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Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Michael Fasullo, PhD Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society, American Society for Biochemistry and Molecular Biology, Genetics Society of America, Environmental Mutagenesis and Genomics Society

Disclosure: Nothing to disclose.

References
  1. Ahmed I, Afzal A. Diagnosis and evaluation of Crouzon syndrome. J Coll Physicians Surg Pak. 2009 May. 19(5):318-20. [Medline].

  2. Cohen MM Jr, Kreiborg S. Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods. Clin Genet. 1992 Jan. 41(1):12-5. [Medline].

  3. Agochukwu NB, Solomon BD, Muenke M. Hearing loss in syndromic craniosynostoses: otologic manifestations and clinical findings. Int J Pediatr Otorhinolaryngol. 2014 Dec. 78(12):2037-47. [Medline].

  4. Cohen MM Jr. Editorial: perspectives on craniosynostosis. Am J Med Genet A. 2005 Aug 1. 136A(4):313-26. [Medline].

  5. Anderson PJ, Hall C, Evans RD. The cervical spine in Crouzon syndrome. Spine. 1997 Feb 15. 22(4):402-5. [Medline].

  6. Hoefkens MF, Vermeij-Keers C, Vaandrager JM. Crouzon syndrome: phenotypic signs and symptoms of the postnatally expressed subtype. J Craniofac Surg. 2004 Mar. 15(2):233-40; discussion 241-2. [Medline].

  7. Reardon W, Winter RM, Rutland P. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994 Sep. 8(1):98-103. [Medline].

  8. Rutland P, Pulleyn LJ, Reardon W. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet. 1995 Feb. 9(2):173-6. [Medline].

  9. Wilkie AO, Slaney SF, Oldridge M. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995 Feb. 9(2):165-72. [Medline].

  10. Di Rocco F, Collet C, Legeai-Mallet L, et al. Crouzon syndrome with acanthosis nigricans: a case-based update. Childs Nerv Syst. 2011 Mar. 27(3):349-54. [Medline].

  11. Muenke M, Gripp KW, McDonald-McGinn DM, et al. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997 Mar. 60(3):555-64. [Medline].

  12. Fenwick AL, Goos JA, Rankin J, et al. Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome. BMC Med Genet. 2014 Aug 31. 15:95. [Medline]. [Full Text].

  13. Arnaud-López L, Fragoso R, Mantilla-Capacho J, Barros-Núñez P. Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin Genet. 2007 Nov. 72(5):405-10. [Medline].

  14. Mir A, Wu T, Orlow SJ. Cutaneous features of crouzon syndrome with acanthosis nigricans. JAMA Dermatol. 2013 Jun 1. 149(6):737-41. [Medline].

  15. Goriely A, Lord H, Lim J, et al. 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. 2010 Aug. 152A(8):2067-73. [Medline].

  16. Tay T, Martin F, Rowe N, Johnson K, Poole M, Tan K. Prevalence and causes of visual impairment in craniosynostotic syndromes. Clin Experiment Ophthalmol. 2006 Jul. 34(5):434-40. [Medline].

  17. Gray TL, Casey T, Selva D, Anderson PJ, David DJ. Ophthalmic sequelae of Crouzon syndrome. Ophthalmology. 2005 Jun. 112(6):1129-34. [Medline].

  18. Taglialatela Scafati C, Aliberti F, Taglialatela Scafati S, Mangone GM, Taglialatela Scafati M. The value of the maxillo-malar osteotomy in the treatment of Crouzon syndrome with exorbitism. Ann Plast Surg. 2008 Sep. 61(3):285-9. [Medline].

  19. Chen H. Crouzon syndrome. Atlas of Genetic Diagnosis and Counseling. 2. New York Dordrecht Heidelberg London: Springer; 2012. Volume 1: 529-535.

  20. Robin NH, Falk MJ, Haldemen-Englert CR. FGFR-related craniosynostosis syndrome. GeneReviews. September, 2007. [Full Text].

  21. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. 2004 Sep. 114(3):889-94. [Medline]. [Full Text].

  22. Schwartz M, Kreiborg S, Skovby F. First-trimester prenatal diagnosis of Crouzon syndrome. Prenat Diagn. 1996 Feb. 16(2):155-8. [Medline].

  23. Abou-Sleiman PM, Apessos A, Harper JC, et al. Pregnancy following preimplantation genetic diagnosis for Crouzon syndrome. Mol Hum Reprod. 2002 Mar. 8(3):304-9. [Medline].

  24. Anderson PJ, Hall C, Evans RD, Harkness WJ, Hayward RD, Jones BM. The cervical spine in Crouzon syndrome. Spine. 1997. 22:402-405.

  25. Bresnick S, Schendel S. Crouzon's disease correlates with low fibroblastic growth factor receptor activity in stenosed cranial sutures. J Craniofac Surg. 1995 May. 6(3):245-8. [Medline].

  26. Chen CP, Lin SP, Su YN, Huang JK, Wang W. A cloverleaf skull associated with Crouzon syndrome. Arch Dis Child Fetal Neonatal Ed. 2006 Mar. 91(2):F98. [Medline].

  27. Cinalli G, Renier D, Sebag G, et al. Chronic tonsillar herniation in Crouzon's and Apert's syndromes: the role of premature synostosis of the lambdoid suture. J Neurosurg. 1995 Oct. 83(4):575-82. [Medline].

  28. Cohen MM. An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic Ser. 1975. 11(2):137-89. [Medline].

  29. Cohen MM Jr. Craniosynostosis update 1987. Am J Med Genet Suppl. 1988. 4:99-148. [Medline].

  30. David DJ, Sheen R. Surgical correction of Crouzon syndrome. Plast Reconstr Surg. 1990 Mar. 85(3):344-54. [Medline].

  31. de Ravel TJ, Taylor IB, Van Oostveldt AJ, et al. A further mutation of the FGFR2 tyrosine kinase domain in mild Crouzon syndrome. Eur J Hum Genet. 2005 Apr. 13(4):503-5. [Medline].

  32. Do Amaral CMR, Di Domizio G, Buzzo CL. Surgical treatment of Apert syndrome and Crouzon anomaly by gradual bone distraction. Online J Plast Reconstr Surg. 1998. 1 July:

  33. Fjortoft MI, Sevely A, Boetto S, et al. Prenatal diagnosis of craniosynostosis: value of MR imaging. Neuroradiology. 2007 Jun. 49(6):515-21. [Medline].

  34. Gorry MC, Preston RA, White GJ. Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. Hum Mol Genet. 1995 Aug. 4(8):1387-90. [Medline].

  35. Hollway GE, Suthers GK, Haan EA. Mutation detection in FGFR2 craniosynostosis syndromes. Hum Genet. 1997 Feb. 99(2):251-5. [Medline].

  36. Jabs EW, Li X, Scott AF, et al. Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet. 1994 Nov. 8(3):275-9. [Medline].

  37. Jarund M, Lauritzen C. Craniofacial dysostosis: airway obstruction and craniofacial surgery. Scand J Plast Reconstr Surg Hand Surg. 1996 Dec. 30(4):275-9. [Medline].

  38. Liptak GS, Serletti JM. Pediatric approach to craniosynostosis [published erratum appears in Pediatr Rev 1999 Jan;20(1):20]. Pediatr Rev. 1998 Oct. 19(10):352; quiz 359. [Medline].

  39. Meyers GA, Day D, Goldberg R. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am J Hum Genet. 1996 Mar. 58(3):491-8. [Medline].

  40. Meyers GA, Orlow SJ, Munro IR. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet. 1995 Dec. 11(4):462-4. [Medline].

  41. Nagase T, Nagase M, Hirose S, Ohmori K. Crouzon syndrome with acanthosis nigricans: case report and mutational analysis. Cleft Palate Craniofac J. 2000 Jan. 37(1):78-82. [Medline].

  42. Park WJ, Meyers GA, Li X. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet. 1995 Jul. 4(7):1229-33. [Medline].

  43. Prevel CD, Eppley BL, McCarty M. Acrocephalosyndactyly syndromes: a review. J Craniofac Surg. 1997 Jul. 8(4):279-85. [Medline].

  44. Wilkes D, Rutland P, Pulleyn LJ. A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. J Med Genet. 1996 Sep. 33(9):744-8. [Medline].

 
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Child with Crouzon syndrome. Note midfacial hypoplasia, proptosis secondary to shallow orbits, and ocular hypertelorism.
 
 
 
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