Sections

Overview

Background

Crouzon syndrome represents the most common syndromic craniosynostosis and was described in 1912 as one of the varieties of craniofacial dysostosis caused by premature obliteration and ossification of two or more sutures, most often coronal and sagittal.^{[1, 2, 3, 4, 5]}Virchow introduced the term craniostenosis.^[6]The type of obliterated sutures determines the type of craniostenosis. Oxycephaly, scaphocephaly, wedge skull, and oblique head are differentiated.^{[1, 3, 4, 6]}Crouzon syndrome with oxycephaly and Apert syndrome with oxycephaly and syndactylia (acrocephalosyndactyly) are the most common types of dysostosis. Some authors connect those syndromes as one, calling it Crouzon-Apert syndrome, but symptomatologic differentiation makes classification difficult. Acanthosis nigricans (shown in the image below) is the main dermatologic manifestation of Crouzon syndrome (see Acanthosis Nigricans).^{[3, 4, 7, 8]}

Acanthosis nigricans of the axillary fossa in Crouzon syndrome.

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Pathophysiology

Dysplasias of the skeleton (including craniofacial dysostosis) are caused by the malformations of the mesenchyme and ectoderm. The unknown teratogenic factors are taken into account. Dysplasias are inherited in an autosomal dominant pattern. Inheritance may come from an affected parent(s), although cases exist in which mutations arise de novo. Mutation of the gene (locus 10q26) for fibroblast growth factor receptor 2 (FGFR2) has been identified as a causative factor for Crouzon syndrome. Typically, the mutations occur on exons 8 or 10. Moreover, the mutation in the transmembrane region of FGFR3 (locus 4p16.3) was detected in this syndrome and was observed in cases with acanthosis nigricans coexistence.^{[2, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]}

Etiology

This syndrome is inherited in an autosomal dominant pattern.^{[3, 18]}

Mutation of FGFR2^C342Y/+ is a marked cause of Crouzon syndrome that is characterized by craniosynostosis and midfacial hypoplasia. Beyond skeletal effects, the FGFR2^C342Y/+ mutation is now implicated in affecting tooth development.^{[18, 20, 21]}

Frequency

The prevalence is very low; Crouzon syndrome is currently estimated to occur in 1 in 25,000 people in the general population.^[4]Crouzon syndrome is rare worldwide.^{[3, 4]}

Race

Race is not noted as a predisposing factor.^[3]

Sex

Sex factor does not play any role.^[3]

Age

Deformation of bony face is visible just after the birth. Other syndrome factors reveal themselves with time.^{[3, 6]}

Prognosis

High intracranial pressure caused by disproportion between craniostenosis and the brain growing may lead to death.^{[1, 3, 6]}

Patient Education

Found to be of high priority among craniofacial microsomia adult patients’ and caregivers’ concerns are etiological understanding, depth and availability of information, and ensuring an accurate diagnosis. Regarding etiology, frequently patients were unsure about the underlying cause. From this misunderstanding, patients were found to self-attribute incorrect origins for the disorder.^[22]

In terms of treatment, patients and caregiver expectations may need to be mitigated. Data and some adult patients having undergone surgical repairs as youths support the idea that parent caregivers may best serve their children by postponing operative intervention until children are older and are able to actively make decisions on their healthcare. Some adult patients also make the case that parents should not project their own apprehensions about the disorder on the children, which may produce negative psychological effects on the afflicted. Medical practitioners should make their best attempts to keep both patients and caregivers involved and informed of treatment plans, risks, alternative approaches where applicable, and follow-up methods of coping should surgery be elected.^{[19, 22, 23, 24]}

Furthermore, providers must exercise caution and precision in their diagnosis of associated breathing disorders. Equivocal usage of choanal atresia and choanal stenosis could add further confusion about not only etiology, but also patient and caregiver beliefs about the success of surgical procedures. Where choanal atresia is responsive to early surgery and may lessen the likelihood of later tracheostomy or continuing management, other obstructions might not be as amenable.^[25]

Clinical Presentation

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Maeda T, Hatakenaka M, Muta H, Nakayama M, Nakazaki Y, Hiroyama T, et al. Clinically mild, atypical, and aged craniofacial syndrome is diagnosed as Crouzon syndrome by identification of a point mutation in the fibroblast growth factor receptor 2 gene (FGFR2). Intern Med. 2004 May. 43(5):432-5. [QxMD MEDLINE Link].
Miklaszewska M. Dysostosis cranio-facialis hederitaria. Miklaszewska M, Wasik F, eds. Dermatologia Pediatryczna. Wrocaw, Poland: Volumed; 2000. Vol 2: 650-4.
Miklaszewska M, Racawska A, Ziarkiewicz M. Syndroma Crouzon and syndromal acanthosis nigricans. Demonstration of case on the meeting of Polish Dermatological Society. February 1990.
Simonin A, Maduri R, Viaroli E, Levivier M, Daniel RT, Messerer M. Correlation between Papilledema and Intracranial Hypertension in Crouzon Syndrome: A Case Report and Review of the Literature. Pediatr Neurosurg. 2019 Jul 3. 1-5. [QxMD MEDLINE Link].
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Kress W, Collmann H, Büsse M, Halliger-Keller B, Mueller CR. Clustering of FGFR2 gene mutations inpatients with Pfeiffer and Crouzon syndromes (FGFR2-associated craniosynostoses). Cytogenet Cell Genet. 2000. 91(1-4):134-7. [QxMD MEDLINE Link].
Wilkes D, Rutland P, Pulleyn LJ, Reardon W, Moss C, Ellis JP, et al. 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. [QxMD MEDLINE Link].
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Al-Namnam NM, Hariri F, Thong MK, Rahman ZA. Crouzon syndrome: Genetic and intervention review. J Oral Biol Craniofac Res. 2019 Jan-Mar. 9 (1):37-39. [QxMD MEDLINE Link].
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Barik M, Bajpai M, Malhotra A, Samantaray JC, Dwivedi S, Das S. Genome-Wide Association Study in Craniosynostosis Condition Using Innovative Systematic Bioinformatic Analysis Tools and Techniques: Future Prospective and Clinical Practice. J Pediatr Neurosci. 2018 Apr-Jun. 13 (2):170-175. [QxMD MEDLINE Link].
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Bemmels H, Biesecker B, Loewenstein J, Krokosky A, Guidotti R, Sutton EJ. Psychological and Social Factors in Undergoing Reconstructive Surgery Among Individuals with Craniofacial Conditions: An Exploratory Study. Cleft Palate Craniofac J. 2012 Feb 8. [QxMD MEDLINE Link].
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Lesciotto KM, Heuzé Y, Jabs EW, Bernstein JM, Richtsmeier JT. Choanal Atresia and Craniosynostosis: Development and Disease. Plast Reconstr Surg. 2018 Jan. 141 (1):156-168. [QxMD MEDLINE Link].
Cohen MM Jr. Let's call it "Crouzonodermoskeletal syndrome" so we won't be prisoners of our own conventional terminology. Am J Med Genet. 1999 May 7. 84(1):74. [QxMD MEDLINE Link].
Ernyei S. Craniofacial dysplasia associated with congenital cataract, impairment of hearing and brachydactyly. Am J Ophthalmol. 1966 Oct. 62(4):697-702. [QxMD MEDLINE Link].
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LeBlanc S, David D, Colley A, Buckley M, Roscioli T, Barnett C. Atypical Skin Manifestations in FGFR2-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum. Mol Syndromol. 2018 May. 9 (3):149-153. [QxMD MEDLINE Link].
Birgfeld CB, Heike CL, Saltzman BS, Leroux BG, Evans KN, Luquetti DV. Reliable classification of facial phenotypic variation in craniofacial microsomia: a comparison of physical exam and photographs. Head Face Med. 2016 Mar 31. 12:14. [QxMD MEDLINE Link].
Panuganti BA, Leach M, Antisdel J. Bilateral meningoencephaloceles with cerebrospinal fluid rhinorrhea after facial advancement in the Crouzon syndrome. Allergy Rhinol (Providence). 2015 Jan. 6 (2):138-42. [QxMD MEDLINE Link].
Prasad M, Shetty AS, Shantaram M. The crouzan syndrome-a case report. J Clin Diagn Res. 2013 May. 7 (5):959-61. [QxMD MEDLINE Link].
Pal US, Gupta C, Chellappa AA. Crouzon syndrome with primary optic nerve atrophy and normal brain functions: A case report. J Oral Biol Craniofac Res. 2012 May-Aug. 2 (2):116-8. [QxMD MEDLINE Link].
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Cinalli G, Renier D, Sebag G, Sainte-Rose C, Arnaud E, Pierre-Kahn A. 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. [QxMD MEDLINE Link].
Canpolat A, Akçakaya MO, Altunrende E, Ozlü HM, Duman H, Ton T, et al. Chiari Type I malformation yielded to the diagnosis of Crouzon syndrome. J Neurosci Rural Pract. 2014 Jan. 5 (1):81-3. [QxMD MEDLINE Link].
Maximino LP, Ducati LG, Abramides DVM, Corrêa CC, Garcia PF, Fernandes AY. Syndromic craniosynostosis: neuropsycholinguistic abilities and imaging analysis of the central nervous system. Arq Neuropsiquiatr. 2017 Dec. 75 (12):862-868. [QxMD MEDLINE Link].
Nørgaard P, Hagen CP, Hove H, Dunø M, Nissen KR, Kreiborg S, et al. Crouzon syndrome associated with acanthosis nigricans: prenatal 2D and 3D ultrasound findings and postnatal 3D CT findings. Acta Radiol Short Rep. 2012. 1 (4):[QxMD MEDLINE Link].
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Lu X, Jorge Forte A, Sawh-Martinez R, Wu R, Cabrejo R, Steinbacher DM, et al. Association of Regional Cranial Base Deformity and Ultimate Structure in Crouzon Syndrome. Plast Reconstr Surg. 2019 Jun. 143 (6):1233e-1243e. [QxMD MEDLINE Link].
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Media Gallery

Acrocephaly, beaked nose, "frog face," and pseudoprognathism of Crouzon syndrome.
Malposed teeth and acanthosis nigricans around the mouth in Crouzon syndrome.
No physiological spinal curvature is observed in Crouzon syndrome.
Acanthosis nigricans of the axillary fossa in Crouzon syndrome.
Short stature and dark skin of Crouzon syndrome.

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Author

Amarateedha Prak LeCourt, MD Resident Physician, Department of Anesthesiology, Naval Medical Center San Diego; Naval Flight Surgeon/Fleet Marine Force Qualified Officer, US Navy

Amarateedha Prak LeCourt, MD is a member of the following medical societies: Aerospace Medical Association, Association of Military Surgeons of the US

Disclosure: Nothing to disclose.

Coauthor(s)

Kristina Marie Dela Rosa, MD Dermatologist, Insight Dermatology, San Diego, CA

Kristina Marie Dela Rosa, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association

Disclosure: Nothing to disclose.

Homavirak Prak, BA Emergency Medical Technician, Basic AirCare Ambulance; Medical Scribe, Progeny Psychiatric Group

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

Grazyna Szybejko-Machaj, MD, PhD Assistant Professor, Department of Dermatology, Wroclaw Medical University

Disclosure: Nothing to disclose.

Lukasz Matusiak, MD, PhD Assistant, Department and Clinic of Dermatology, Venereology and Allergology, Medical University of Wroclaw

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Mieczyslawa Miklaszewska, MD, to the development and writing of this article.

Crouzon Syndrome

Background

Pathophysiology

Etiology

Epidemiology

Frequency

Race

Sex

Age

Prognosis

Patient Education

References

Tables

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