• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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Crouzon Syndrome

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Last updated: 7/25/2023
Years published: 1987, 1990, 1992, 1999, 2000, 2003, 2007, 2016, 2019, 2023


Acknowledgment

NORD gratefully acknowledges Nathaniel H. Robin, MD, Professor, Department of Genetics and Pediatrics, University of Alabama at Birmingham, for assistance in the preparation of this report.


Disease Overview

Summary

Crouzon syndrome is a rare genetic disorder. It is a form of craniosynostosis, a condition in which there is premature fusion of the fibrous joints (sutures) between certain bones of the skull. The sutures allow an infant’s head to grow and expand. Eventually, these bones fuse together to form the skull. In Crouzon syndrome, the sutures fuse prematurely affecting the proper growth of the skull and head and potentially altering the shape and development of the skull. Certain bones in the face may be affected as well. The severity of craniosynostosis can be different in one infant when compared to another. Symptoms primarily include differences of the face and head. Intelligence is usually not affected. Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, usually FGFR2, and is inherited in an autosomal dominant pattern.

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Synonyms

  • craniofacial dysostosis
  • craniostenosis, Crouzon type
  • Crouzon craniofacial dysostosis
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Signs & Symptoms

Crouzon syndrome, also known as craniofacial dysostosis, is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis) and distinctive facial features. Cranial and facial malformations may vary, ranging from mild to potentially severe, including among members of the same family (kindred).

For example, the degree of cranial malformation is variable and depends on the specific cranial sutures involved as well as the order and rate of progression. In most affected individuals, there is premature fusion of the sutures (i.e., coronal and sagittal sutures) between bones forming the forehead (frontal bone) and the upper sides of the skull (parietal bones). In addition, the suture between the back and the sides of the skull (i.e., lambdoidal suture) or other sutures may be involved in some people. In most individuals with Crouzon syndrome, early sutural fusion causes the head to appear unusually short and broad (brachycephaly). In other patients, the head may appear long and narrow (scaphocephaly) or triangular (trigonocephaly). Rarely, premature closure of multiple sutures (known as Kleeblattschadel type craniosynostosis) causes the skull to be divided into three lobes (cloverleaf skull deformity). In children with Crouzon syndrome, craniosynostosis typically begins during the first year of life and progresses until approximately age two to three. However, craniosynostosis may sometimes be apparent at birth or, more rarely, may not be noted during early childhood.
In most individuals, there is unusual shallowness of the orbits or the bony cavities of the skull that accommodate the eyeballs. As a result, the eyeballs appear to protrude or bulge forward (proptosis). Affected individuals are unusually susceptible to developing inflammation of the front, transparent regions of the eyes (i.e., exposure keratitis) as well as the membranes that line the inner surfaces of the eyelids and cover the whites of the eyes (exposure conjunctivitis). This effect is most apparent before 2 years of life. Crouzon syndrome is also often associated with additional eye characteristics including eyes that are spaced apart wider than usual (hypertelorism) and eyes that are crossed or do not point in the same direction (strabismus), which could be due to the shape of the orbit, or abnormalities in the muscles attached to the eye (anomalous extraocular muscles). There is also a higher incidence of refractive errors than in the general population. In over 1/3 of individuals, the various eye abnormalities can lead to a loss in vision.

Crouzon syndrome is associated with additional craniofacial characteristics. Affected individuals often have a prominent forehead (frontal bossing); a curved nose; unusually flat or underdeveloped mid-facial regions (midface hypoplasia); and a short upper lip. In addition, a small, underdeveloped upper jaw (hypoplastic maxilla) with protrusion of the lower jaw (relative mandibular prognathism) may also occur. Clefting of the lip and/or palate (incomplete closure of the palate or an abnormal groove in the upper lip) can occur rarely. Typical dental problems include a highly arched narrow palate with crowded teeth, and upper and lower teeth that don’t meet when biting (malocclusion).
Approximately 30% of individuals with Crouzon syndrome develop hydrocephalus, a condition which is characterized by impaired flow or absorption of the fluid (i.e., cerebrospinal fluid [CSF]) that circulates through cavities (ventricles) of the brain and the spinal canal, potentially leading to increasing fluid pressure within the skull (intracranial pressure) and the brain and other associated findings.

Some affected individuals have hearing impairment due to an inability to transmit sound impulses to the brain (sensorineural hearing loss). In some infants, breathing problems may occur during the first few years due to a greatly reduced cross-sectional area of the airway. In severe instances, this can lead to life-threatening breathing complications, requiring creation of a surgical airway (tracheostomy).

While extracranial manifestations in Crouzon syndrome are not as common as with other craniosynostosis syndromes, up to 1/3 of individuals can have C2-C3 vertebral fusion.

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Causes

Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, most commonly FGFR2. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

The variants in the FGFR gene that cause Crouzon syndrome are inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. .

In most individuals, the disorder occurs because of spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR). Variants that disrupt the functioning of such proteins may result in abnormalities of bone growth and development, ultimately leading to certain malformations of the craniofacial area. Evidence indicates that different variants in the FGFR2 gene may cause several other related disorders, including Apert syndrome, isolated coronal synostosis, Beare-Stevenson syndrome, Pfeiffer syndrome and Jackson-Weiss syndrome. In addition, according to some reports, certain FGFR2 variants may result in Crouzon syndrome in some families, whereas the same variants cause Pfeiffer syndrome in other families. The implications of such findings are not completely understood. (For further information on these disorders, please see the “Related Disorders” section of this report below.)

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Affected populations

Crouzon syndrome affects males and females. Some articles in the medical literature report that males are affected more often than females. Crouzon syndrome is estimated to affect about 1.6 in 100,000 people in the general population. All forms of craniosynostosis are estimated to affect about 1 in 2,000-2,5000 live births.

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Diagnosis

Crouzon syndrome is usually diagnosed at birth or during infancy based upon a thorough clinical evaluation, identification of characteristic physical findings and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) or other imaging studies.

Clinical Testing and Workup


CT scanning and MRIs are used to help detect or characterize certain abnormalities that may be associated with the disorder (e.g., craniosynostosis, other skeletal abnormalities, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues. Molecular genetic testing can confirm a diagnosis of Crouzon syndrome in some people. Molecular genetic testing can detect variants in the FGFR2 gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories.

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Standard Therapies

Treatment
The treatment of Crouzon syndrome is directed toward the specific symptoms that are apparent in each individual. Surgery is the main form of therapy for affected children, but not all children will require surgery. Surgery is performed to create and ensure that there is enough room within the skull for the developing brain to grow; to relieve intracranial pressure (if present); and to improve the appearance of an affected child’s head. If determined necessary, these surgeries may begin during infancy, with the last of them taking place during teenage years.

Affected children should be seen at craniofacial clinics, which are often affiliated with major pediatric hospitals or medical centers. These clinics have a team of physicians and other healthcare providers who are experienced in treating craniofacial disorders. A team of specialists will work together to plan and carry out a child’s treatments. Such specialists include pediatricians, neurosurgeons, plastic surgeons, otolaryngologists, medical geneticists, audiologists, ophthalmologists, dental specialists, social workers and other healthcare professionals. Genetic evaluation is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Jones KL, Jones MC, del Campo Casanelles. Eds. Crouzon syndrome (craniofacial dysostosis). In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:540.
Long MD, Lin KYK. Crouzon Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:710-711.

JOURNAL ARTICLES
Bhattacharjee K, Rehman O, Venkatraman V, et al. Crouzon syndrome and the eye: An overview. Indian J Ophthalmol. 2022;70(7):2346-2354.

Raffaini M, Magri AS, Genitori L, Arcuri F. Algorithm to the treatment of Crouzon syndrome. J Craniomaxillofac Surg. 2022;50(2):124-133.

Lu X, Forte AJ, Park KE, et al. Airway growth in preoperative patients with Crouzon syndrome. Facial Plast Surg Aesthet Med. 2021;23(3):191-197.

Chung SA, Lee SY. Anomalous extraocular muscles in Crouzon syndrome with V-pattern exotropia. Indian J Ophthalmol. 2020;68(5):924-926.

Al-Namnam NM, Hariri F, Thong MK, Rahman ZA. Crouzon syndrome: Genetic and intervention review. J Oral Biol Craniofac Res. 2019;9(1):37-39.

Lu X, Forte AJ, Sawh-Martinez R, et al. Orbit, zygoma, and maxilla growth patterns in Crouzon syndrome. Int J Oral Maxillofac Surg. 2019;48(3):309-321.

Coll G, Sakka L, Botella C, et al. Pattern of closure of skull base synchondroses in Crouzon syndrome. World Neurosurg. 2018;109:e460-e467.

Abu-Sittah GS, Jeelani O, Dunaway D, Hayward R. Raised intracranial pressure in Crouzon syndrome: incidence, causes, and management. J Neurosurg Pediatr. 2016;17:469-475. https://www.ncbi.nlm.nih.gov/pubmed/26613275

Agochukwu NB Solomon BD, Muenke M. Hearing loss in syndromic craniosynostosis: otologic manifestations and clinical findings. Int J Pediatr Otorhinolaryngol. 2014;78:2037-2047. https://www.ncbi.nlm.nih.gov/pubmed/25441602

Helman SN, Badhey A, Kadakia S, Myers E. Revisiting Crouzon syndrome: reviewing the background and management of multifaceted disease. Oral Maxillofac Surg. 2014;18:373-379. https://www.ncbi.nlm.nih.gov/pubmed/25245177

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;15:95. https://www.ncbi.nlm.nih.gov/pubmed/25174698

Fischer S, Tovetjarn R, Maltese G, et al. Psychosocial conditions in adults with Crouzon syndrome: a follow-up study of 31 Swedish patients. J Plast Surg Hand Surg. 2014;48:244-247. https://www.ncbi.nlm.nih.gov/pubmed/24328900

Reitsma JH, Balk-Leurs IH, Ongkosuwito EM, Wattel E, Prahl-Andersen B. Dental maturation in children with the syndrome of Crouzon and Apert. Cleft Palate Craniofac J. 2014;51:639-644. https://www.ncbi.nlm.nih.gov/pubmed/24021057

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 “parental age-effect” syndromes. Am J Med Genet. 2010;152A:2067-2073. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988406/

INTERNET
Wenger T, Miller D, Evans K. FGFR Craniosynostosis Syndromes Overview. 1998 Oct 20 [Updated 2020 Apr 30]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1455/ Accessed July 25, 2023.

Arnaud E, Collet C, Di Rocco F. Crouzon disease. Orphanet. November 2013. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=207#:~:text=The%20facial%20dysmorphology%20is%20characterized,only%20slightly%20visible%20at%20birth.
 Accessed July 25, 2023.

Genetics Home Reference website. Crouzon syndrome. Jan 2023. Available at: https://medlineplus.gov/genetics/condition/crouzon-syndrome/  Accessed July 25, 2023.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:123500; Last Update:05/15/2019. Available at: https://omim.org/entry/123500  Accessed July 25, 2023.

Firth HV. Craniosynostosis syndromes. UpToDate, Inc. Last updated: Jan 27, 2023. Available at: https://www.uptodate.com/contents/craniosynostosis-syndromes Accessed July 25, 2023.

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