eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Crouzon Syndrome

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Sep 10, 2009

Introduction

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.

    Child with Crouzon syndrome. Note midfacial hypo...

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

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    Child with Crouzon syndrome. Note midfacial hypo...

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

Pathophysiology

  • 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.

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

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

Race

  • Crouzon syndrome has no race predilection.

Sex

  • Crouzon syndrome has no known sex predilection.

Age

  • The condition is detected in the newborn or infant period because of dysmorphic features.

Clinical

History

  • Family history may reveal individuals with mild Crouzon syndrome.
  • Craniofacial abnormalities are often present at birth and may progress with time.
  • Decreased mental function is present in approximately 12% of the patients.
  • Headaches and failing vision are attributable to elevated intracranial pressure.
  • Visual disturbance can result from corneal injury due to exposed conjunctivitis or keratitis.
  • Conductive deafness is common because of ear canal stenosis or atresia.
  • Upper airway obstruction develops secondary to septal deviation, mid nasal abnormalities, choanal abnormalities, and nasopharyngeal narrowing.
  • Ménière disease and seizures may develop.

Physical

  • Skull
    • Craniosynostosis: Craniosynostosis commonly begins during the first year of life and usually completes by the second or third year. Coronal and sagittal sutures are most commonly involved, resulting in acrocephaly, brachycephaly, turricephaly, oxycephaly, flat occiput, and high prominent forehead with or without frontal bossing. Ridging of the skull is usually palpable. Cloverleaf skull is rare (only 7%) and occurs in the most severely affected individuals.3
    • Flattened sphenoid bone
    • Shallow orbits
    • Hydrocephalus (progressive in 30%)
  • Face: Midface (maxillary) hypoplasia may be present.
  • Eyes
    • Exophthalmos (proptosis) secondary to shallow orbits resulting in frequent exposure conjunctivitis or keratitis
    • Ocular hypertelorism
    • Divergent strabismus
    • Rare occurrence of nystagmus, iris coloboma, aniridia, anisocoria, microcornea, megalocornea, cataract, ectopia lentis, blue sclera, glaucoma, luxation of the eye globes, papilledema, and optic atrophy from raised intracranial pressure leading to blindness
  • Nose
    • Beaked appearance
    • Compressed nasal passage
    • Choanal atresia or stenosis
    • Deviated nasal septum
  • Mouth
    • Mandibular prognathism
    • Overcrowding of upper teeth, malocclusions, and V-shaped maxillary dental arch
    • Narrow, high, or cleft palate and bifid uvula
    • Occasional oligodontia, macrodontia, peg-shaped, and widely spaced teeth
  • Ears
    • Narrow or absent ear canals
    • Deformed middle ears
  • Other skeletal features
    • Cervical fusion (18%), C2-C3, C3-C4, and C5-C64
    • Block fusions involving multiple vertebrae
    • Subluxation of the radial heads
    • Ankylosis of the elbows
  • Skin: Approximately 5% of patients have acanthosis nigricans, which is detectable after infancy. The hallmark of these lesions is a darkened thickened skin with accentuated markings and a velvety feel.
  • CNS
    • Approximately 73% of patients have chronic tonsillar herniation (47% have progressive hydrocephalus).
    • Syringomyelia may be present.
  • Postnatal subtype of Crouzon syndrome (in patients at risk, such as family members of patients with Crouzon syndrome, or those with some degree of exorbitism at birth) from birth to at least age 3 years5
    • Development of digital impressions and/or ossification of sutures starting at the occipital region of the skull
    • Development of a prominent bregma
    • Development of “spontaneous” intracranial hypertension
    • Progressive characteristic crouzonoid features such as progressive exorbitism

Causes

  • Crouzon syndrome is caused by mutations in the FGFR2 gene, mapped to chromosome locus 10q25-10q26. The FGFR2 gene mutations also cause Pfeiffer syndrome and Apert syndrome.6,7,8 Mutations have been reported in the third immunoglobulinlike domain. Different mutations have been detected in both exon IIIa and exon IIIc. Most of these mutations are missense, although several different mutations leading to alternative splicing have been recognized.
  • Fifty percent of cases of Crouzon syndrome are not inherited and are the result of new mutations.
  • Crouzon syndrome with acanthosis nigricans is always due to an Ala391Glu mutation within the transmembrane region of the FGFR3 gene.
  • Crouzon syndrome exhibits locus heterogeneity with causal mutations in FGFR2 and FGFR3 in different affected individuals, similar to that demonstrated in Pfeiffer syndrome with FGFR1 and FGFR2 mutations.
  • FGFR2 mutation detection rate has been observed in more than 50% of patients with Crouzon syndrome; numbers reflect "sensitivity" (ie, probability that an individual with the phenotype will have a positive result). Note that FGFR2 mutations are also observed in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome. The phenotypic spectrum of the FGFR3 P250R mutation, called Muenke craniosynostosis or FGFR3 -associated coronal synostosis,9 is so widely variable that patients with this specific mutation had been previously diagnosed as having Crouzon syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Jackson-Weiss syndrome, and nonsyndromic craniosynostosis.
  • A newly identified mutation in the tyrosine kinase I domain of the FGFR2 gene (1576A>G, encoding the missense substitution Lys526Glu) is associated with variable expressivity of Crouzon syndrome, including clinical nonpenetrance.

More on Crouzon Syndrome

Overview: Crouzon Syndrome
Differential Diagnoses & Workup: Crouzon Syndrome
Treatment & Medication: Crouzon Syndrome
Follow-up: Crouzon Syndrome
Multimedia: Crouzon Syndrome
References
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References

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Further Reading

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Keywords

acrocephalosyndactyly type II, craniofacial dysostosis, craniostenosis Crouzon type, Crouzon craniofacial dysostosis, calvarial deformities, facial anomalies, exophthalmos, craniosynostosis, Crouzon syndrome, Crouzon's syndrome, hypertelorism, exophthalmos, strabismus, beaked nose, short upper lip, hypoplastic maxilla, mandibular prognathism, fibroblast growth factor receptor-2, FGFR2 gene, FGFR3 gene, FGFR1 gene, upper airway obstruction, respiratory distress, septal deviation, conductive deafness, Ménière disease

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Contributor Information and Disclosures

Author

Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

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
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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 and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor of Genetics, Munroe Meyer Institute, Professor, Department of Pediatrics, Pathology and Microbiology, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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