eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Crouzon Syndrome

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

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 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.

Differential Diagnoses

Apert Syndrome

Other Problems to Be Considered

• Beare-Stevenson syndrome (OMIM 123790) - Associated with cutaneous disorders (ie, cutis gyrata and acanthosis nigricans) and FGFR2 mutations
• Carpenter syndrome (OMIM 201000) - Autosomal recessive linked, peculiar face, absence of osseous fusion of hand bones, presence of preaxial polydactyly of hands and/or feet
• Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome) - Craniofacial features similar to those observed in patients with classic Crouzon syndrome (craniosynostosis with Crouzonoid facies), in addition to acanthosis nigricans and other severe physical manifestations, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas¹⁰ ; caused by G → A transition at nucleotide 1172 of FGFR3, resulting in an Ala391Glu (GCG → GAG) mutation in the transmembrane domain
• FGFR3- associated coronal synostosis syndrome - Variable clinical presentation overlapping with Pfeiffer, Jackson-Weiss, or Saethre-Chotzen syndrome phenotypes (Some individuals with a disease-causing mutation may have no clinical problems.)
• Jackson-Weiss syndrome (OMIM 123150) - Broad great toes with varus deviation and tarsal/metatarsal fusions, lack of thumb abnormalities, craniofacial features suggestive of Pfeiffer syndrome, FGFR2 mutations
• Pfeiffer syndrome (OMIM 101600) - Both hand and foot abnormalities characterized by broad thumbs and halluces with occasional cutaneous syndactyly, mild cranial deformities, lack of osseous fusion of the phalanges, FGFR1 and FGFR2 mutations
• Saethre-Chotzen syndrome (OMIM 101400) - Characteristic facies, relatively mild cranial deformity, normal thumbs, lack of osseous fusion of the hand bones (Approximately 75% of patients have identifiable mutations in the TWIST gene.)

Workup

Laboratory Studies

• Molecular analysis in Crouzon syndrome
  • More than 50% of patients with Crouzon syndrome have FGFR2 mutations. FGFR2 mutations are also observed in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome.
  • All patients with associated acanthosis nigricans have the FGFR3 Ala391Glu mutation. If testing is performed on a child with features of Crouzon syndrome during the first year of life (before the usual onset of acanthosis nigricans), concurrently testing for FGFR2 and FGFR3 mutations is recommended.

Imaging Studies

• Skull radiography
  • Radiographic findings demonstrate synostosis, craniofacial deformities, digital markings of skull, basilar kyphosis, widening of hypophyseal fossa, small paranasal sinuses, and maxillary hypoplasia with shallow orbits.
  • The coronal, sagittal, lambdoidal, and metopic sutures may be involved.
• Cervical radiography
  • Radiologic abnormalities include butterfly vertebrae and fusions of the bodies and the posterior elements.
  • Cervical fusions are present in approximately 18% of patients. C2-C3 and C5-C6 are affected equally.
  • Block fusions involving multiple vertebrae are also observed.
• Limb radiography
  • Hand abnormalities are radiographically detectable by metacarpophalangeal analysis, although the hands are considered normal clinically.
  • Subluxation of the radial head occurs.
• CT scanning: Comparative 3-dimensional reconstruction analysis of the calvaria and cranial bases precisely defines the pathologic anatomy and permits specific operative planning.
• MRI: MRI is used to demonstrate occasional corpus callosum agenesis and optic atrophy.

Other Tests

• Sleep study
• Psychometric evaluation

Histologic Findings

• Immunohistochemical analysis of cranial sutures, performed with labeled anti-FGFR2 antibodies, reveals that sutures from children with Crouzon syndrome demonstrate lower levels of FGFR2 activity in both stenosed and nonstenosed sutures compared with children with a nonsyndromic isolated coronal stenosis.

Treatment

Medical Care

• A high prevalence of visual impairment in patients with craniosynostotic syndromes such as Crouzon syndrome was reported; almost half of the cases were due to potentially correctable causes, including amblyopia and ametropia.¹¹ Optic atrophy remains an important cause of visual impairment.
• Early detection of eye problems to reduce amblyopia by correction of refractory errors and timely treatment of strabismus and patching is indicated. Optic atrophy remains an important cause of visual impairment before decompressive craniectomy.¹²
• To relieve airway obstruction, a nasal continuous positive airway pressure device may be needed.
• Close otologic and audiologic follow-up is indicated to detect sensorineural hearing loss.
• Management of speech may be necessary.

Surgical Care

• The goal is to stage reconstruction to coincide with facial growth patterns, visceral function, and psychosocial development.
• Surgical treatment varies according to the variable expressivity of the disease and usually begins during a child’s first year with fronto-orbital advancement with cranial decompression. Subsequent development of midfacial hypoplasia needs correction. Procedures for this purpose include the Le Fort III osteotomy or its segmental variants, monobloc frontofacial advancement, or bipartition osteotomy.¹³
• Early craniectomy with frontal bone advancement is most often indicated to prevent or treat increased intracranial pressure because newborns with Crouzon syndrome develop multiple suture synostoses and fused synchondroses.
• Fronto-orbital and midfacial advancements help in the cosmetic reconstruction of facial dysmorphisms.
• A new technique, craniofacial disjunction, followed by gradual bone distraction (Ilizarov procedure) has been reported to produce complete correction of exophthalmos and improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone graft in patients aged 6-11 years.
• Adult Crouzon syndrome, often presenting with marked midface hypoplasia and exorbitism, can be corrected by orbital decompression and zygomaticomaxillary advancement.¹³
• The following treatments may be necessary:
  • Shunting procedures for hydrocephalus
  • Tracheostomy for airway compromise
  • Myringotomy to drain middle ear secretions secondary to distorted nasopharynx
  • Orthodontic management

Consultations

• Neurosurgeon
• Neuroradiologist
• Plastic surgeon
• Oromaxillofacial surgeon
• Craniofacial anesthesiologist
• Orthodontist
• Dentist
• Orthopedist
• Ophthalmologist
• Clinical geneticist
• Speech, physical, and occupational therapists
• Psychosocial team

Diet

• No special diet is required.

Activity

• Restriction of activity is not necessary.

Medication

• Drug therapy currently is not a component of the standard of care for Crouzon syndrome. See Treatment.

Follow-up

Further Inpatient Care

• Admit the patient with Crouzon syndrome for surgical intervention.
• Tracheostomy may be needed for airway management.

Further Outpatient Care

• Carefully monitor postoperative complications.

Transfer

• Transfer may be indicated for further diagnostic evaluation and surgical intervention.

Complications

• Wound infections, frontal bone osteomyelitis, extradural abscess, and periorbital abscess
• Increased intracranial pressure and postoperative hydrocephalus
• Cerebrospinal fluid (CSF) leak
• Respiratory distress and obstructive sleep apnea
• Facial nerve palsy, blindness, diplopia, and velopharyngeal incompetence
• Optic atrophy remains an important cause of visual impairment before decompressive craniectomy.

Prognosis

• Prognosis depends on malformation severity.
  • Craniosynostosis can result in brain compression and mental retardation in severely affected individuals unless relieved by early craniectomy.
  • Innovations in craniofacial surgery have enabled patients to achieve their full potential by maximizing their opportunities for intellectual growth, physical competence, and social acceptance.
• Patients usually have a normal lifespan.

Patient Education

• Crouzon Support Network
  PO Box 1272
  Edmonds, WA 98020
  Phone: 425-672-1697
• National Organization for Rare Disorders, Inc. (NORD)
  PO Box 8923
  New Fairfield, CT 06812-8923
  Phone: 800-999-6673
  Fax: 203-746-6481
  email: orphan@nord-rdb.com
• Children's Craniofacial Association
  13140 Coit Road
  Dallas, TX 75240
  Phone: 800-535-3643
• Forward Face, The Charity for Children with Craniofacial Conditions
  317 East 34th Street, Suite 901A
  New York, NY 10016
  Phone: 212-684-5860
  Phone: 800-393-FACE
  Fax: 212-684-5864
• FACES: The National Craniofacial Association
  PO Box 11082
  Chattanooga, TN 37401
  Phone: 800-332-2373 or 423-266-1632
  email: faces@faces-cranio.org

Miscellaneous

Medicolegal Pitfalls

• Failure to perform an early craniectomy
• Failure to provide adequate genetic counseling
• Failure to recognize premature closure of sutures early in life

Special Concerns

• Genetic counseling should include discussion of the following:^14,15
  • The risk that an affected individual will have affected offspring is 50%.
  • The recurrence risk for unaffected parents is negligible except in the case of germinal mosaicism. The risk for future siblings depends on the proportion of germ cells bearing the mutant allele.
  • An advanced paternal age effect in new mutations has been reported.
• Prenatal diagnosis¹⁶
  • Identification of the disease-causing FGFR2 mutation allows prenatal diagnosis using chorionic villus sampling (CVS) in the first trimester or amniocentesis in the second trimester.¹⁷
  • Exophthalmos and ocular hypertelorism can be detected by ultrasonography. Prenatal diagnosis of craniosynostosis is difficult and could benefit from 3-dimensional ultrasonography and 3-demensional CT scanning.
  • Prenatal MRI has diagnostic value when synostosis is suspected based on ultrasonography findings. MRI is accurate in detection of associated brain abnormalities, which is an important prognostic issue in this disease.
  • Preimplantation genetic diagnosis for Crouzon syndrome by blastomere biopsy samples from cleavage-stage embryos may be detected by mutation analysis.

Multimedia

Media file 1: Child with Crouzon syndrome. Note midfacial hypoplasia, proptosis secondary to shallow orbits, and ocular hypertelorism.

References

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

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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

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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