02 December 2007

Crouzon Syndrome

Crouzon Syndrome

Article Last Updated: Nov 14, 2007

AUTHOR AND EDITOR INFORMATION

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida

Harold Chen is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society

Editors: Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center

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. 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.

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 and FGFR3 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. 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 mildly affected individuals.
  • 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.
    • 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 and C5-C6
    • 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.

Causes

  • Crouzon syndrome is caused by mutations in the FGFR2 gene, which is mapped to chromosome locus 10q25-10q26. 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,1 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.

DIFFERENTIALS

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
  • Crouzonodermoskeletal syndrome - Crouzon syndrome with acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation, caused by G-to-A transition at nucleotide 1172 of FGFR3, resulting in an ala391-to-glu (GCG-to-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

Lab Studies

  • Molecular analysis

·

    • 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

  • 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.
  • 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.
  • Genetic counseling should include discussion of the following:

·

    • 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.

Surgical Care

  • The goal is to stage reconstruction to coincide with facial growth patterns, visceral function, and psychosocial development.
  • 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.
  • 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 this syndrome. See Treatment.

FOLLOW-UP

Further Inpatient Care

  • Admit the patient 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

MISCELLANEOUS

Medical/Legal 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

  • Prenatal diagnosis

·

    • 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.
    • 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. Click to see larger pictureClick to see detailView Full Size Image Media type: Photo

REFERENCES

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Crouzon Syndrome excerpt

Article Last Updated: Nov 14, 2007

Reference Link:

http://www.emedicine.com/ped/topic511.htm
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