Genetics of Crouzon Syndrome Clinical Presentation

Updated: May 06, 2015
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
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Presentation

History

The following should be taken into account:

  • 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, midnasal abnormalities, choanal abnormalities, and nasopharyngeal narrowing
  • Ménière disease and seizures may develop

According to a study by Agochukwu et al of hearing loss in craniosynostosis syndromes, the incidence of hearing loss is 74% in Crouzon syndrome and 14% in Crouzon syndrome with acanthosis nigricans. [3]

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Physical

See the list below:

  • 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. [4]
    • 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-C6 [5]
    • 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 years [6]
    • 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
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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. [7, 8, 9] 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 (OMIM: 612247) represents a clinically and genetically distinct entity from the "classic" Crouzon syndrome. Indeed, associated with craniosynostosis, several organs are also affected. A recurrent mutation, Ala391Glu, in the fibroblast growth factor receptor (FGFR) 3 gene, is responsible for this syndrome, which allows for proper information and genetic counseling. [10]

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, [11] 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.

Fenwick et al reported the existence of two separate mutations of the same nucleotide, c.1083A>G and c.1083A>T, that apparently interfere with FGFR2 splicing, causing mild Crouzon syndrome. The two mutations, each of which was present in a different family, seem to encode a synonymous change at the Pro361 codon. [12]

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