Genetics of Crouzon Syndrome Workup

Updated: Dec 05, 2018
  • Author: Marie M Tolarova, MD, PhD, DSc; Chief Editor: Maria Descartes, MD  more...
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Workup

Laboratory Studies

Molecular genetic analysis

Identification of a mutation in the proband should be followed by genetic testing of the parents. It has been suggested to start with testing for FGFR3 mutations, followed by testing for FGFR2, FGFR1, and TWIST1 mutations. [11]  The detection rate of known mutations varies in different craniosynostosis syndromes (see Table 2).

Table 2.  Efficiency (mutation detection rate) of molecular testing* (Open Table in a new window)

Syndrome

Gene

Mutation Detection Rate

Pfeiffer

FGFR1,FGFR2

  67%

Apert

FGFR2

>98%

Crouzon

FGFR2

>50%

Crouzonodermoskeletal  

FGFR3

 100%

Muenke

FGFR3

 100%

Saethre-Chotzen

TWIST1

   46-80%

*Adapted from Kimonis et al (2007). [11]

The presence of parental mosaicism can be checked by DNA sequencing technology. Findings may be helpful in genetic counseling with regard to recurrence risk of paternal age–effect syndromes in a family with a single affected child. [40]

All Crouzon-like 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), concurrent testing for FGFR2 and FGFR3 mutations is recommended.

Prenatal diagnosis may be carried out by chorionic villus sampling in the 10th to 14th week of gestation. Preimplantation genetic diagnosis is possible for parents who have been identified as heterozygotes for the mutation.

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Imaging Studies

Imaging studies are a necessary part of the diagnosis of Crouzon syndrome and of treatment planning, management, and monitoring.

In the initial diagnosis of craniosynostosis, brain computed tomography (CT) scanning or magnetic resonance imaging (MRI) are used to evaluate the patient for hydrocephalus and structural anomalies. Three-dimensional (3D) CT scanning to assess the endocranial and ectocranial surfaces of the skull is considered the gold standard for determining the presence of craniosynostosis. [11]

Midface hypoplasia and orthodontic and surgical treatment of malocclusions require lateral cephalograms, panoramic radiographs, and cone-beam CT scanning. Additional imaging studies are needed for assessment of upper airway obstruction.

Skull radiography

Radiographic findings demonstrate synostosis, craniofacial deformities, digital markings of the 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 with equal frequency. Block fusions involving multiple vertebrae are also observed.

Limb radiography

Hand abnormalities are radiographically detectable by metacarpophalangeal analysis, although the hands could be considered normal clinically. Subluxation of the radial head occurs.

CT scanning

Comparative 3D reconstruction analysis of the calvaria and cranial base precisely defines the pathologic anatomy and permits specific operative planning.

MRI

MRI is used to demonstrate occasional corpus callosum agenesis and optic atrophy.

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