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At a glance

Craniofacial dysostosis syndrome with skull deformities similar to Apert Syndrome but absent syndactyly. Characteristic features include exophthalmos, hypertelorism, beaked nose, maxillary hypoplasia, and micrognathia.

Synonyms

Crouzon Craniofacial Dysostosis; Craniofacial Dysostosis; Fibroblast Growth Factor Receptor 2 (FGFR-2) Deficiency; Oxycephaly-Acrocephaly; Virchow Oxycephaly.

History

First described in 1912 by the French neurologist Octave Crouzon (1874–1938).

Incidence

1:25,000 to 60,000 live births.

Genetic inheritance

Autosomal dominant, but de novo mutations are present in up to 60%. There is a high penetrance with a variable expression. Several sporadic cases have been linked to advanced paternal age. Similar to Apert Syndrome, Crouzon Syndrome results from mutations in the gene encoding FGFR-2, which has been mapped to chromosome 10q26. (However, Crouzon Syndrome with acanthosis nigricans results from a mutation in the FGFR-3 gene mapped to chromosome 4p16.3.)

Pathophysiology

The mutation increases the maturation rate of cells in the osteoblastic lineage. During fetal development, premature ossification with increased subperiosteal bone formation in the calvarium is responsible for craniosynostosis. The mutation involves only one of the multiple tissue-specific isoforms involved in the osteogenesis of the frontal bones of the skull. This results in premature synostosis of the coronal, sagittal, and occasionally lambdoid sutures beginning in the first year of life. The degree, rate, and order of fusions determine the extent of deformity.

Diagnosis

The clinical suspicion is based on the triad of craniosynostosis, midfacial hypoplasia, and exophthalmos, which is then further supported with radiographic findings and confirmed with genetic sequencing.

Clinical aspects

The coronal and sagittal sutures are most commonly involved. While bicoronal fusion appears at about the same age, the sagittal and lambdoid sutures close significantly earlier than in Apert Syndrome, which might explain why Arnold-Chiari malformation is much more common in Crouzon Syndrome than in Apert Syndrome (72% and 2%, respectively). Fusion of the cranial base sutures occurs also earlier and potentially leads to the higher incidence of jugular foramen stenosis in Crouzon Syndrome. The typical cranial malformation consists of brachycephaly with high forehead and flat occiput, but scaphocephaly, trigonocephaly, and cloverleaf skull have all been described. Increased intracranial pressure (ICP) has been found in up to 60% of patients. Approximately one fourth of patients have fused cervical vertebrae, which in contrast to Apert Syndrome (C5-C6) most commonly affect C2-C3. Scoliosis can occur later in life. Maxillary hypoplasia, relative mandibular prognathism (although the mandibular body may be shortened), parrot-beaked nose (psittichorhina) are common, and choanal stenosis or atresia has been described. Short upper lip and high-arched palate with lateral swelling (rarely with cleft lip/palate), bifid uvula, and dental crowding are frequent, whereas macroglossia is not. Abnormal tracheal cartilage (eg, tracheal cartilaginous sleeve with vertically fused or absent tracheal ...

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