Crouzon Disease

Crouzon disease is characterized by craniosynostosis and facial hypoplasia.

Epidemiology

The estimated prevalence in the general population of Europe is 0.9/100,000 .

Clinical description

Craniosynostosis is variable but many sutures are usually involved. The facial dysmorphology is characterized by ocular hypertelorism, small beaked nose, proptosis, exophthalmos, hypoplastic maxilla and mandibular prognathism. The synostosis is evolutive and is usually either not visible or only slightly visible at birth. It usually manifests by the age of 2 years and becomes progressively more severe. However, precocious and congenital forms have been reported in which hypoplasia of the upper maxilla is pronounced and leads to respiratory difficulties, and the exophthalmia is severe resulting in palpebral malocclusion. Hydrocephaly, descent of the cerebellar tonsils and anomalies in jugular venous drainage are also frequently observed in Crouzon disease and may pose therapeutic problems. Two thirds of patients with Crouzon disease have intracranial hypertension, which may lead to blindness.

Etiology

Crouzon disease is caused by mutations of the fibroblast growth factor receptor FGFR2 (10q25.3-q26) with 80% being located to the immunoglobulin (Ig)-like domain III (IgIII domain) of the extracellular region and an additional 20% of mutations being located in the IgI-IgII domains, transmembrane and tyrosine kinase regions. A distinct form of Crouzon disease associated with acanthosis nigricans has been reported and is caused by a specific mutation (p.Ala391Glu) in the transmembrane domain of another protein from the same family, FGFR3 (Crouzon syndrome - acanthosisnigricans; see this term). Moreover, mutations in ERF (19q13.2) gene encoding the ETS2 repressor, resulting in anosteogenic stimulation, have been associated to a Crouzon-like syndrome.

Genetic counseling

The disease is transmitted in an autosomal dominant manner with variable penetrance.

Management and treatment

Surgical interventions are aimed at preventing cerebral, ophthalmological or respiratory complications and correcting the cranio-facial dysmorphy. The craniofacial surgical approach adopted needs to take into account both the cranial and facial synostosis and should be tailored to each patient.