Crouzon Syndrome-Acanthosis Nigricans Syndrome

Crouzon syndrome with acanthosis nigricans (CAN) is a very rare, clinically heterogeneous form of faciocraniostenosis with Crouzon-like features and premature synostosis of cranial sutures (Crouzon disease, see this term), associated with acanthosis nigricans (AN; see this term).

Epidemiology

CAN has an estimated prevalence of 1/1,000,000 newborns. Fewer than 70 cases have been described in the medical literature. A female-to-male sex ratio of 2.4:1 has been reported.

Clinical description

All patients have congenital craniofacial abnormalities consistent with classic Crouzon syndrome including craniosynostosis, midface hypoplasia, shallow orbits with exophthalmos, down-slanting palpebral fissures and hypertelorism, maxillary hypoplasia with convex nose and posteriorly angulated ears. The synostosis usually involves the coronal sutures. Cases of cloverleaf skull have also been reported. Patients also develop velvety hyperpigmented skin (AN) within the first decade of life, found primarily in body folds such as the neck, axillae, eyelids, and the perioral, inguinal and perianal areas. The skin disorder is sometimes widespread and develops early compared to classic AN. Craniovertebral junction and vertebral anomalies such as mild alterations of the interpediculate distances of the distal vertebral column are subtle and inconstant. Choanal atresia or stenosis is often present (41%), and is considered highly suggestive of CAN. Other commonly reported signs include hydrocephalus (43%), oral abnormalities such as cleft palate (see this term), dental malocclusion, cementomas of the jaw (34%), and melanocytic nevi (25%). Kidney involvement has also been reported. Some of these specific features are rare in patients with classic Crouzon syndrome. Intellectual disability, hearing loss and speech delay are uncommon. The severity is the same in affected males and females.

Etiology

CAN is caused by a specific p.Ala391Glu mutation in the fibroblast growth-factor receptor 3 FGFR3 gene (4p16.3), involved in regulation of cell proliferation, differentiation and apoptosis. AN is associated with inadequate stimulation of various fibroblast growth-factor receptors.

Genetic counseling

Most cases are sporadic, associated with paternal aging, although familial cases consistent with autosomal dominant inheritance have been reported.