craniofrontonasal

Craniofrontonasal syndrome, also known as craniofrontonasal dysplasia (CFND or CFNS), is a rare congenital disorder affecting craniofacial and skeletal development. It is caused by pathogenic variants in the EFNB1 gene, located on the X chromosome, which encodes ephrin-B1, a protein involved in cell signaling and boundary formation during embryogenesis.

Inheritance is X-linked dominant. Females are typically more severely affected than males, an effect attributed to cellular interference from random X-inactivation. Affected males can have milder or variable features, and some individuals with EFNB1 mutations may have a limited phenotype.

Core clinical features often include bifid (split) nasal tip, broad nasal root, frontonasal dysplasia with hypertelorism (widely spaced eyes), and coronal craniosynostosis leading to abnormal skull shape. Midface hypoplasia, shallow orbits, and orbital or eyelid anomalies may be present. Some individuals show dental abnormalities or limb anomalies, such as atypical finger or toe development, though these are variable.

Diagnosis is based on clinical assessment supported by radiologic imaging to evaluate craniosynostosis and facial structure, with confirmation by molecular genetic testing for EFNB1 mutations. Differential diagnosis includes other frontonasal dysplasias and craniosynostosis syndromes.

Management requires a multidisciplinary approach, including neurosurgical or craniofacial surgical planning for craniosynostosis and midface support, orthopedic or hand surgery for limb issues when present, dental and orthodontic care, and developmental or speech therapies. Regular follow-up is important to monitor growth, neurodevelopment, and psychosocial well-being.

Prognosis varies with severity and timely intervention; many individuals achieve good functional outcomes with appropriate treatment, though facial features can be a persistent consideration.