craniofrontonasal syndrome

Craniofrontonasal syndrome is an X-linked malformation condition primarily affecting craniofacial and skeletal development. It is caused by pathogenic variants in the EFNB1 gene, which plays a key role in cell signaling and tissue patterning during development. , although the condition follows an X-linked pattern, affected females typically present with more severe features compared to males, who may be only mildly affected. Precise prevalence estimates are not available, and our understanding continues to evolve with modern clinical care.

Individuals with craniofrontonasal syndrome commonly exhibit distinctive facial features, including a depressed nasal ridge, midline defects of the nose, hypertelorism, frontal bossing, and a wide nasal bridge. Skeletal anomalies such as craniosynostosis, clinodactyly of the 5th finger, brachydactyly, and, in some cases, congenital pseudoarthrosis of the clavicle are also observed. In addition, digital anomalies like syndactyly and other limb differences have been reported. Cognitive involvement is present in a subset of affected individuals, with intellectual disability noted in some cases. Not all individuals experience every feature, and severity varies considerably.

Craniofrontonasal syndrome is caused by mutations in the EFNB1 gene, which encodes a protein essential for cell-to-cell communication during the development of facial and skeletal structures. The condition follows an X-linked dominant pattern, meaning that a single altered copy of EFNB1 can lead to the syndrome, with females often displaying more pronounced clinical features due to differences in X-inactivation. This unique inheritance pattern underscores the importance of genetic counseling for families to understand recurrence risks and to guide family planning decisions.

Currently, management focuses on supportive care and symptom management, as there are no approved or foundational therapies specifically for craniofrontonasal syndrome. Treatment plans are individualized and typically involve a multidisciplinary team to address the craniofacial, skeletal, and cognitive aspects of the condition. Regular surveillance is an essential part of long-term care, ensuring that emerging complications are identified early. Patients and their families are encouraged to discuss available management options and the potential benefits of genetic counseling with their healthcare team.

The outlook for individuals with craniofrontonasal syndrome varies widely, with outcomes depending on the specific features and severity of the condition as well as access to multidisciplinary care. With current standards of care, many affected individuals achieve a good quality of life, although some may require ongoing surgical interventions and supportive therapies. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists experienced in managing this condition, and genetic counseling can provide additional guidance for family planning.