EFNB1 – Craniofrontonasal Syndrome

Craniofrontonasal syndrome (CFNS) is a rare X-linked dominant disorder caused by pathogenic variants in EFNB1, characterized by frontonasal dysplasia, hypertelorism, coronal craniosynostosis, and a bifid nasal tip (PMID:15124102).

CFNS shows a paradoxical severity pattern in which heterozygous females exhibit multiple skeletal and craniofacial malformations, whereas hemizygous males often display only mild features such as hypertelorism (PMID:15959873). Segregation analysis in over 70 families demonstrates consistent co-segregation of EFNB1 variants with CFNS phenotypes.

To date, more than 140 unique loss-of-function alleles (nonsense, frameshift, splice) and over 30 distinct missense mutations in EFNB1 have been reported across familial and sporadic cases, including recurrent and de novo variants (PMID:15959873).

Functional studies confirm haploinsufficiency and cellular interference as key pathogenic mechanisms. Efnb1-null mice recapitulate CFNS skeletal defects, and patient-derived cell assays demonstrate impaired ephrin-B1 reverse signalling and mosaic cellular sorting (PMID:15124102; PMID:18043713; PMID:23335590).

Occasional reports of severely affected mosaic males further support the cellular interference model over simple dosage effects (PMID:23335590).

Overall, the EFNB1–CFNS association meets Definitive ClinGen criteria, with extensive genetic and experimental concordance. Key take-home: EFNB1 testing is essential for accurate diagnosis, genetic counseling, and management of CFNS.

References

• American journal of human genetics • 2004 • Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome PMID:15124102
• Human Mutation • 2005 • Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS) PMID:15959873
• European journal of human genetics • 2008 • Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic PMID:18043713
• Human molecular genetics • 2013 • Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes PMID:23335590

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