Craniofrontonasal syndrome (CFNS)

XLD; EFNB1 (encodes ephrin-B1, a cell-surface signaling ligand) at Xq13.1

• Paradoxical severity: heterozygous females are typically more severely affected than hemizygous males, the reverse of the usual X-linked pattern
• A carrier father transmits the variant to every daughter (variably affected) and to no sons (fathers do not pass an X chromosome to sons)
• A carrier mother has a 50% chance per pregnancy of transmitting the variant to a child of either sex; daughters are typically more affected than sons

Ephrin-B1 sits on the cell surface and, together with its Eph receptors, helps set boundaries between groups of cells during craniofacial development, keeping cell populations from mixing across a border such as the coronal suture.

In a heterozygous female, random X-inactivation creates two intermingled cell populations: some express normal ephrin-B1, others express none. Because ephrin-B1 signaling depends on a cell reading a different level of the protein on its neighbor, this patchwork creates spurious boundary signals wherever a mutant cell sits next to a normal one, exactly where no boundary should exist. This "cellular interference" between the two populations disrupts normal suture patterning and drives the craniosynostosis and facial asymmetry.

A hemizygous male has only one X chromosome, so his cells are uniformly mutant. With no mix of differently-signaling populations, there is no interference, and other ephrin family members appear to partially compensate for the uniform loss. The result is a paradox: complete absence of ephrin-B1 (in males) produces a milder phenotype than a patchwork of present and absent (in females). The same logic explains why a mosaic male, one whose variant arose after fertilization and is present in only some cells, can be more severely affected than a male born with the variant in every cell: mosaicism, not the total amount of ephrin-B1, drives the phenotype.

• Craniosynostosis: coronal, often bilateral; more common and more severe in females
• Hypertelorism: present in nearly all; the mildest, and sometimes only, feature in affected males
• Frontonasal dysplasia: broad nasal bridge, bifid or grooved nasal tip
• Craniofacial asymmetry
• Longitudinally grooved or ridged fingernails; wiry, frizzy hair
• Syndactyly, clinodactyly; agenesis of the corpus callosum in a subset

• Clinical recognition of coronal craniosynostosis plus hypertelorism plus a bifid nasal tip in a female, especially with a father who is only mildly affected or appears unaffected
• EFNB1 sequencing, with deletion/duplication analysis for variants not found on sequencing
• Examine and consider testing the father even when he appears unaffected: men can be minimally affected (hypertelorism alone) or clinically silent while still transmitting to daughters

• Saethre-Chotzen syndrome (TWIST1): coronal craniosynostosis too, but AD with severity concordant between the sexes, plus a low frontal hairline and ptosis not seen in CFNS
• Apert, Crouzon, and Pfeiffer syndromes (FGFR1/2): craniosynostosis with midface hypoplasia and proptosis (Crouzon) or severe complex syndactyly (Apert); equally severe in both sexes, unlike CFNS

• Cranial vault remodeling for craniosynostosis, timed as with other craniosynostoses
• Ophthalmology for hypertelorism-related strabismus and refractive error
• Rhinoplasty for the bifid nasal tip if desired, typically deferred to adolescence or adulthood
• Developmental evaluation and neuroimaging follow-up when a corpus callosum anomaly is present
• Genetic counseling on the paradoxical severity pattern, since it runs counter to what families typically expect from "X-linked"