A newly discovered PAX7 variant associated with craniofacial duplication: a case report

Diprosopus (craniofacial duplication) is an exceedingly rare craniomaxillofacial dysmorphosis, considered a subgroup of conjoined twins, with phenotypes ranging from partial structural duplication to complete dicephalus. Its embryogenesis and molecular mechanisms remain poorly understood. This study describes a case of partial dentofacial duplication and reports novel genetic findings to explore potential etiology.

A newborn Kazak male was referred for a prenatal-detected maxillary mass. Physical examination revealed left complete unilateral cleft lip and a 2.5 × 3.0 cm soft tissue mass (accessory upper lip with a central sinus tract) originating from the ipsilateral upper lip. CT confirmed duplicated, translocated maxillary arches and widened nasal bone. The patient underwent two surgeries (at 11 months and 4 years of age) for cleft lip repair, duplicated maxilla excision, and bony contouring. Long-term follow-up showed unimpaired feeding and speech. Whole-exome sequencing (WES) of the patient and mother identified a shared heterozygous missense variant: PAX7 c.1033G > C (p.Ala345Pro, NM_001135254.1), classified as a variant of uncertain significance (VUS) per ACMG/AMP guidelines.

This is the first report of a PAX7 VUS associated with craniofacial duplication. PAX7 plays critical roles in craniofacial development, and the conserved Ala345 residue suggests potential functional impact. While causality is not established, this finding links PAX7 to a rare duplication phenotype, providing a preliminary molecular basis for future prenatal screening and mechanistic studies. Additional functional validation and larger cohort studies are needed to confirm pathogenicity.