PAX3 – Craniofacial-Deafness-Hand Syndrome

Craniofacial-deafness-hand syndrome is an extremely rare autosomal dominant disorder characterized by absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small nose with slitlike nares, hypertelorism, short palpebral fissures, and limited wrist movement with ulnar deviation of the fingers. In one pedigree, a heterozygous missense variant c.141C>G (p.Asn47Lys) in the paired domain of PAX3 co-segregated with disease in a mother and two offspring, with unaffected relatives lacking the allele (PMID:8664898).

A second unrelated proband, a 21-year-old male, was found to carry a novel c.91A>C (p.Thr31Pro) substitution in PAX3, confirming autosomal dominant inheritance and expanding the phenotypic spectrum to include cardiomegaly, pulmonary hypertension, and patent ductus arteriosus, although these cardiovascular features may represent secondary findings (PMID:39850491). Both variants affect evolutionarily conserved residues within the paired domain, implicating impaired DNA binding consistent with pathogenic PAX3 alleles in Waardenburg syndromes. No functional assays have been reported specifically for craniofacial-deafness-hand syndrome, but pathogenicity is supported by analogy to in vitro and in vivo studies of PAX3 paired-domain mutations. Overall, two unrelated alleles with co-segregation in one family provide Limited clinical validity under ClinGen criteria. Key take-home: PAX3 missense variants in the paired domain should be considered in patients presenting with the characteristic craniofacial, auditory, and hand anomalies of craniofacial-deafness-hand syndrome.

References

• Human mutation | 1996 | Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome. PMID:8664898
• Frontiers in genetics | 2024 | Case Report: Craniofacial deafness hand syndrome with unusual cardiovascular symptoms and lack of holistic care. PMID:39850491

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