IRF6 – Popliteal Pterygium Syndrome

Popliteal pterygium syndrome (PPS) is a rare autosomal dominant disorder characterized by cutaneous webbing across the popliteal fossa, orofacial clefts, syndactyly, and genital anomalies. Heterozygous mutations in IRF6 (HGNC:6121) on chromosome 1q32.2 underlie PPS, with overlapping features of Van der Woude syndrome, confirming IRF6 as the major locus for these phenotypes.

Genetic analyses in 37 unrelated PPS families identified IRF6 pathogenic variants in 97% of cases, predominantly missense changes clustering in the DNA-binding domain and occasional truncating alleles, including de novo stop codons in two kindreds (PMID:19282774). A Moroccan infant with classic PPS harbored the recurrent c.250C>T (p.Arg84Cys) mutation (PMID:25547932). Multigenerational pedigrees demonstrate cosegregation of IRF6 variants with PPS features and occasional phenotypic variability between PPS and Van der Woude presentations (PMID:16160700).

Inheritance of PPS is autosomal dominant with high, but incomplete, penetrance. Segregation analyses across families document 37 additional affected relatives carrying IRF6 mutations. No recessive cases are reported, and de novo mutations account for a minority of sporadic presentations.

The IRF6 variant spectrum in PPS includes primarily missense substitutions (e.g., c.250C>T (p.Arg84Cys)), with fewer frameshift and splice-site alleles. Recurrent hot-spot mutations at codon Arg84 underscore the critical role of the DNA-binding domain. Deep intronic and complex rearrangements disrupting IRF6 have been reported, further expanding the mutational landscape.

Functional studies in Irf6-null mice recapitulate human PPS features, with abnormal craniofacial and limb morphogenesis due to keratinocyte differentiation defects (PMID:17041601). In vitro assays show missense variants such as p.Ser424Leu reduce IRF6 transcriptional activity to <10% of wild-type, consistent with a dominant-negative mechanism.

No studies refute the IRF6–PPS association; variant pathogenicity is supported by segregation, de novo events, and concordant functional data. Together, these data qualify IRF6–PPS as a definitive gene–disease relationship in ClinGen scoring.

Key Take-home: IRF6 sequencing is essential for definitive PPS diagnosis, enabling targeted management, genetic counseling, and prenatal testing in affected families.

References

• Journal of medical case reports • 2014 • Clinical and molecular findings in a Moroccan patient with popliteal pterygium syndrome: a case report. PMID:25547932
• European Journal of Human Genetics • 2005 • Novel and de novo mutations of the IRF6 gene detected in patients with Van der Woude or popliteal pterygium syndrome. PMID:16160700
• Nature Genetics • 2006 • Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). PMID:17041601

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