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Focal facial dermal dysplasia Type IV (FFDD4) is a rare autosomal recessive disorder characterized by congenital atrophic, scar-like preauricular skin lesions along the fusion line of the maxillary and mandibular prominences (MONDO:0013997). Initial exome sequencing in a consanguineous family with two affected siblings identified compound heterozygous CYP26C1 variants: a seven-base pair duplication, c.844_851dup (p.Glu284fsTer128) and a missense change, c.1433G>A (p.Arg478His) ([PMID:23161670]). The duplication led to a premature stop codon; the missense allele showed no residual activity in mammalian expression assays.
Sequencing of four additional unrelated FFDD4 patients and eight TWIST2-negative FFDD II/III patients revealed that three FFDD4 cases were homozygous for c.844_851dup, whereas no CYP26C1 mutations were detected in other FFDD subtypes, confirming locus specificity ([PMID:23161670]). A subsequent study reported two further unrelated FFDD4 patients carrying four CYP26C1 mutations—one missense (c.230C>G (p.Arg77Pro)) and two splice-site changes (c.1191+1G>T and c.1191+2insT)—all predicted damaging by in silico tools and validated in parental segregation analyses ([PMID:29263414]).
A founder effect was demonstrated in the Belgian population, where two additional FFDD4 cases were homozygous for a recurrent CYP26C1 frameshift variant on a shared 700 kb haplotype ([PMID:39828664]). Together, these data encompass at least 8 probands from 6 unrelated families with definitive autosomal recessive segregation.
Functional studies in mice show Cyp26c1 expression precisely along the first branchial arch fusion line, mirroring human lesion sites ([PMID:23161670]). Loss-of-function assays confirm that frameshift alleles abolish retinoic acid catabolism, implicating haploinsufficiency as the pathogenic mechanism. Modifier studies in zebrafish and mammalian chondrocytes further support enzyme dosage sensitivity in craniofacial development.
There are no reports disputing the CYP26C1–FFDD4 association. The cumulative genetic and experimental findings fulfill ClinGen criteria for a strong gene–disease association, with robust segregation, replication, and mechanistic concordance.
Key take-home: Biallelic loss-of-function CYP26C1 variants cause FFDD Type IV via disrupted retinoic acid catabolism along the preauricular fusion line, enabling molecular diagnosis and genetic counseling.
Gene–Disease AssociationStrong8 probands in 6 unrelated families, autosomal recessive segregation, supportive functional data Genetic EvidenceStrong8 probands across 6 families with biallelic variants including frameshift, missense, and splice-site mutations and confirmed parental segregation Functional EvidenceModerateMouse expression along preauricular fusion line; in vitro assays demonstrate loss of function; zebrafish models support pathogenicity |