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Acral peeling skin syndrome (APSS) is a rare, autosomal recessive genodermatosis that is characterized by painless and spontaneous exfoliation of the skin on the distal extremities. Multiple independent case reports and multi‐patient studies have implicated mutations in the TGM5 gene as the underlying genetic driver of this condition (PMID:22429841, PMID:24019772). The clinical spectrum can be variable even within families, with some cases initially misdiagnosed as other blistering disorders. The evidence emphasizes the importance of re‐evaluating clinical diagnoses when characteristic acral skin peeling is observed.
Detailed genetic analyses across diverse populations have uncovered a broad variant spectrum in TGM5. In one study, 59 probands from 52 families were ascertained, reinforcing autosomal recessive inheritance and revealing numerous novel mutations (PMID:24628291). Segregation analyses in these families have identified several affected relatives with the disease phenotype, adding weight to the association and supporting its diagnostic relevance. These findings support the use of genetic testing in cases of unexplained acral desquamation.
At the molecular level, pathogenic TGM5 variants are dominated by missense mutations, with the recurrent c.337G>T (p.Gly113Cys) variant being frequently observed in multiple unrelated families (PMID:24019772, PMID:24628291). This variant has been identified in both case reports and multi‐patient studies, underscoring its role as a founder mutation in certain populations. The consistency of the genetic findings across different cohorts significantly bolsters the gene–disease association.
Functional assessments of TGM5 mutations have provided important mechanistic insights into the pathogenesis of APSS. In vitro studies using patient-derived keratinocytes have demonstrated altered expression and distribution of epidermal differentiation markers and key proteins such as corneodesmosin, which are essential for cell–cell adhesion in the upper epidermis (PMID:22622422, PMID:25644735). These experimental data align well with the clinical and genetic observations and support a pathogenic mechanism based on impaired cross-linking of structural proteins in the skin.
Integration of the genetic and functional evidence presents a coherent narrative supporting a strong association between TGM5 mutations and acral peeling skin syndrome. Despite the inherent heterogeneity in clinical presentations, the cumulative data from case reports, multi-patient studies, and functional assessments exceed the maximum ClinGen scoring cap and are highly supportive of diagnostic utility. This integrated evidence has important implications for genetic counseling and precision dermatology, as early and accurate identification of TGM5 mutations can guide both diagnosis and treatment.
Key take‑home sentence: The robust genetic and functional evidence linking TGM5 mutations to acral peeling skin syndrome supports its use as a definitive diagnostic marker in clinical practice.
Gene–Disease AssociationStrongOver 59 probands from 52 families with positive segregation and multiple independent case reports support an autosomal recessive inheritance pattern with robust clinical correlation (PMID:24628291). Genetic EvidenceStrongMultiple studies have identified a spectrum of TGM5 mutations, including a recurrent founder variant c.337G>T (p.Gly113Cys) in independent families, which supports a strong genetic basis (PMID:24019772, PMID:24628291). Functional EvidenceModerateFunctional assays demonstrate altered epidermal differentiation and compromised cell–cell adhesion in keratinocytes carrying TGM5 mutations, validating the pathogenic mechanism (PMID:22622422, PMID:25644735). |