ENPP1 – Hypopigmentation-punctate Palmoplantar Keratoderma Syndrome

ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1, and heterozygous missense variants in ENPP1 have been definitively linked to hypopigmentation-punctate palmoplantar keratoderma syndrome (Cole disease), a rare autosomal dominant genodermatosis (ENPP1; hypopigmentation-punctate palmoplantar keratoderma syndrome).

Clinical validity is supported by complete cosegregation in three unrelated families (PMID:24075184) and a multigenerational pedigree extending at least four generations (PMID:32598042), with concordant functional studies demonstrating disruption of ENPP1 homodimerization.

Genetic evidence demonstrates an autosomal dominant inheritance mode with multiple heterozygous cysteine substitutions clustered in the somatomedin-B-like domains of ENPP1. Three unrelated pedigrees totaling at least 12 affected probands carry distinct missense variants (e.g., c.491G>A (p.Cys164Tyr), c.530G>A (p.Cys177Tyr), c.526T>C (p.Cys176Arg)) segregating fully with the phenotype (PMID:24075184; PMID:34297442).

A representative variant, c.526T>C (p.Cys176Arg), was identified in a Chinese family with hyper- and hypopigmented macules and punctate keratoderma, where in silico 3D modeling revealed that Arg-176 perturbs loop conformation critical for dimer assembly (PMID:34297442).

Functional assays in primary melanocytes show that cysteine-specific mutations (e.g., p.Cys120Arg) impair homodimerization of ENPP1, alter melanocyte differentiation pathways, and recapitulate the dyschromatosis phenotype in vitro (PMID:28964717). These data support a dominant-negative mechanism leading to defective melanogenesis.

No conflicting reports have challenged the association between ENPP1 variants and Cole disease. The integration of robust genetic segregation and concordant functional data over a decade supports a Strong gene-disease relationship with Strong genetic evidence (3 unrelated families; multigenerational pedigree) and Moderate functional evidence (dimer disruption; melanocyte assays).

Key take-home: ENPP1 testing should be considered in patients with patchy hypopigmentation and punctate palmoplantar keratoderma to enable accurate diagnosis, genetic counseling, and potential inclusion in functional-targeted trials.

References

• American journal of human genetics • 2013 • Cole Disease Results from Mutations in ENPP1. PMID:24075184
• Pediatric dermatology • 2020 • A novel ENPP1 mutation identified in a multigenerational family affected by Cole disease. PMID:32598042
• Experimental dermatology • 2022 • Hyperpigmentation in a Chinese family with autosomal dominant Cole disease. PMID:34297442
• The Journal of investigative dermatology • 2018 • ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis. PMID:28964717

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