Cole disease (OMIM 615522) is understood to be caused by mutations in ENPP1. It’s a rare autosomal dominant or recessive genodermatosis characterized by guttate hypopigmentation and punctate palmoplantar keratoderma. The Literature reports only some cases with autosomal recessive inheritance with hyperpigmentation. A case report investigated the molecular basis of people with hyperpigmentation, hypopigmentation, and punctate keratoderma in a Chinese family.

The investigators subjected a Chinese pedigree of suspected Cole disease with hyperpigmentation to mutation detection within the ENPP1 gene. They amplified all exons of the ENPP1 gene and adjacent exon-intron border sequences using polymerase chain reaction and directly sequenced. Further, they predicted the Three-dimensional (3D) models of the wild-type and mutated ENPP1 proteins by PyMOL viewer.

They found, both the proband and his affected father to hold a heterozygous missense mutation p.C176R in ENPP1. In silico modeling of the ENPP1 wild-type and ENPP1 with the p.C176R mutation demonstrated that the residue Arg-176 disturbed the fold of the loop conformation. Thus, supported with clinical and genetic findings, a diagnosis of Cole disease was rendered. The researchers identified a heterozygous mutation, p.C176R, within the ENPP1 gene in a Chinese family with Cole disease. Thus this study clearly showed that hyperpigmentation could also present in Cole disease in cases with autosomal dominant inheritance. This data expand the phenotypic spectrum of ENPP1 mutations underlying Cole disease.

Source: Li Z, Wang L, Wang S. Hyperpigmentation in a Chinese family with autosomal dominant Cole disease. Exp Dermatol. 2021 Jul 23. doi: 10.1111/exd.14434. Epub ahead of print. PMID: 34297442.