The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders. What's already known about this topic? Inherited defects affecting vitamin B12 (cobalamin, cbl) metabolism can result in various haematological and neurological abnormalities, as well as occasional changes in the skin. Nine different metabolic defects in the intracellular processing of cbl have been reported, which led to isolated methylmalonic aciduria and/or isolated homocystinuria. The most recently described disease subtype is cblJ, resulting from mutations in ABCD4; three individuals with ABCD4 mutations have been described. What does this study add? We identified a homozygous missense mutation in ABCD4 in a 12-year-old girl with progressive hyperpigmentation. ABCD4 mutations can lead to skin hyperpigmentation in the absence of any neurological abnormalities, thus ABCD4 is a further candidate gene for familial progressive hyperpigmentation. Treatment with oral cbl can reduce the hyperpigmentation that results from ABCD4 mutations over several months.
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