Analysis of genotype/phenotype correlations in Japanese patients with dyschromatosis symmetrica hereditaria

Dyschromatosis symmetrica hereditaria (DSH) is one of the genetic pigmentation disorders and shows characteristic mixture of hyper- and hypo-pigmented small macules on the extremities. Heterozygous mutations in the adenosine deaminase acting on RNA1 gene (ADAR1) cause DSH. In the present study, we report five cases of DSH and identify a distinct known mutation in each patient. Furthermore, we review previously described cases with the five ADAR1 mutations found in the present study. We reviewed clinical and molecular findings in the present and previously reported cases and found an identical mutation can result in various phenotypic severities, even in one family. We found novel phenotype-genotype correlations between the presence/absence of facial lesions and the ADAR1 mutation c.3286C>T. The absence of freckle-like macules in the face was found to be more commonly associated with the mutation c.3286C>T than with the other 4 ADAR1 mutations (odds ratio = 0.056 [95% CI: 0.007–0.47, p < 0.005]). We objectively evaluated the severity of skin manifestations in the extremities using our definition of severity levels for such manifestations. This is the first semi-quantitative evaluation of skin manifestations in DSH. Using our definition, we found that patients with facial lesions with or without hypopigmented macules tend to show more severe symptoms on the extremities than patients without facials lesions show. Furthermore, no significant difference in the severity of the skin lesions was observed between the upper and the lower extremities, suggesting that sun exposure does not affect significantly the pathogenesis of DSH skin lesions.