Dyschromatosis symmetrica hereditaria (DSH, OMIM 127400), initially known as reticulated acropigmentation of Dohi, was first described by Toyama in 1929. It is a rare pigmentary genodermatosis that is characterized by onset of hyper- and hypopigmented macules on the face and dorsal aspects of the extremities in infancy or early childhood. DSH was previously reported mainly in Japanese and Chinese patients, but a few cases have been reported in different races including Koreans, Indians, Europeans, and South Americans. DSH generally shows an autosomal-dominant pattern of inheritance with high penetrance, but sporadic cases have been reported. Pathogenic mutations were identified in the double-stranded RNA-specific adenosine deaminase (ADAR1) gene. The ADAR1 gene, which spans 30 kb and contains 15 exons, is expressed ubiquitously all over the skin, but the molecular pathogenesis of DSH is yet to be clarified. Histological studies have shown abundant melanin pigment in the withaferin a cost and melanocytes in the hyperpigmented macules and reduced melanization in hypopigmented macules.
Most articles so far were case reports especially of those with novel mutations of the ADAR1 gene. To our knowledge, we describe herein the largest series of patients with DSH in Taiwan—25 cases. Through these cases and literature review, we hope to delineate the unique clinical, histological, and genetic features of DSH.
We were able to identify 35 patients with clinical or pathological diagnosis of “dyschromatosis” or “acropigmentation of Dohi” in the computerized database at the Department of Dermatology at National Cheng-Kung University Hospital from 1992 to 2011. Six patients were excluded by pathological biopsy under the diagnoses of vitiligo, postinflammatory alternation, focal hypopigmentation, dyschromatic amyloidosis, amyloidosis cutis dyschromica, and solar lentigo. Two other patients were excluded under the clinical diagnosis of dyschromatosis lentiginosis and dyschromatosis universalis hereditaria (DUH). Due to unavailable photographic documentation and being relatives of the index cases, two additional patients were also excluded. Based on characteristic clinical features, 25 patients were identified under the clinical diagnosis of DSH. Clinical charts and archival photographs were reviewed to determine the distribution of skin lesions, age of onset, family history, and associated diseases. Experienced pathologists performed histological analyses for those who underwent skin biopsy. Mutational analysis of the ADAR1 gene was performed as previously described.
A total of 25 patients (mean age at diagnosis 20.3 years, range 3–68 years) were given the clinical diagnosis of DSH (Table 1). The male:female ratio was 14:11.
Fourteen index cases (56%) had disease onset between birth and childhood (up to an age of 8 years). A positive family history was noted in 14 patients (56%). Pattern of inheritance was basically autosomal dominant. Twelve patients (48%) had typical hypo- and hyperpigmented macules distributed on the dorsal aspects of the extremities (Figure 1). In addition to the extremities, two (8%) and one (4%) patients had cutaneous lesions distributed over trunk and neck, respectively, and 10 patients (40%) had freckle-like macules on the face. Six patients (24%) had coexistence of other diseases, including palmoplantar keratoderma, chronic urticaria, suspected collagen vascular disease, seizure, mental retardation, autism, keratoderma tylodes palmaris progressive, tardive dystonia, mood disorder, and psoriasis.
Twelve patients (48%) with genetic mutation analyses were further examined for family history, nucleotide change, amino-acid change, and position of mutation (Table 2). Three of the 12 patients (25%) did not demonstrate mutation in the ADAR1 gene but were still diagnosed with DSH based on clinical grounds. Four of the 12 patients (33%) did not have a family history of DSH, implicating a de novo origin. We have previously identified and published novel mutations found in Patients 2, 5, and 10.