Necrostatin 1 br Histopathology Skin biopsy specimens were o
Histopathology Skin biopsy specimens were obtained from seven patients (28%). Six of those had pathological findings consistent with the diagnosis of DSH. Fontana-Masson stain revealed hyper- and hypomelanization in hyper- and hypopigmented lesions, respectively. In Patient 5, immunostaining for Melan-A revealed normal density and morphology of basal melanocytes in the hyperpigmented lesion but reduced number of basal melanocytes in the hypopigmented lesion. Ultrastructural study was done in Patient 10, which showed a large number of fully melanized melanosomes of varying sizes, often in large clusters, in the basal Necrostatin 1 of hyperpigmented macules. In the hypopigmented lesion, most keratinocytes showed few or no melanosomes. In both lesions, basal melanocytes were not easily found. In Patient 3, pathological findings showed vacuolar interface dermatitis with focal epidermal atrophy and abundant melanophages, suggestive of collagen vascular disease. Immunostaining for Melan-A revealed scattered melanocytes along the basal layer in an uneven distribution and reduced in some foci. Nonetheless, the diagnosis of DSH was supported by mutation analysis.
Discussion DSH was formerly considered to be a Japanese-specific genodermatosis, with a few cases reported among Koreans, Indians, Europeans, and South Americans. In the two reviews of the 185 reported cases from Japan and the 136 from China, clinical manifestations varied among different races or countries. In addition to the typical distribution of the extremities and face seen in Japanese, pigmentary change was noted on the neck and chest in the Chinese population. This may have implied that differences in the distribution of the skin lesions could be related to race and environment. Skin manifestations in our patients were similar to those reported from China (Table 3). Adenosine deaminase acting on the RNA (ADARs) represents one type of RNA-editing enzyme. It catalyzes deamination of adenosine to inosine in dsRNA. This alteration has been demonstrated to promote the survival and function of many tissues, including vertebra, heart, liver, and brain. Specifically, ADAR1 is essential for maintenance of hematopoiesis in the fetal liver and adult bone marrow. It is also an essential suppressor of interferon signaling that may protect organisms from the deleterious effects of interferon activation associated with many pathological processes including chronic inflammation, autoimmune disorders, and cancer. Genetic mutation in the double-stranded RNA-specific adenosine deaminase (ADAR1) gene is responsible for the altered production or distribution of melanin to the units of epidermal melanization. ADAR1 protein’s target gene(s) in the skin still remains unknown. Two isoforms of ADAR1 protein are generated by translation from distinct transcripts directed by different promoters: an interferon-inducible full-length ADAR1 (p150) and a constitutively expressed N-terminal truncated ADAR1 protein (p110). Kondo et al suggested that only the p150 protein and the interferon-inducible mechanism may be responsible for the etiology of DSH. It has been reported that the p150 protein is involved in antiapoptotic pathways and also appears to regulate cellular siRNA. Taken these together, perhaps the melanocytes harboring ADAR1 mutation are more prone to proapoptotic stimuli that resulted in melanocyte depletion seen in hypopigmented lesions. It is unknown why pigmentary changes in DSH are localized specifically on dorsum of hands and feet. Miyamura et al speculated that during development, distal migration of melanoblasts from the neural crest to the skin is associated with a greater reduction in ADAR activity at anatomic sites most distant from the neural crest. Impaired RNA editing from adenosine to inosine may result in differentiations of melanoblasts into either hyper- or hypoactive melanocytes that colonize the skin in an irregular distribution. This may contribute to the preferential distribution of the mottled hyper- and hypopigmentation seen on dorsum of hands and feet in DSH. Although DSH generally shows an autosomal-dominant pattern of inheritance with high penetrance, clinical features were not always similar among the patients in a pedigree. Other factors such as viral infections in utero and in infancy, and repeated exposure to ultraviolet light, could influence the phenotype expression to some extent. We have previously discussed the possible role of sunlight in the pathogenesis of DSH. The index case developed asymptomatic mixture of small hyper- and hypopigmented macules on the back of the hands and feet in childhood. DSH was further confirmed with mutation analysis, in which the daughter and younger sister of the index case had the same mutation. Significant improvement of the dyspigmentation was seen after strict sun protection. This may suggest that some variable environmental factors such as sun exposure could influence the phenotypes. Further studies are needed to elucidate the role of sunlight in the pathogenesis and/or progression of pigment alterations in DSH. Due to the current lack of active treatment, vigorous protection from sunlight is still encouraged.