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    • According to Lai et al more than

    2018-11-15

    According to Lai et al, more than 122 different ADAR1 mutations have been detected. The full-length 1226-aa ADAR1 protein contains six functional domains including dsRNA adenosine deaminase domain (ADEAMc). The ADEAMc, which encompasses Necrostatin 1 886–1221, has been proposed as a hot spot for mutations. About 62% of the currently known mutations for DSH have been reported in this domain. Patient 6 had a missense mutation located within this domain. The other domains are two Z-DNA-binding domains and three dsRNA-binding motif (DRBM) repeats. Patients 2, 9, and 11 had mutation located in DRBM2, whereas Patients 3 and 4 in DRBM1 and DRBM3, respectively. Due to the limited number of patients with mutation analysis in this series, we could not claim conclusive hot spot for mutations in our study. DSH generally shows an autosomal-dominant pattern of inheritance, but cases of autosomal-recessive type and spontaneous origin have been noted, mainly in the West. We have previously identified two novel deletion mutations of the ADAR1 gene. Family pedigree of both patients suggested sporadic cases of DSH. To date, clinical manifestations observed in patients with DSH showed no obvious phenotypic variations and no evident genotype–phenotype correlations between affected individuals. No correlation was found between the extent of skin lesions and the mutations sites. Even in the same pedigree, the extent of skin lesions differed among patients. As mentioned earlier, some variable environmental factors such as sun exposure could influence the phenotypes. Histological studies characteristically show abundant melanin pigment in keratinocytes and melanocytes in hyperpigmented macules but reduced melanization in hypopigmented ones. To assess epidermal melanization and melanocytic density, Masson-Fontana staining and immunostaining for S-100 and Melan-A are helpful. From experience, we believe that Melan-A is superior to S-100 in displaying better morphology and larger number of melanocytes in the epidermis. Sheu and Yu noted decreased epidermal melanocyte counts in both hyper- and hypopigmented lesions. Similarly in our data, Patients 8 and 10 showed reduced number of melanocytes in both lesions. Patient 5, however, had normal and reduced number of melanocytes in the hyper- and hypopigmented macules, respectively. The difference might be attributable to the different sampling or assessment methods. Ultrastructural study was done in Patient 10, which revealed large clusters of melanosomes in the keratinocytes and a few melanocytes with dendrites containing melanosomes. In the hypopigmented lesion, melanocytes were small and not easily found. Most keratinocytes showed few or no melanosomes. Our findings are consistent with those of previous reports. Sheu and Yu precisely described small or immature melanosomes scattered sparsely in the melanocytes but many small ones in the adjacent keratinocytes in the hyperpigmented area. Melanocyte abnormalities of the hypomelanotic skin included decrease in the number of melanocytes, fatty degeneration, swollen mitochondria, large vacuolization of the cytoplasm, and condensed, irregularly shaped nucleus. In general, DSH is not accompanied by systemic involvement or common associated disorder. Despite the rarity of extracutaneous manifestations, we have previously identified Patient 10 with DSH and seizure, mental retardation, and autistic disorder. Similarly, Patients 9 and 23 also had the coexistence of seizure and tardive dystonia with mood disorder, respectively. Hypotonia, mental retardation, agitation, schizophrenia, type I neurofibromatosis, thalassemia, polydactyly, and torsion dystonia had been observed in other cases of DSH elsewhere. Tojo et al reported a mutation of p.G1007R in the ADAR1 gene in a DSH patient accompanied by dystonia and mental deterioration. Interestingly, the same mutation was also reported by Kondo et al in a DSH patient associated with dystonia, mental deterioration,and brain calcification. Clearly, the relationship between DSH and neurological or mental disorder deserves to be further clarified. In Patient 25, we also observed association with psoriasis. Shi et al recently reported the coexistence of DSH and psoriasis in a 28-year-old man. He had a single-nucleotide transversion (T to A at the base 2632) and a two-nucleotide deletion (2633–2634delCT) in the ADAR1 gene. The patient had no family history of psoriasis. Because both diseases are quite different in entities, coexistence of these two unrelated diseases may simply be coincidental without significant intrinsic factors.