Correspondence: Tamio Suzuki, M.D., Ph.D., Department of Dermatology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. Email: email@example.com
Dyschromatosis symmetrica hereditaria (DSH) is a rare pigmentary genodermatosis, which is acquired by autosomal dominant inheritance with high penetrance. Most cases of this condition have been reported from East Asian countries, including Japan, China and Taiwan. Its symptoms are mixed hyper- and hypopigmented macules on the dorsal aspect of the hands and feet and freckle-like macules on the face. The gene responsible for DSH has been identified as adenosine deaminase acting on RNA1 (ADAR1). The ADAR1 protein catalyzes the transformation of adenosine to inosine in dsRNA substrates (so-called A-to-I editing) and is involved in various activities, such as viral inactivation, structural change of the protein and the resultant cell survival. However, its function in the skin and role in the development of DSH are still unknown. To date, more than 100 mutations of ADAR1 have been reported in patients with DSH, and the catalytic domain deaminase is believed to be crucial to the activities of this gene. Some complications of DSH have been reported and, intriguingly, several patients have been reported to develop neurological symptoms, such as dystonia and mental deterioration. Because ADAR1 plays various important roles in human tissue, we believe that a clarification of the pathogenesis of DSH will promote the understanding of the physiological functions of ADAR1, which will have significant scientific implications.
HISTORICAL AND CLINICAL OVERVIEW OF DYSCHROMATOSIS SYMMETRICA HEREDITARIA
Dyschromatosis symmetrica hereditaria (DSH; Mendelian Inheritance in Man no. 127400) is a rare pigmentary genodermatosis of autosomal dominant inheritance with high penetrance. In 1910, Toyama reported the first case of a unique pigmentation pattern on the dorsal aspect of the distal extremities; later, he named this entity DSH. Initially, most cases from Japan had been reported in Japanese. Oyama et al. reviewed 185 cases of DSH from Japanese, English and some European published work. After ADAR1 was identified as the gene responsible for DSH, many additional cases of mutations of this gene have been reported, mainly from East Asia.[6-8] Case reports have also been published from India, Europe and South America. While many cases reported to date are familial, some sporadic cases have also been reported. The exact frequency of DSH is unknown; this is explained by the fact that patients with DSH usually manifest only skin symptoms, which may lead to underreporting because some patients may not mind the skin lesions.
Dyschromatosis symmetrica hereditaria is clinically manifested by intermingled hyper- and hypopigmented macules on the dorsal aspect of the distal extremities and freckle-like macules on the face (Fig. 1). The rashes usually appear in infancy or early childhood. Fundamentally, the symptoms of DSH are limited to the skin (the complications of this disease are discussed later in this manuscript). At first, hypopigmented macules appear on the dorsal aspect of hands and feet without any obvious antecedent event, but these hypopigmented macules are not sometimes recognized because of their faintness and incomplete leukoderma. Freckle-like macules also appear on the face. The development of hypopigmented plaques is followed by the appearance of scattered hyperpigmented macules within the hypopigmented regions. Very interestingly, once these hypo- and hyperpigmented lesions are fully established, they persist throughout life, without any change in color or distribution.
Histologically, the number of the melanocytes in the hypopigmented areas of the skin are markedly lower than that in the skin of normal control persons. In another study, melanin deposition was also found to be scarce in the hypopigmented areas, while it was abundant in the hyperpigmented areas. Electron microscopic examination has revealed that the cells of the lesions exhibit degenerative mitochondria and cytoplasmic vacuole formation,[13, 14] which is indicative of apoptosis. The hyperpigmented areas of the lesions show small or immature melanosomes scattered sparsely in the melanocytes and many small melanosomes dispersed or aggregated in the adjacent keratinocytes. These findings suggest the melanosome transfer from the melanocyte to the keratinocyte is more active than its production in the melanocyte.
The presentation of a typical case of DSH is different from that of other hereditary pigmentary disorders, such as “reticulate acropigmentation of Kitamura” (RA) and dyschromatosis universalis hereditaria (DUH). RA is characterized by atrophic pigmented macules on the dorsal aspect of the hands and feet and palmoplantar pits. DUH presents with hyper- and hypopigmented macules distributed all over the body. In addition, ADAR1 mutation analysis has shown that these entities are genetically distinct.
Mild cases or early-stage xeroderma pigmentosum (XP) is another condition included in the differential diagnosis of DSH. XP is distinguished from DSH by the development of progressively worsening skin symptoms, such as xerosis, atrophy, telangiectasia, and skin tumors on sun-exposed areas, as the patients grow older. The conditions are also distinct genetically.
ADAR1 AND ITS FUNCTIONS
Towards the end of the 1990s, linkage analyses of families affected by DSH were performed to identify the responsible gene, and several reports have since been published from Japan in 2000 and China in 2003. Eventually, in 2003, Miyamura et al. identified adenosine deaminase acting on RNA1 (ADAR1) as the gene responsible for DSH.
ADAR1 maps to chromosome 1q21.1–21.2, spans up to 40 kb, and contains 15 exons. It produces interferon-inducible or long-form (p150) and constitutively expressed or short-form (p110) ADAR1 protein, due to alternative splicing. Because the p110 isoform does not contain the first ATG translation initiation codon in exon 1, translation begins at codon 296 located in exon 2, and its transcript is truncated at the N-terminal. The ADAR1 protein is expressed ubiquitously in human tissue. The p150 protein is expressed in both the nucleus and the cytoplasm, whereas the p110 protein is primarily expressed in the nucleus. The p150 protein includes two series of Z-DNA-binding domains in the N-terminal region (Zα and Zβ), three series of dsRNA-binding domains (DRB) and a deaminase domain in the C-terminal region. Because of the truncation at the N-terminal side, the p110 form lacks the Zα motif (Fig. 2). Although the Zα domain is presumed to play some role in antiviral response, the mechanism still remains to be clarified.
ADAR1 catalyzes the conversion of adenosine (A) to inosine (I) in dsRNA substrates, a process known as A-to-I editing (Fig. 3). The catalytic action of ADAR1 for A-to-I modification changes adenosine of dsRNA to inosine. This action reduces double-strandness and provides amino acid substitution in the protein-translation machinery, thereby leading to the change in the sequence information and structures, because I is recognized as G instead of A by ribosomes and polymerases.
Previous in vitro studies suggest ADAR1 is involved in several physiological activities, such as virus inactivation (e.g. measles virus, HIV and hepatitis C virus) and alteration in the properties of the neurotransmitter receptor for l-glutamate (GluR) and serotonin (5-HT2cR) through this A-to-I editing process. Recent studies have revealed that ADAR1 is one of the important modulators of the innate antiviral response. Because interferons are cytokines with antiviral activity, the interferon-inducible isoform, p150, is assumed to be involved in the course of viral infections.[27, 29, 30]
A study on Adar1-null knockout mice also showed embryonic lethality and widespread apoptosis in various organs, indicating that Adar1 also plays a crucial role in cell survival in many tissues and protection against stress-induced apoptosis. Recently, an epidermis-specific Adar1 knockout mouse model was generated. Histologically, this gene knockout resulted in massive necrosis of the epidermis in FVB background mice and thickening of keratinocytes and the stratum corneum in B6 background mice. Therefore, Adar1 was thought to be an essential molecule for the maintenance of skin integrity, although the detailed function of Adar1 in the skin remains unknown.
ADAR1 MUTATIONS IN DSH
Since the publication of the report indicating that DSH is caused by a pathological mutation of ADAR1 in 2003,  52 missense mutations, 45 frame-shift mutations, 21 nonsense mutations and nine splice-site mutations have been reported to date (Tables 1 and 2). While the majority of them are missense or frame-shift mutations within the deaminase domain, frame-shift and nonsense mutations outside the deaminase domain leading to premature termination (without the deaminase domain) have also been reported. In vitro mutagenic analysis of ADAR1 has shown that some specific amino acid changes within the deaminase domain completely abolishes A-to-I editing activity. Recently, a missense mutation located within the dsRNA-binding domain (p.A561V) was identified in a Japanese pedigree. The dsRNA-binding motif is known to show a high homology and is conserved in several species. These data on mutation sites and findings of in vitro studies indicate that both the deaminase domain and the dsRNA-binding domain are quite important for exerting ADAR1 catalytic activity.
Table 1. ADAR1 mutational spectrum in patients with DSH (missense mutation)
Some mutations have been reported to occur upstream of the initiate codon of p110 isoform. In these cases, the expression of the p150 isoform is considered to be decreased or lost, while that of p110 is retained. Considering these findings, the p150 isoform is presumed to play a more crucial role than p110 in the pathogenesis of DSH.
The relationship between gene penetrance and genotype–phenotype correlations in the large Japanese pedigrees has been reported.  A study revealed that although the degree of these lesions vary among patients, all the carriers of the ADAR1 mutation had skin lesions, indicating that gene penetrance of DSH is 100%. Clinical features were not always similar among the patients with the same mutation in the pedigree, thereby suggesting that some factors, such as viral infection in utero and/or in infancy and exposure to ultraviolet light, may affect the phenotype expression.
COMPLICATION OF DSH
Various complications have been reported in patients with DSH. Intriguingly, two patients harboring the c.3019G>A (p.G1007R) mutation developed mental deterioration, dystonia and brain calcification.[38, 39] In addition, Patrizi et al. and Kaliyadan et al. reported torsion dystonia, developmental regression, and dystonia in patients with DSH, although the investigators did not perform genetic analysis. On the other hand, in another case of the c.3019G>A (p.G1007R) mutation, no neurological abnormality was noted. Thus, the relationship between this mutation and neurological symptoms is still unknown.
Recently, other complications such as acral hypertrophy, psoriasis[42, 43] and depression have also been reported, but none of them have consistent mutations and the significant relationship with DSH is still unknown.
PATHOGENESIS OF DSH
As mentioned above, previous in vitro studies have indicated that ADAR1 is related to viral inactivation; ADAR1-null knockout mice have been reported to show extensive apoptosis in many organs. Histological and electron microscopic examination has revealed that the number of the melanocytes in the hypopigmented areas of patients with DSH is obviously lower than that in normal skin and that the melanocytes show degenerative vacuolation, which is indicative of apoptosis. Considering these findings, we speculate that the apoptosis in melanocytes with ADAR1 mutation is triggered by some stress factors, such as viral infection; this leads to the formation of hypopigmented lesions. Then, the remnant melanocytes in the bulge area of hair follicles migrate toward the epidermis to form hyperpigmented macules, which eventually leads to the appearance of the unique clinical features of DSH. This hypothesis, however, still leaves some questions, such as the following, unanswered: Why are these regenerated pigment macules darker than the unaffected skin? Why does this rash appear only in face and dorsal aspects of the extremities?
Because ADAR1 plays several important roles in human tissue, we believe that clarifying the pathogenesis of DSH would facilitate the understanding of the physiological function of ADAR1 and have significant scientific implications. To this end, we have been trying to establish the in vitro model of DSH and elucidate its pathogenesis.
This work was supported by a grant from the Ministry of Health, Labor, and Welfare of Japan (Health and Labor Sciences Research Grants; Research on Intractable Diseases; H24-039) and a grant (no. 22591236) from the Ministry of Education, Sports, Culture, Science and Technology of Japan to T. S.