Alternative titles; symbols
SNOMEDCT: 239085000; ORPHA: 41; DO: 0060257;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.3 | Dyschromatosis symmetrica hereditaria | 127400 | Autosomal dominant | 3 | ADAR | 146920 |
A number sign (#) is used with this entry because dyschromatosis symmetrica hereditaria (DSH) is caused by heterozygous mutation in the DSRAD gene (ADAR; 146920) on chromosome 1q21.
Dyschromatosis symmetrica hereditaria (DSH), also called symmetric dyschromatosis of the extremities and symmetric or reticulate acropigmentation of Dohi (Komaya, 1924), is characterized by hyperpigmented and hypopigmented macules on the face and dorsal aspects of the extremities that appear in infancy or early childhood. DSH generally shows an autosomal dominant pattern of inheritance with high penetrance. The condition has been reported predominantly in Japanese and Chinese individuals.
Aicardi-Goutieres syndrome-6 (AGS6; 615010) is an allelic disorder, and patients have been reported who exhibit features of both disorders.
Review of Reticulate Pigment Disorders
Muller et al. (2012) reviewed the spectrum of reticulate pigment disorders of the skin, tabulating all reported cases of patients with Dowling-Degos disease (see DDD1; 179850), reticulate acropigmentation of Kitamura (RAK; 615537), reticulate acropigmentation of Dohi (RAD), Galli-Galli disease (GGD), and Haber syndrome (HS). Of 82 cases, 26 (31.7%) were clinically diagnosed as DDD, 13 (15.9%) as RAD, 11 (13.4%) as GGD, 8 (9.8%) as RAK, and 8 (9.8%) as HS; in addition, 16 (19.5%) of the cases showed overlap between DDD and RAK. Muller et al. (2012) also published photographs of an affected individual exhibiting an overlap of clinical features of DDD, GGD, RAD, and RAK. The authors noted that in reticulate disorders of the skin, the main disease entity is DDD, with a subset of cases exhibiting acantholysis (GGD), facial erythema (HS), or an acral distribution (RAD; RAK). Muller et al. (2012) concluded that all reticulate pigment diseases of the skin are varying manifestations of a single entity.
Genetic Heterogeneity of Reticulate Pigment Disorders
For a discussion of genetic heterogeneity of reticulate pigment disorders, see 179850.
Patrizi et al. (1994) described a 9-year-old Caucasian girl with a mixture of hyperpigmented and hypopigmented macules on the backs of the feet. Two brothers had the same lesions, and all had small freckle-like pigmented macules on their face. The father showed large symmetrical hypopigmented vitiligo-like macules which had been present on the backs of his hands and the tops of his feet since childhood. Large symmetrical hypopigmented vitiligo-like macules were found also around his eyes and mouth, on his knees, and on his penis. These hypopigmented macules had progressively widened after the age of 28 years. The 9-year-old daughter had, since the age of 7 years, also shown a neurologic disorder diagnosed as idiopathic torsion dystonia. In all 4 patients, no cellular abnormality in DNA repair was demonstrated, thus excluding a mild form of xeroderma pigmentosum. Torsion dystonia (TYD1; 128100) maps to 9q34. Because of the family of Patrizi et al. (1994), the DSH gene was hypothesized to be located on chromosome 9, but studies of 3 Japanese families with DSH by Kono et al. (2000) excluded chromosome 9.
Oyama et al. (1999) reported a Japanese family with DSH. The proband was an 11-year-old male, born following a normal pregnancy and delivery. At the age of 1 year, he developed pea-sized pigmented macules on the face. The small hyperpigmented and hypopigmented macules spread gradually on the dorsal aspects of the extremities. The number of skin lesions increased until he was 4 years of age. The mother, a 50-year-old woman, had had an asymptomatic mixture of hyperpigmented and hypopigmented small macules on the backs of her hands and feet as well as scattered small pigmented macules on her face since childhood. Her father, twin brothers of her father, and her grandmother had also had the same skin lesions.
Oyama et al. (1999) reviewed 185 cases of DSH reported since 1923. The differential diagnosis was considered to include dyschromatosis universalis hereditaria (DUH; 127500). DUH was once considered to be a generalized form of DSH; however, Suenaga (1952) pointed out that skin lesions in DUH appear predominantly on the trunk. DSH can closely resemble a mild form of xeroderma pigmentosum (see 278700).
In Italy, Danese et al. (1997) observed a family with affected members in at least 3 generations. The proband was a 21-year-old white woman who had progressive reticulate hyper- and hypopigmentation on the volar surface of the forearms and the dorsa of the hands. There were no pits or breaks in the epidermal ridge pattern on the palms.
Urabe and Hori (1997) described a Japanese family with DSH with an autosomal recessive inheritance pattern. Alfadley et al. (2000) described 3 black sibs from the Middle East, a 20-year-old male and his 19- and 18-year-old sisters, who had progressive reticulate hyperpigmented and hypopigmented macules over the dorsa of hands and feet, which began in early childhood. There were no palmar pits or breaks of the epidermal rete ridge pattern, nor was there a family history of any pigmentary skin disease. Findings from 3 skin biopsies from 1 patient were consistent with DSH. These finding suggested to the authors that DSH may be inherited in an autosomal recessive manner.
Chao et al. (2006) reported 3 affected members of a Taiwanese family segregating DSH. Strict avoidance of sunlight by the proband and her affected daughter led to improvement in the skin lesions.
Dong et al. (2009) reported a 12-year-old Chinese girl with DSH and mutation in the ADAR gene. She had asymptomatic hypopigmented small macules on the extensor aspect of her fingers and toes at birth, and later developed a mixture of hyper- and hypopigmented macules that were irregular in size and shape on the dorsal aspect of her hands and feet. She also had freckles on her face. The skin lesions became more pronounced after sun exposure. Her father and paternal grandfather also developed a mixture of hyper- and hypopigmented macules of various sizes on the dorsal extremities in childhood.
Clinical Variability
Tojo et al. (2006) reported a 22-year-old Japanese woman who had DSH associated with dystonia, mental deterioration, intracranial calcifications (see AGS6, 615010), and a mutation in the ADAR gene. The proband was noted to have pea-sized pigmented macules on her face by age 3 years, and the small hyper- and hypopigmented macules spread gradually to the dorsal aspect of her extremities. School records and motor function were normal in childhood. She developed neurologic symptoms including gait disturbance and dystonic posturing of the legs at age 17, and became wheelchair-bound by age 22. Intellectual deterioration started at age 21. Brain CT showed calcification of basal ganglia, cerebral white matter, and dentate nucleus of cerebellum. Her father had had typical skin lesions of DSH noted at age 2 years, and he lost the ability to ride a motorbike in adult life with the development of intellectual deterioration. No brain imaging was reported, and he died of calcific aortic valve stenosis at Age 38. The authors noted the report of Patrizi et al. (1994) of a 9-year-old Caucasian girl with DSH who developed torsion dystonia at age 7 years.
Kondo et al. (2008) described an 11-year-old Japanese boy with DSH associated with dystonia, mental deterioration, brain calcification, and mutation in the ADAR gene. He developed neurologic features at age 3 years, including axial torsion dystonia and loss of intellectual skills. Brain CT showed basal ganglia, cerebral white matter, and dentate nucleus calcification. His mother had faint hypopigmented macules on the dorsa of the fingers, but no neurologic features were reported.
Miyamura et al. (2003) stated that the prevalence of DSH in the Japanese population is estimated to be 1.5 per 100,000.
Zhang et al. (2003) performed a genomewide search in 2 large Chinese families with DSH and identified a locus at chromosome 1q11-q21 with a cumulative maximum 2-point lod score of 8.85 at marker D1S2343 (recombination fraction = 0.00). Haplotype analyses indicated that the disease gene is located within the 11.6-cM region between markers D1S2696 and D1S2635.
Miyamura et al. (2003) performed a genomewide search in 3 families with DSH and mapped the DSH locus to 1q21.3, within a 500-kb critical region bounded proximally by IL6R (147880) and distally by KCNN3 (602983).
Miyamura et al. (2003) suggested that the patients reported by Xing et al. (2003) showing linkage to 6q24.2-q25.2 in fact had dyschromatosis universalis hereditaria, as indicated by photographs showing dyschromatosis over most of their entire bodies.
The transmission pattern of DSH in the families reported by Miyamura et al. (2003) was consistent with autosomal dominant inheritance.
In affected members of 4 Japanese families segregating DSH, Miyamura et al. (2003) identified heterozygous mutations in the ADAR gene (146920.0001-146920.0004).
In affected members of 6 Chinese multigeneration families and 2 sporadic patients with DSH, Zhang et al. (2004) identified 7 novel heterozygous mutations in the ADAR gene.
In a 22-year-old Japanese woman who had DSH associated with dystonia, mental deterioration, and intracranial calcifications, Tojo et al. (2006) identified heterozygosity for a missense mutation in the ADAR gene (G1007R; 146920.0011). Her unaffected mother and sister did not carry the mutation; DNA was unavailable from her affected deceased father.
In a Taiwanese woman with DSH, Chao et al. (2006) identified heterozygosity for a nonsense mutation in the ADAR gene (Q693X; 146920.0005) that segregated with disease in the family.
In affected members of a large 5-generation Chinese family with DSH, Xing et al. (2007) identified heterozygosity for a 2-bp deletion in the ADAR gene (146920.0006).
In an 11-year-old Japanese boy who had DSH associated with dystonia, mental deterioration, and intracranial calcifications, Kondo et al. (2008) identified heterozygosity for the previously reported G1007R mutation in the ADAR gene (146920.0011). His mother, who had skin lesions but no neurologic features, was also heterozygous for the mutation.
In a 12-year-old Chinese girl with DSH and her affected father and paternal grandfather, Dong et al. (2009) sequenced the ADAR gene and identified heterozygosity for an H958R substitution in all 3. The mutation was not found in the proband's unaffected paternal uncle and aunt, or in 50 unrelated Chinese controls.
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Chao, S.-C., Huang, C.-Y., Yang, M.-H. A novel nonsense mutation of the DSRAD gene in a Taiwanese family with dyschromatosis symmetrica hereditaria. Europ. J. Derm. 16: 449-540, 2006. [PubMed: 16935814]
Danese, P., Zanca, A., Bertazzoni, M. G. Familial reticulate acropigmentation of Dohi. J. Am. Acad. Derm. 37: 884-886, 1997. [PubMed: 9366859] [Full Text: https://doi.org/10.1016/s0190-9622(97)80018-7]
Dong, Y., Xiao, S., Ren, J., Huo, J., Liu, Y., Li, X. A novel missense mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. Europ. J. Derm. 19: 270-272, 2009. [PubMed: 19251566] [Full Text: https://doi.org/10.1684/ejd.2009.0639]
Komaya, G. Symmetrische Pigmentanomalie der Extremitaeten. Arch. Derm. Syph. 147: 389-393, 1924.
Kondo, T., Suzuki, T., Ito, S., Kono, M., Negoro, T., Tomita, Y. Dyschromatosis symmetrica hereditaria associated with neurological disorders. J. Derm. 35: 662-666, 2008. [PubMed: 19017046] [Full Text: https://doi.org/10.1111/j.1346-8138.2008.00540.x]
Kono, M., Miyamura, Y., Matsunaga, J., Tomita, Y. Exclusion of linkage between dyschromatosis symmetrica hereditaria and chromosome 9. J. Derm. Sci. 22: 88-95, 2000. [PubMed: 10674821] [Full Text: https://doi.org/10.1016/s0923-1811(99)00050-x]
Miyamura, Y., Suzuki, T., Kono, M., Inagaki, K., Ito, S., Suzuki, N., Tomita, Y. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am. J. Hum. Genet. 73: 693-699, 2003. [PubMed: 12916015] [Full Text: https://doi.org/10.1086/378209]
Muller, C. S. L., Tremezaygues, L., Pfohler, C., Vogt, T. The spectrum of reticulate pigment disorders of the skin revisited. Europ. J. Derm. 22: 596-604, 2012. [PubMed: 23018017] [Full Text: https://doi.org/10.1684/ejd.2012.1829]
Oyama, M., Shimizu, H., Ohata, Y., Tajima, S., Nishikawa, T. Dyschromatosis symmetrica hereditaria (reticulate acropigmentation of Dohi): report of a Japanese family with the condition and a literature review of 185 cases. Brit. J. Derm. 140: 491-496, 1999. [PubMed: 10233273] [Full Text: https://doi.org/10.1046/j.1365-2133.1999.02716.x]
Patrizi, A., Manneschi, V., Pini, A., Baioni, E., Ghetti, P. Dyschromatosis symmetrica hereditaria associated with idiopathic torsion dystonia: a case report. Acta Derm. Venerol. 74: 135-137, 1994. [PubMed: 7911621] [Full Text: https://doi.org/10.2340/0001555574135137]
Suenaga, M. Genetical studies on skin diseases. VII. Dyschromatosis universalis hereditaria in five generations. Tohoku J. Exp. Med. 55: 373-376, 1952. [PubMed: 14950856] [Full Text: https://doi.org/10.1620/tjem.55.373]
Tojo, K., Sekijima, Y., Suzuki, T., Suzuki, N., Tomita, Y., Yoshida, K., Hashimoto, T., Ikeda, S. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov. Disord. 21: 1510-1513, 2006. [PubMed: 16817193] [Full Text: https://doi.org/10.1002/mds.21011]
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Xing, Q., Shu, A., Yu, L., Zhang, A., Du, J., Xuan, J., Wang, L., He, G., Meng, J., Li, X., Feng, G., He, L. Novel deletion mutation of DSRAD in a Chinese family with dyschromatosis symmetrica hereditaria (DSH). Europ. J. Derm. 17: 247-248, 2007. [PubMed: 17478391] [Full Text: https://doi.org/10.1684/ejd.2007.0161]
Xing, Q., Wang, M., Chen, X., Feng, G., Ji, H., Yang, J., Gao, J., Qin, W., Qian, X., Wu, S., He, L. A gene locus responsible for dyschromatosis symmetrica hereditaria (DSH) maps to chromosome 6q24.2-q25.2. Am. J. Hum. Genet. 73: 377-382, 2003. [PubMed: 12815562] [Full Text: https://doi.org/10.1086/377007]
Zhang, X.-J., Gao, M., Li, M., Li, M., Li, C.-R., Cui, Y., He, P.-P., Xu, S.-J., Xiong, X.-Y., Wang, Z.-X., Yuan, W.-T., Yang, S., Huang, W. Identification of a locus for dyschromatosis symmetrica hereditaria at chromosome 1q11-1q21. J. Invest. Derm. 120: 776-780, 2003. [PubMed: 12713580] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12130.x]
Zhang, X.-J., He, P.-P., Li, M., He, C.-D., Yan, K.-L., Cui, Y., Yang, S., Zhang, K.-Y., Gao, M., Chen, J.-J., Li, C.-R., Jin, L., Chen, H.-D., Xu, S.-J., Huang, W. Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria. Hum. Mutat. 23: 629-630, 2004. [PubMed: 15146470] [Full Text: https://doi.org/10.1002/humu.9246]