Clinical Overlaps in Reticulate Pigmentary Disorders: A Study of Three Cases.

Reticulate pigmentary disorders are autosomal dominant pigmentary disorders caused by abnormalities in the keratin 5 and keratin 14 genes. Here, we report three cases of reticulate hyperpigmentation disorders with clinical overlaps of the reticulate acropigmentation of Kitamura, Dowling-Degos disease (DDD), and dyschromatosis symmetrica hereditaria (DSH), all three having limited treatment options.

Investigation of the pathogenesis of ADAR1 gene in dyschromatosis symmetrica hereditaria.

The pathogenesis of dyschromatosis symmetrica hereditaria (DSH) has not been well defined. In this study, we sought to investigate the influence of the ADAR1 gene on DSH both in vitro and in vivo. Morpholino knockdown of adar1 in zebrafish produced phenotypes characterized by polarity changes, and abnormal migration and distribution of melanocytes. Differential expression of C-KIT and distinct patterns of apoptosis between hyperpigmented and hypopigmented areas in DSH patient were detected by means of immunohistochemical methods and TUNEL assays, respectively. This study revealed that adar1 knockdown in a zebrafish model resulted in abnormal migration and changes in the cell polarity of melanocytes, and provided novel insight into the mechanism of DSH pathogenesis.

Dyschromatosis symmetrica hereditaria: A clue to early diagnosis of Aicardi-Goutières syndrome.

A 6-year-old female with a history of Aicardi-Goutières syndrome (AGS) presented to dermatology clinic with hypopigmented and hyperpigmented macules and patches consistent with dyschromatosis symmetrica hereditaria (DSH). Previous genetic workup demonstrated a de novo, heterozygous mutation in the adenosine deaminase acting on RNA 1 (ADAR) gene. While the co-occurrence of AGS and DSH has previously been described in mutations of the ADAR gene, our case highlights the potential association between these disorders that may aid in earlier future diagnosis of AGS.

Inherited Reticulate Pigmentary Disorders.

Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs include dyschromatosis symmetrica hereditaria (DSH), dyschromatosis universalis hereditaria (DUH), reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), dyskeratosis congenita (DKC), Naegeli-Franceschetti-Jadassohn syndrome (NFJS), dermatopathia pigmentosa reticularis (DPR), and X-linked reticulate pigmentary disorder. Although reticulate pattern of pigmentation is a common characteristic of this spectrum of disorders, the distribution of pigmentation varies among these disorders, and there may be clinical manifestations beyond pigmentation. DSH, DUH, and RAK are mostly reported in East Asian ethnicities. DDD is more common in Caucasians, although it is also reported in Asian countries. Other RPDs show no racial predilection. This article reviews the clinical, histological, and genetic variations of inherited RPDs.

A Case Report of Dyschromatosis Symmetrica Hereditaria with Glucose-6-Phosphate Dehydrogenase Deficiency.

Dyschromatosis symmetrica hereditaria (DSH) is a pigmented genetic skin disorder with an incompletely understood pathogenesis characterized by reticular hyper- and hypopigmented skin patches on the dorsal aspect of the extremities, freckle-like patches on the face, and unaffected palms and feet. There is no effective treatment available. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has not been reported in the literature of DSH. We describe for the first time a case of DSH with G6PD deficiency and a family history of psychosis.

Identification of Two Novel Frameshift Mutations of the ADAR1 Gene in Two Chinese Families With Dyschromatosis Symmetrica Hereditaria.

Background: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant skin disease. The mutation of the ADAR1 gene is the pathogenesis of this disorder. Aims: This study aimed to identify the mutations of the ADAR1 gene in two Chinese families with DSH. Methods and Materials: Eight patients from two Chinese families were diagnosed with DSH clinically. Blood samples were collected from the patients and unaffected individuals. Sanger sequencing for all polymerase chain reaction products of the whole coding regions of the ADAR1 gene was performed to identify the mutations. Mutation Taster software was used to predict the impact of the variant on the resultant protein. Results: The c.3358-3359insT (p.L1053fs-1092X) mutation in exon 12 was found in affected members of the pedigree1. In pedigree2, the c.3820-3821insG (p.G1207fs-1213X) mutation in exon 15 was found. These two mutations were not found in 100 unrelated healthy people. In this study, both mutations were damaged by the Mutation Taster software. Conclusions: We identified two novel frameshift mutations in the ADAR1 gene. Our study expands the database of ADAR1 gene mutations in DSH.

Mutation analysis of the ADAR gene in two cases of dyschromatosis symmetrica hereditaria and a survey of their families / 中华皮肤科杂志

Objective:To investigate two Chinese pedigrees with dyschromatosis symmetrica hereditaria (DSH) , and to analyze gene mutations in the pedigrees.Methods:Clinical data were collected from two probands with DSH and other family members in their pedigrees. Peripheral blood samples were obtained from the two probands, their parents and 100 unrelated healthy controls. Gene mutations were detected by using a skin-targeted sequencing panel, and then verified by Sanger sequencing.Results:Case 1, an 18-year-old male patient, presented with millet-sized hyperpigmented and hypopigmented macules scattered on the dorsum of both hands and feet at the age of 5 years, and his mother had similar manifestations. A novel heterozygous frameshift mutation c.1970dupT (p.F657fs) was identified in exon 5 of the ADAR gene in case 1 and his mother, but not found in his father. Case 2, an 8-year-old male patient, presented with mottled rice- to soybean-sized brown hyperpigmented macules and hypopigmented macules on the face and neck, lower back, buttocks, lower limbs, as well as hands and feet, and his father presented with similar manifestations. A known heterozygous frameshift mutation c.2433_2434delAG (p.T811fs) was identified in exon 7 of the ADAR gene in case 2 and his father, but not found in his mother. Neither of the two mutations was identified in the 100 unrelated healthy controls.Conclusion:In this study, a novel mutation c.1970dupT (p.F657fs) in the ADAR gene was identified in a patient with DSH.

Pathogenesis of a variant in the 5' untranslated region of ADAR1 in dyschromatosis symmetrica hereditaria.

Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis caused by mutations in ADAR1. In this study, we performed mutation analysis on a family that included typical DSH patients. No mutations were found in any coding regions or exon-intron boundary regions of ADAR1, but a previously unreported non-coding heterozygous variant, c.-60A>G, was found in the 5' untranslated region (5'UTR) of ADAR1 in the proband and her mother. The function of 5'UTR in mRNA is not well-understood. To understand the pathogenesis of the variant and the function of the 5'UTR of ADAR1, we constructed two reporter genes carrying the ADAR1 5'UTR sequence with/without the variant between the PGK promoter and a luciferase coding sequence, and performed luciferase assays, semi-quantitative PCR analyses, and polysomal assays. In human melanocytes, c.-60A>G induced a 16% reduction in transcription and a 51% reduction in translation. Our results indicate that the 5'UTR c.-60A>G variant adversely affects the post-transcriptional step in gene expression, leading to DSH. Detailed functional assays of the 5'UTR of ADAR1 in the present study revealed the gene expression to be not only downregulated, but also upregulated by defects in 5'UTR depending on the locations. The regulation of translation by 5'UTR is very complicated.

Seven novel mutations of ADAR in multi-ethnic pedigrees with dyschromatosis symmetrica hereditaria in China.

BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH;OMIM: #127400) is a rare autosomal dominant skin disease of hyperpigmented and hypopigmented macules on the dorsal aspects of the feet and hands. The adenosine deaminase RNA-Specific (ADAR;OMIM: *146920) gene was identified as causing DSH. Although more than 200 mutations are reported, no research has included the pedigrees of ethnic minorities in China. To investigate clinical features and genetic factors among multi-ethnic families, seven multi-ethnic pedigrees with DSH were collected for analysis of hereditary characteristics and ADAR mutations. METHODS: All 15 exons and exon-intron sequences of the ADAR gene were amplified and Sanger sequenced from 25 patients and 36 normal controls from seven multi-ethnic DSH families with 100 healthy normal controls. Seven mutations were analyzed by Polyphen 2, SIFT and Provean. All mutations in ADAR with DSH were reviewed and genetic and clinical features were summarized for analysis. The ADEAMc domain may be a hot spot of ADAR mutations among patients with DSH. RESULTS: Seven novel mutations were identified in seven multi-ethnic pedigrees: c.497delA(p.Arg105fs), c.3352C>T(p.Gln1058*) and c.3722delT(p.Ser1181fs) were found in three Uygur families with DSH; c.1330A>G(p.Val332Met) and c.2702A>T(p.His841Leu) were found in two Kazakh pedigrees and c.1176G>A(p.Lys326Glu) and c.2861G>A(p.Arg892His) in two Hui pedigrees. We summarized 203 different mutations of ADAR from people with DSH. CONCLUSIONS: Seven novel mutations were identified in seven multi-ethnic families with DSH. Our study expands the genetic spectrum of ADAR mutations in DSH.

Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura: An update.

Dyschromatosis symmetrica hereditaria (DSH) and reticulate acropigmentation of Kitamura (RAK) are rare, inherited pigmentary diseases. DSH shows a mixture of pigmented and depigmented macules on the extremities. RAK shows reticulated, slightly depressed pigmented macules on the extremities. The causative gene of DSH was clarified as ADAR1 by positional cloning including linkage analysis and haplotype analysis in 2003. Ten years later, the causative gene of RAK was identified as ADAM10 by whole-exome sequencing, in 2013. ADAR1 is an RNA-editing enzyme which catalyzes the deamination of adenosine to inosine (A-to-I) in double-stranded RNA substrates during post-transcription processing. Inosine acts as guanine during translation, resulting in codon alterations or alternative splice sites that lead to functional changes in proteins when they occur in coding regions. In 2012, it was clarified that ADAR1 mutations cause Aicardi-Goutières syndrome 6, which is a severe genetic inflammatory disease that affects the brain and the skin. A zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), is involved in the ectodomain shedding of various membrane proteins and shows various functions in vivo. ADAM10 is known to be involved in the ectodomain shedding of Notch proteins as substrates in the skin. We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease similar to RAK) is associated with the Notch signaling pathway. In addition, ADAM10 mutations proved to be associated with late-onset Alzheimer disease. This review comprehensively discusses the updated pathophysiology of those genetic pigmentary disorders.

Recurrent Encephalopathy with Spinal Cord Involvement: An Atypical Manifestation of Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome (AGS) is a rare, genetic inflammatory disease due to mutations in any of the seven genes discovered to date (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1). Clinical onset is seen most commonly in utero or in infancy; irritability, feeding difficulties, jitteriness, microcephaly, abnormal movements, seizures, bone marrow suppression, and liver dysfunction are seen either during the neonatal age group or within the first few months of life with abrupt onset of neurologic regression and slowing of head growth. Diffusely abnormal white matters with swelling of frontal or temporal lobes, cerebral atrophy, and intracranial calcification are typical neuroradiologic abnormalities. However, ADAR mutation, a recently discovered AGS gene, can cause late-onset acute or subacute onset of severe dystonia and features of bilateral striatal necrosis on neuroimaging, in the absence of other typical features of AGS. We report a detailed description of a 5-year-old boy who had a recurrent encephalopathic presentation in the setting of infection. Magnetic resonance imaging (MRI) of brain revealed prominent and fairly symmetrical signal abnormalities in the cerebellar peduncles, thalamus, midbrain, and pons. His throat swab was positive for influenza B, and he was initially diagnosed with influenza encephalopathy. He had a recurrence after 18 months of his initial presentation, and his brain MRI showed extensive areas of signal abnormality similar to, but more extensive than, his previous scan. Extensive spinal cord swelling was also seen. His chronic skin finding was recognized as dyschromatosis symmetrica hereditaria (DSH), and genetic testing revealed compound heterozygous mutations of ADAR gene - causative for AGS. This is the first presentation of recurrent acute encephalopathy in the setting of documented ADAR mutation with the longest interval documented between two acute presentations. This is also the first documentation of extensive spinal cord involvement, which will expand its phenotype. This case also highlights the importance of early identification of DSH, a subtle but characteristic skin lesion of ADAR mutations, for prompt diagnosis of this rare condition.

Four novel mutations of ADAR1 in Chinese patients with dyschromatosis symmetrica hereditaria.

BACKGROUND: Novel mutations in adenosine deaminase acting on RNA 1 gene (ADAR1) are responsible for dyschromatosis symmetrica hereditaria (DSH). DSH patients display a mixture of hyperpigmented and hypopigmented macules on the dorsal aspects of the extremities, and freckle-like macules on the face. AIMS: To provide new evidence for further study of the etiopathogenisis of DSH. METHODS: Genomic DNA was extracted and used as a template for the polymerase chain reaction (PCR) amplification of all 15 coding exons as well as intron-exon boundaries of ADAR1. The PCR products were sequenced directly. RESULTS: We identified eight mutations of ADAR1 in four Chinese pedigrees and four individual patients, which were c.2722G>T, p.(Asp908Tyr), c.1657delA, p.(Ser553fs), c.2563_2564delCT, p.(Leu855fs), c.526T>G, p.(Leu176Val) as well as four previously reported mutations c. 3363_3364insT, p.(Lys1122fs), c. 2865_2866delGT, p.(Val955fs), c.1630C>T, p.(Arg544X), and c.2894C>T, p.(Pro965Leu). In silico analysis predicted that all the mutations reported were pathogenic. LIMITATIONS: We did not study how ADAR1 played its role in DSH. So, the exact pathogenic mechanism of ADAR1 in DSH patients wasn't clarified in this study. CONCLUSION: We found four novel ADAR1 mutations in this study. Our results enlarge the database on ADAR1 mutations associated with DSH.

Identification of a novel c. 2633_2634del CT variant of the ADAR gene in a patient with dyschromatosis symmetrica hereditaria / 中华医学遗传学杂志

Objective@#To explore the genetic etiology of two unrelated patients with dyschromatosis symmetrica hereditaria.@*Methods@#Variant analysis of the ADAR gene was carried out by Sanger sequencing.@*Results@#Patient 1 was found to harbor a c. 2633_2634delCT (p.Ser878fs) in exon 8 of the ADAR gene. The same variant was not found among 100 unrelated individuals. No pathogenic variant of the ADAR gene was found in patient 2. Functional prediction of the ADAR c. 2633_2634delCT (p.Ser878fs) variant indicated it to be pathogenic by losing a catalytic structural domain.@*Conclusion@#The c. 2633_2634delCT (p.Ser878fs) variant of the ADAR gene probably underlies the pathogenesis of DSH in one of the patients.

Analysis of genotype/phenotype correlations in Japanese patients with dyschromatosis symmetrica hereditaria.

Dyschromatosis symmetrica hereditaria (DSH) is one of the genetic pigmentation disorders and shows characteristic mixture of hyper- and hypo-pigmented small macules on the extremities. Heterozygous mutations in the adenosine deaminase acting on RNA1 gene (ADAR1) cause DSH. In the present study, we report five cases of DSH and identify a distinct known mutation in each patient. Furthermore, we review previously described cases with the five ADAR1 mutations found in the present study. We reviewed clinical and molecular findings in the present and previously reported cases and found an identical mutation can result in various phenotypic severities, even in one family. We found novel phenotype-genotype correlations between the presence/absence of facial lesions and the ADAR1 mutation c.3286C>T. The absence of freckle-like macules in the face was found to be more commonly associated with the mutation c.3286C>T than with the other 4 ADAR1 mutations (odds ratio = 0.056 [95% CI: 0.007-0.47, p < 0.005]). We objectively evaluated the severity of skin manifestations in the extremities using our definition of severity levels for such manifestations. This is the first semi-quantitative evaluation of skin manifestations in DSH. Using our definition, we found that patients with facial lesions with or without hypopigmented macules tend to show more severe symptoms on the extremities than patients without facials lesions show. Furthermore, no significant difference in the severity of the skin lesions was observed between the upper and the lower extremities, suggesting that sun exposure does not affect significantly the pathogenesis of DSH skin lesions.

Eight Novel Mutations of the ADAR1 Gene in Chinese Patients with Dyschromatosis Symmetrica Hereditaria.

AIMS: To identify potential novel gene mutations in Chinese patients with dyschromatosis symmetrica hereditaria (DSH). METHODS: We enrolled 8 Chinese patients with familial DSH, 5 Chinese patients with sporadic DSH, and 100 randomly selected healthy individuals in this study. The genome of each participant was extracted from peripheral blood samples. Sanger sequencing of the ADAR1 gene was performed after polymerase chain reaction amplifications. Comparisons between the DNA sequences of the affected individuals and the NCBI database were performed. RESULTS: We detected eight novel heterozygous mutations and five previously reported mutations in the ADAR1 gene in our patients. The novel mutations include c.1934 + 3A>G, c.2749A>G, c.2311insA, c.3233G>A, c.3019 + 1G>T, c.2894C>A, c.1202_1205del, and c.2280C>A. These detected novel mutations are predicted to induce two frame-shift mutations, one nonsense mutation, three missense mutations, and two splice-site mutations. CONCLUSIONS: The findings of this study expand our knowledge of the range of ADAR1 gene mutations in DSH and will contribute to identifying correlations between the various DSH phenotypes and genotypes. Furthermore, they may provide insight into the underlying pathogenic mechanism.

Mutation analysis of the ADAR1 gene in a pedigree with dyschromatosis symmetrica hereditaria / 中华皮肤科杂志

Objective To detect mutations in the ARAD1 gene in a pedigree with dyschromatosis symmetrica hereditaria (DSH).Methods Genomic DNA was extracted from the peripheral blood of 8 family members (including 5 patients with DSH and 3 unaffected members) in the pedigree with DSH,as well as 100 unrelated healthy controls.All the 15 exon sequences of the ADAR1 gene were amplified by polymerase chain reaction (PCR)followed by direct sequencing.Then,mutations were detected in comparison with the standard sequence of the ADAR1 gene in Genebank.Results A nonsense mutation C.1420C ＞ T (p.Arg474X) was identified at position 1 420 in exon 2 of the ADAR1 gene in the 5 patients with DSH,but not in the 3 unaffected members or 100 unrelated healthy controls.Conclusion The nonsense mutation C.1420C ＞ T in the ADAR1 gene is the causative mutation in the pedigree with DSH.

Dyschromias: A Series of Five Interesting Cases from India.

Dyschromatosis is a pigmentary genodermatosis which presents with hyper and hypopigmented skin lesions giving a mottled appearance. It is a rare entity in India reported mainly in the East Asian population. Classically, two forms have been described; dyschromatosis universalis hereditaria (DUH) and dyschromatosis symmetrica hereditaria. Here we report four cases of DUH and one case of dyschromatosis symmetrica hereditaria from India.

Diverse selective regimes shape genetic diversity at ADAR genes and at their coding targets.

A-to-I RNA editing operated by ADAR enzymes is extremely common in mammals. Several editing events in coding regions have pivotal physiological roles and affect protein sequence (recoding events) or function. We analyzed the evolutionary history of the 3 ADAR family genes and of their coding targets. Evolutionary analysis indicated that ADAR evolved adaptively in primates, with the strongest selection in the unique N-terminal domain of the interferon-inducible isoform. Positively selected residues in the human lineage were also detected in the ADAR deaminase domain and in the RNA binding domains of ADARB1 and ADARB2. During the recent history of human populations distinct variants in the 3 genes increased in frequency as a result of local selective pressures. Most selected variants are located within regulatory regions and some are in linkage disequilibrium with eQTLs in monocytes. Finally, analysis of conservation scores of coding editing sites indicated that editing events are counter-selected within regions that are poorly tolerant to change. Nevertheless, a minority of recoding events occurs at highly conserved positions and possibly represents the functional fraction. These events are enriched in pathways related to HIV-1 infection and to epidermis/hair development. Thus, both ADAR genes and their targets evolved under variable selective regimes, including purifying and positive selection. Pressures related to immune response likely represented major drivers of evolution for ADAR genes. As for their coding targets, we suggest that most editing events are slightly deleterious, although a minority may be beneficial and contribute to antiviral response and skin homeostasis.