The Analysis Of Clinical Characteristics And Gene Mutation In The Dyschromatosis Hereditaria And Poikiloderma Congenita

ObjectivesThe aim of this study is to summarize and analyze the clinical features and the basis of molecular genetics of two cases of dyschromatosis symmetrica hereditaria(DSH)families,one case of dyschromatosis universalis hereditaria(DUH)family and one case of poikiloderma congenita(Rothmund-Thomason syndrome,RTS)family,and the correlation between genotype and clinical phenotype in these three inherited pigmented disorders.Methods1.We performed careful physical examination in all patients from two DSH families,one DUH family and one RTS family,and summarize their clinical features.2.The mutation analysis of causative gene were carried out by whole exome sequencing(WES)and Sanger sequencing in two DSH families,one DUH family and one RTS family.Then,gene annotation and functional prediction were performed for associated variations by using ANNOVAR software,and whether the mutation is deleterious or not was verified.3.We have reviewed all articles associated with DSH,DUH and RTS,and explore the correlations between genotype and clinical phenotype in these three inherited disorders.Results1.The affected individuals in both DSH families presented with reticular brown hyperpigmented and hypopigmented macules symmetrically distributed over the dorsa of their hands and feet.Moreover,the dorsal aspect of their elbows and knees were also affected.The affected individuals in DUH family presented with widespread scattered 2-4mm in diameter,hyperpigmented macules mixed with some irregular hypopigmented macules over their whole body.Reticulate appearance was also observed in some affected individuals.The affected individuals in RTS family presented with diffuse tiny light brown macules mingled with hypopigmented spots.In addition,They had multiple reticular telangiectasia on the face,diffuse sparse scalp hairs and absence of eyebrows,eyelashes and armpit hairs.However,the abnormality of skeletal development and vision was not observed.2.Two heterozygous insert mutations c.614＿615ins A(p.N205Kfs*13)in exon 2,c.1675＿1676ins T(p.Q559Lfs*63)in exon 3 of ADAR1 gene were respectively identified in DSH family 1 and 2.A heterozygous missense mutation c.1553A>C(p.Q518P)in exon15 of SASH1 gene was identified in DUH family.None of mutations in RECQL4 gene was detected in RTS family.3.The analysis of association between genotype and clinical phenotype showed that facial involvement was more frequently observed in the DSH patients with greater severity of lesions on the limbs.Moreover,a heterozygous missense mutation c.3019G>A(p.Gly1007Arg)was associated with nervous system disorders.The most prominent feature in DUH patients with SASH1 variants was generalized light brown to dark brown macules similar to leopard’s spots,especially on the sun-exposed areas,while the characteristic manifestation of ABCB6 variants was typically generalized mottled hyperpigmented and hypopigmented macules arranging in a reticular pattern.Osteosarcoma and skeleton defects were associated with RECOL4 gene mutation while ANAPC1 mutations are specific to individuals with RTS type 1with juvenile cataracts.Conclusions1.There was heterogeneity of clinical phenotype in DSH,DUH and RTS.2.The pathogenic basis of molecular genetics was determined in two DSH family,one DUH family.Probably,there was genetic heterogeneity in the RTS family,and it was likely caused by the pathogenic mutation in other gene except RECQL4.3.There is some correlation between genotype and clinical phenotype in the DSH,DUH and RTS.