皮肤病综合征

20062234角膜炎、鱼鳞病、耳聋综合征的GJB2基因突变研究/张锡宝(广州市皮研所),魏生才,王艳芳…∥中华皮肤科杂志.-2006,39(3).-146~148提取国内首例角膜炎、鱼鳞病、耳聋综合征(KID)患者及其家族成员的基因组DNA,采用聚合酶链反应扩增GJB2基因和GJB6基因所有的外显子及其邻近的剪切点,并进行双向直接测序。结果KID综合征患者的GJB6基因未见变化,GJB2基因核苷酸序列exon2第148位碱基由G突变成A,导致蛋白第50位的天冬氨酸转换成天冬酰胺(D50N)。提示GJB2基因突变可能是本例KID的致病基因。图1表1参10(董妍)20062235Klippel-T…     

角膜炎、鱼鳞病、耳聋综合征一例及GJB2基因突变研究

目的 探讨角膜炎、鱼鳞病及耳聋综合征患者临床特征和GJB2基因突变情况,为该病临床与基因诊断提供依据。方法 收集1例角膜炎、鱼鳞病及耳聋综合征患者的临床资料,提取患者及家族成员的外周血DNA,用PCR扩增GJB2基因外显子2及其附近的剪切点,DNA直接测序法进行基因突变检测。结果 该患者存在血管化角膜炎、鱼鳞病及先天性耳聋三联征的典型临床特征,检测到GJB2基因中核苷酸序列外显子2第148位碱基由G突变为A,导致编码的连接蛋白Cx26第50位的天冬氨酸转换成天冬酰胺（D50N）。其未患病的母亲及哥哥未检测到突变位点。结论 GJB2基因突变（D50N）可能是引起鱼鳞病、角膜炎及耳聋综合征患者临床表型的原因。     

先天性角膜炎-鱼鳞病-耳聋综合征GJB2基因突变分析

目的报告1例角膜炎-鱼鳞病-耳聋综合征(Keratitis-Ichthyosis-Deafness syndrome,KID)并进行基因检测。方法收集1例KID患者的临床资料,提取患者及其家族成员(父母和奶奶)的外周血DNA进行基因突变检测。结果患者皮损组织病理检查示角化过度伴疣状增生改变。基因检测示GJB2基因外显子2中的第148位碱基发生G→A杂合突变(c. 148G→A),导致其编码的连接蛋白Cx26第50位氨基酸发生错义突变(p. Asp50Asn)。结论根据患者典型的临床表现和基因检测结果诊断为角膜炎-鱼鳞病-耳聋综合征。基因检测更明确该病诊断。     

伴皮肤鳞状细胞癌的角膜炎-鱼鳞病-耳聋综合征一例GJB2基因突变研究并文献复习

目的 以GJB2基因为候选基因,研究1例伴有皮肤鳞状细胞癌的角膜炎-鱼鳞病-耳聋综合征患者的分子病因。 方法 收集1例伴有皮肤鳞状细胞癌的角膜炎-鱼鳞病-耳聋综合征患者临床资料,提取患者及其父母的外周血DNA,用PCR扩增GJB2基因的第2外显子后直接测序,检测患者GJB2基因的突变情况。 结果 患者GJB2基因中核苷酸序列外显子2第148位碱基由G突变为A（c.148G > A）,此突变导致GJB2基因第50位氨基酸密码子由GAC替换为AAC,其编码的连接蛋白Cx26第50位天冬氨酸转换成天冬酰胺（p.Asp50Asn ）。此外,GJB2基因外显子2第79位碱基由G突变为A（c.79G > A）,突变导致连接蛋白Cx26第27位的缬氨酸转换成异亮氨酸（p.Val27Ile）。患者的父母未检测到GJB2基因突变位点。文献检索发现国外已有13例角膜炎-鱼鳞病-耳聋综合征伴皮肤黏膜鳞状细胞癌的病例报道,经过基因测序确诊的7例患者均为GJB2基因c.148G > A突变。结论 GJB2基因突变可能是导致本例角膜炎-鱼鳞病-耳聋综合征临床表型的致病原因,c.148G > A突变位置可能与皮肤鳞状细胞癌发生有关。     

角膜炎-鱼鳞病-耳聋综合征

目的:报告1例角膜炎-鱼鳞病-耳聋综合征并进行基因检测。方法:收集1例角膜炎-鱼鳞病-耳聋综合征患儿的临床资料,提取患儿及其家族成员(父母和舅舅)外周血DNA进行基因突变检测。结果:该患儿皮损组织病理检查示鱼鳞病样改变。基因检测示GJB2基因外显子2中的第148位碱基发生G→T杂合突变(c.148G→T),导致其编码的第50位氨基酸发生错义突变(p.Asp50Tyr)。结论:根据患儿典型的临床表现和基因检测结果诊断为角膜炎-鱼鳞病-耳聋综合征。基因检测有助于明确该病诊断。     

皮肤病综合征

20130590角膜炎、鱼鳞病、耳聋综合征一例及GJB2基因突变研究/张玲琳(上海市皮肤病医院),唐黎,王宏伟…∥中华皮肤科杂志.-2012,45(8).-597～599收集1例角膜炎、鱼鳞病及耳聋综合征患者的临床资料,提取患者及家族成员的外周血DNA,用PCR扩增GJB2基因外显子2及其附近的剪切点。DNA直接测序法进行基因突变检测。结果:该患者存在血管     

1例先天性角膜炎、鱼鳞病、耳聋综合征患者的护理

正角膜炎、鱼鳞病、耳聋综合征(简称KID综合征)是一种少见的遗传性皮肤病,1915年Burns首次对该病进行描述,认为该病具有特殊及广泛的皮肤角化,可累及口腔黏膜、耳、眼和鼻等部位~([1])。1981年Skinner等将其命名为角膜炎、鱼鳞病、耳聋(KID)综合征~([2])。至1996年全球有文献记载符合诊断标准的病例约6l例,因此在治疗和护理中缺乏有效的经验。目前对于     

一例伴丘疹性损害的先天性无毛症患者的基因突变研究

目的 研究1例伴丘疹性损害的先天性无毛症患者基因突变情况.方法 采用PCR和DNA直接测序法检测伴丘疹性损害的先天性无毛症HR基因的突变.同时对2个与秃发相关的基因GJB6和CDSN基因进行突变检测.结果 在HR基因、GJB6基因和CDSN基因所检测的区域中均未检测到突变.在HR基因和CDSN基因上发现了数处单核苷酸多态性(SNP).结论 在该伴丘疹性损害的先天性无毛症家庭中未检测到HR、GJB6和CDSN基因的突变.     

表皮松解性角化过度型鱼鳞病二例及其基因突变的研究

目的 研究二例表皮松解性角化过度型鱼鳞病患者基因突变情况。方法 取患者皮损进行组织病理及电镜检查;提取患者外周血DNA,采用聚合酶链反应及DNA直接测序方法,检测患者皮损角蛋白10(K10)及角蛋白1(K1)基因突变;等位基因特异性引物PCR及限制性内切酶片段长度多态性方法筛查正常人群中该等位基因频率。结果 2例患者均存在K1或K10基因的杂合点突变,即K10基因第2140位G→A,K1基因第4226位G→A,分别导致K10第156位的精氨酸变为组氨酸(R156H)及K1第477位氨基酸从谷氨酸变为赖氨酸(E477K),而正常对照无此替代。结论 K10R156H及K1E477K为导致这2例患者临床表型的特异突变。     

板层状鱼鳞病TGM1基因突变研究

目的 探讨一个板层状鱼鳞病家系转谷氨酰胺酶1基因(TGM1)的突变.方法 提取板层状鱼鳞病患者及家族成员的基因组DNA,采用PCR扩增TGM1基因所有的外显子及其邻近的剪切点并进行双向直接测序,并对TGM1基因的同源性进行分析.结果 板层状鱼鳞病患者TGM1基因存在异常:外显子3的第504位碱基由胞嘧啶突变为胸腺嘧啶,使第142位氨基酸由精氨酸(R)转变为半胱氨酸(C),即R142C错义突变;外显子7的第1122位碱基由胞嘧啶突变为胸腺嘧啶,使348位氨基酸由精氨酸(R)突变为终止密码(R348X),导致其编码的蛋白缺失了C端的470个氨基酸.其父亲为R142C杂合子,母亲为R348X突变杂合子;R142C错义突变位于TGM1基因保守区域.结论 该板层状鱼鳞病患者存在转谷氨酰胺酶1基因的R142C错义突变和R348X无义突变.     

Mutation of GJB2 in a Chinese patient with keratitis–ichthyosis–deafness syndrome and brain malformation

Objective.  Keratitis–ichthyosis–deafness syndrome (KID) is a rare congenital disorder. Mutations in the GJB2 gene have recently been identified as the causative mutations of KID.
Aim.  To define the GJB2 mutation in a Chinese patient with KID and brain malformation.
Methods.  Genomic DNA was extracted from peripheral blood and used to amplify the GJB2 gene. Direct sequencing and endonuclease digestion were used for mutation analysis.
Results.  We identified a heterozygous missense mutation (D50N) in the GJB2 gene in this patient.
Conclusions.  These results indicate that KID syndrome in this patient was caused by a dominant mutation of GJB2 .     

Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome

BACKGROUND: Germline missense mutations in the GJB2 gene that encodes connexin-26 (Cx26) have recently been found to be the cause of the keratitis-ichthyosis-deafness (KID) syndrome. OBJECTIVES: To define the GJB2 mutations in three Japanese patients with KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used to amplify the GJB2 gene. Direct sequencing and endonuclease digestion were used for mutation analysis and DNA-based diagnosis. RESULTS: We identified two heterozygous mis-sense mutations (D50Y, D50N) in the GJB2 gene in three Japanese patients with KID syndrome. All mutations were located on the first extracellular domain of Cx26. CONCLUSIONS: These data expand the GJB2 mutation database and show that a dominant mutation of Cx26 can cause KID syndrome in Japanese patients.     

HID and KID syndromes are associated with the same connexin 26 mutation

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a debilitating ectodermal dysplasia that predisposes patients to develop squamous cell carcinomas in addition to leading to profound sensory deafness and erythrokeratoderma. We recently demonstrated that KID can be caused by a specific missense mutation in connexin 26 (GJB2). Another syndrome, called hystrix-like ichthyosis-deafnesss (HID) syndrome, strongly resembles the KID syndrome. These disorders are distinguished mainly on the basis of electron microscopic findings. We hypothesized that KID and HID syndromes may be genetically related. OBJECTIVE: To demonstrate by mutation analysis that HID and KID syndromes are genetically indistinguishable. METHODS: DNA was extracted from paraffin-embedded tissue samples of the first HID syndrome patient described in the literature. Since the KID syndrome mutation abolishes an AspI restriction site, we were able to screen the patient's DNA by polymerase chain reaction and subsequent restriction enzyme analysis. RESULTS: Restriction analysis of the connexin 26 gene in HID syndrome demonstrated the presence of the KID syndrome mutation that we previously described. This result was confirmed by direct DNA sequencing. CONCLUSIONS: We show that KID and HID syndromes are identical at the molecular level and confirm the clinical impression that these syndromes are one and the same. That previous clinical reports made a distinction may be a consequence of sampling artefacts; alternatively, genetic background effects such as the presence of concurrent mutations in other skin-expressed genes may modify the phenotype.     

A rare connexin 26 mutation in a patient with a forme fruste of keratitis–ichthyosis–deafness (KID) syndrome

Background  Keratitis–ichthyosis–deafness (KID) syndrome is a rare ectodermal dysplasia characterized by generalized erythrokeratotic plaques, sensorineural hearing loss, and vascularizing keratitis. Cutaneous changes and hearing loss typically present in early childhood, whereas ocular symptoms present later. Mutations in the connexin (Cx) 26 gene, GJB2 , are now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation.
Methods  A rare patient demonstrating features of incomplete KID syndrome associated with an uncommon Cx26 gene mutation is described.
Results  The patient presented late in adolescence with partial features of KID syndrome. There was limited cutaneous involvement and the rare association of cystic acne. Both hearing impairment and ophthalmic involvement were mild in severity. Genetic mutation analysis revealed a previously described, rare mutation in GJB2 , resulting in a glycine to arginine change at codon 12 (p.G12R).
Conclusions  This report describes a patient exhibiting characteristics suggestive of a late-onset, incomplete form of KID syndrome with the GJB2 mutation (p.G12R). The p.G12R mutation has only been described in one other patient with KID syndrome, whose clinical presentation was not characterized.     

二例可变性红斑角化症患者GJB3、4基因突变研究

目的 探讨2例散发可变性红斑角化症（EKV）患者的GJB3和GJB4基因突变。 方法 提取EKV患者、家族成员及正常人基因组DNA,采用PCR扩增GJB3和GJB4基因所有外显子及其邻近的剪切点,进行双向直接测序。结果 1例EKV患者GJB4基因未见变化,GJB3基因的第134位碱基鸟嘌呤（G）被胞嘧啶（C）替换,导致蛋白质第45位的甘氨酸转换成丙氨酸（G45A）。另1例EKV患者GJB3、GJB4均未发现突变。结论 1例 EKV患者存在GJB3基因G45A错义突变。     

Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia

Connexins are integral membrane proteins forming aqueous gap junction channels that allow the diffusional exchange of ions and small metabolites between cells, thus coordinating metabolic activities in multicellular tissues. Dominant mutations in the Cx26 gene GJB2 have been shown to cause keratitis-ichthyosis-deafness (KID) syndrome, palmoplantar keratoderma associated with hearing loss, and Vohwinkel syndrome. Missense mutations in the closely related Cx30 gene GJB6 underlie Clouston syndrome (autosomal dominant hidrotic ectodermal dysplasia). We report a 6-y-old boy with phenotypic characteristics of KID syndrome as well as atrichia. In contrast to other KID syndrome patients, molecular analysis of the connexin gene GJB2 did not disclose a pathogenic mutation, although the patient was homozygous for a common polymorphism (V27I) in the coding sequence of Cx26. Nevertheless, screening of GJB6 revealed a heterozygous missense mutation (V37E) predicted to alter sequence and charge of the first transmembrane helix of Cx30, which was previously implicated in Clouston syndrome (Smith et al, 2002). The presence of a pathogenic Cx30 mutation and the lack of a pathologic molecular change in Cx26 in this patient, whose clinical features predominantly resemble KID syndrome, suggest genetic heterogeneity of KID syndrome and underscore that mutations in Cx30, similar to those in Cx26 or Cx31, can cause different phenotypes. Based on our results, connexin gene mutations should be considered in patients presenting with congenital sensorineural hearing loss and disorders of cornification, and screening of several connexin genes with known cutaneous phenotype, such as those for Cx26, Cx30, Cx30.3, and Cx31, may be required.     

Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin

Neuroectodermal syndromes involving the skin and inner ear may be associated with mutations in connexin proteins, which form gap junctions important for intercellular communication. Vohwinkel syndrome (keratodermia mutilans with hearing loss) and keratitis-ichthyosis-deafness (KID) syndrome are rare ectodermal dysplasias associated with dominant mutations in the GJB2 gene encoding connexin 26. We report here two patients, one with KID and one with Vohwinkel syndrome. Both displayed unusual clinical features and responded well to long-term treatment with oral retinoid. Mutation analysis revealed a novel GJB2 mutation p.Gly59Ser in the patient with Vohwinkel syndrome, whereas a recurrent mutation p.Asp50Asn was found in the patient with KID syndrome. The clinical features, particularly a proneness to skin cancer in the patient with Vohwinkel syndrome, are discussed in relation to the identified genotypes.     

Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations

Porokeratotic eccrine ostial and dermal duct nevus, or porokeratotic eccrine nevus (PEN), is a hyperkeratotic epidermal nevus. Several cases of widespread involvement have been reported, including one in association with the keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26). The molecular cause is, as yet, unknown. We have noted that PEN histopathology is shared by KID. The clinical appearance of PEN can resemble that of KID syndrome. Furthermore, a recent report of cutaneous mosaicism for a GJB2 mutation associated with KID describes linear hyperkeratotic skin lesions that might be consistent with PEN. From this, we hypothesized that PEN might be caused by Cx26 mutations associated with KID or similar gap junction disorders. Thus, we analyzed the GJB2 gene in skin samples from two patients referred with generalized PEN. In both, we found GJB2 mutations in the PEN lesions but not in unaffected skin or peripheral blood. One mutation was already known to cause the KID syndrome, and the other had not been previously associated with skin symptoms. We provide extensive functional data to support its pathogenicity. We conclude that PEN may be caused by mosaic GJB2 mutations.