Siemens大疱性鱼鳞病1例临床特征及基因突变分析

目的 报告1例散发的Siemens大疱性鱼鳞病的临床特征及KRT2基因突变情况。方法 收集患者临床资料,并对其进行皮损组织病理、直接免疫荧光等检查;采集患者及其父母外周血进行基因测序,选取100例无亲缘关系的健康人作为对照,分析可疑致病位点。结果 患者自幼发病,皮损表现为躯干及四肢角化过度伴鳞屑,脐周、双膝关节及踝关节处有深棕色波纹状角化,局部可见典型“蜕皮”现象,周围呈领圈状脱屑,不伴掌跖角化。下腹部可见簇集性小脓疱。腹部脓疱行组织病理示：表皮网篮状角化过度,角质层下水疱形成,内含中性粒细胞及渗出物。脓疱的细菌培养呈阴性。直接免疫荧光示：IgA、IgG、C3均阴性。患者KRT2基因存在杂合错义突变c.1459G>A(p.E487K),而患者父母此位点未发现突变。结论 该患者诊断为Siemens大疱性鱼鳞病,其临床表型由KRT2基因c.1459G>A(p.E487K)杂合突变所致。     

Siemens大疱性鱼鳞病基因突变研究及文献回顾分析

目的 确定1个Siemens大疱性鱼鳞病(ichthyosis bullosa of Siemens,IBS)家系的致病基因,探讨本病基因型、表型及两者间关系.方法 收集1个IBS家系先证者及其父母的临床资料,采集他们和100例无亲缘关系的健康对照者的外周血标本,提取DNA.应用二代皮肤靶向测序包检测该家系的基因突变,...     

大疱性鱼鳞病样红皮病遗传学研究进展

先天性大疱性鱼鳞病样红皮病(BCIE)属于常染色体显性遗传性疾病,主要由KRT1和KRT10基因突变引起。近年来对BCIE的基因遗传学研究取得了很大进展,本文就该病的遗传模式、遗传学研究策略和研究进展进行了综述。     

大疱性鱼鳞病样红皮病1例

患儿女,8月龄,因全身皮肤反复发生红斑、脱屑8个月就诊。其母诉称患儿出生后次日即出现全身皮肤红斑及脱屑,并有蚕豆大小水疱数个。疱壁薄,轻触碰即破,约1周疱干涸,形成鳞屑,反复发作至今。有时水疱较大如核桃。患儿系34周早产儿。母孕期无上感及特殊用药史。父母非近亲婚配,生育2胎,长子已14岁,健康。患儿为第2胎。家族中无类似疾病及鱼鳞病等皮肤病史。患儿发育差,消瘦,体重5ｋｇ,余未见特殊。皮肤科情况:全身皮肤除颜面外弥漫性潮红、干燥及脱屑,几乎无正常皮肤可见。双小腿伸侧可见大小不等的疣状角化鳞屑性损害。左小腿有蚕豆至5分币大…     

先天性大疱性鱼鳞病样红皮病1例

先天性大疱性鱼鳞病样红皮病（bullous congenital ichthyosiform erythroderma,BCIE）又称表皮松解性角化过度（epidermolytic hyperkeratosis,EHK），是一种罕见的常染色体显性遗传性疾病，现将所见1例报告如下。     

先天性大疱性鱼鳞病样红皮病角蛋白10的新发突变

目的: 检测1例先天性大疱性鱼鳞病样红皮病患者KRT1和KRT10基因突变.方法: 提取患者及其家人外周血DNA,PCR扩增KRT1和KRT10基因编码区的全部外显子及其侧翼序列并测序,以100名正常人作对照.结果: 该患者KRT10基因第1号外显子中的第466位碱基发生C→T杂合突变(c.C466T),导致其编码第156位氨基酸发生错义突变(p.R156C),患者父母、妹妹及正常对照均未发现该突变,提示其为新发突变.结论: KRT10基因的c.C466T错义突变可能为引起该患者临床表型的病因.     

手足复发型大疱型表皮松解症角蛋白5基因突变位点的检测

为了探讨角蛋白基因５和手足复发型大疱型表皮松解症的关系，利用建立在聚合酶链反应基础上的基因突变检测技术、单链构象多肽性和ＤＮＡ测序方法，对一个手足复发型大疱型表皮松解症的家系进行了角蛋白５基因突变位点检测。结果发现角蛋白５的非螺旋区（即Ｌ１－２区）第３２７个密码子第三个碱基有Ｇ→Ｔ的替换，导致蛋氨酸变成了异亮氨酸。这一突变引起了角蛋白结构的异常，不能装配形成正常的张力微丝，造成临床上的水疱、大疱和     

非大疱性先天性鱼鳞病样红皮病1例

报告1例非大疱性先天性鱼鳞病样红皮病。患者男,15岁。全身皮肤潮红、脱屑15年,继发双手畸形。组织病理示:表皮角化过度伴角化不全,棘层增生,棘层上部可见部分细胞空泡样变性,真皮乳头层及浅层毛细血管增生,管周有少量淋巴细胞浸润。X线片示:双手指间关节屈曲、畸形。     

角蛋白10突变致先天性大疱性鱼鳞病样红皮病1例

目的 检测1例先天性大疱性鱼鳞病样红皮病(BCIE)患者KRT1和KRT10基因突变。方法 提取患者及其家人外周血DNA,PCR扩增KRT1和KRT10基因编码区的全部外显子及其侧翼序列并测序,检测潜在的基因突变。结果 该患者KRT10基因第1号外显子中的第467位碱基发生G→A杂合突变(c.467G>A),导致其编码的第156号氨基酸发生错义突变(p.Arg156His),患者父亲、母亲、姐姐均未发现该突变。患者及其母亲第7号外显子中的1 654～1 683位点发生重复突变,即NM＿000421.5:c.1654＿1683dup,该突变导致其编码的556至565位的氨基酸发生甘氨酸重复(p.Gly556＿Gly565dup),该突变呈杂合状态,患者父亲、姐姐均未发现该突变,提示其为新发突变。KRT1基因未检测到突变。结论 KRT10基因的c.467G>A错义突变是本例BCIE的致病原因,NM＿000421.5:c.1654＿1683dup重复突变可能不会导致BCIE。     

先天性大疱性鱼鳞病样红皮病并发蒙古斑

1 病历摘要 患儿女,4岁7个月.全身红斑、水疱、鳞屑4年半,于2009年11月20日就诊于我科.患儿出生时即发现左侧髋部、臀部及左下肢大片蓝灰色斑疹,出生1个月后双肘部伸侧出现红斑,红斑基础上出现水疱、糜烂,易抓破,覆铠甲状鳞屑.近几年逐渐累及躯干、四肢,冬重夏轻.曾用鱼肝油滴剂口服及多种糖皮质激素软膏外搽效果不佳而来就诊.患儿为第一胎足月顺产,父母非近亲结婚,家族中无类似皮肤病史及其它遗传病史.     

Hot spot mutations in keratin 2e suggest a correlation between genotype and phenotype in patients with ichthyosis bullosa of Siemens

Ichthyosis bullosa of Siemens (IBS) is a rare disorder of cornification characterized by blister formation in the upper suprabasal layers of the epidermis. Molecular analysis of IBS has identified mutations in the keratin 2e (K2e) gene, which is located in the type II keratin gene cluster on chromosome 12q. We have studied two IBS families and have identified heterozygous point mutations in codon 493 of the K2e gene in both families. Whereas a non-conservative amino acid substitution at position 117 of the 2B region of K2e (E117K) was associated with a severe phenotype in family 1, family 2 showed mild clinical features as a result of a conservative substitution (E117D). These data suggest a phenotype-genotype correlation in these families.     

Ichthyosis bullosa of Siemens: report of a family with evidence of a keratin 2e mutation, and a review of the literature

We report a large family with ichthyosis bullosa of Siemens (IBS) including eight affected members spanning three generations. The classical features of the disease were consistently observed with blistering, superficial peeling of the skin, and localized lichenified hyperkeratosis mainly confined to the limbs. Phenotypic variation, however, was also observed with some individuals exhibiting unusual clinical features. Specifically, the index patient was erythrodermic at birth; she subsequently developed a widespread pustular eruption. Erythroderma is classically absent in IBS and pustulation is very unusual. She also had hypertrichosis of the limbs, as did an affected female first cousin. This has not previously been reported in IBS. Electron microscopy showed complex aggregates of keratin in the spinous and granular layers associated, in places, with remarkably little cell lysis. Sequencing of genomic DNA revealed a mutation (E493K) in keratin 2e. A review of the literature on IBS indicates that E493K is the most commonly reported mutation to date and might represent a mutational hotspot for this disease.     

Weber-Cockayne亚型单纯型大疱性表皮松解症一家系报告

目的:研究Weber-Cockayne亚型单纯型大疱性表皮松解症(EBS-WC)一家系的基因突变,并进行产前诊断。方法:应用PCR及DNA直接测序方法明确突变位点,针对所发现的突变以限制性内切酶片段长度多态性(RFLP)分析加以验证,在此基础上于妊娠24周时对从胎儿羊水所提取的DNA进行测序及酶切验证。结果:该家系患者存在角蛋白(keratin,KRT)5基因突变:第7外显子第1388位碱基由胸腺嘌呤突变为胞嘧啶,导致第463位氨基酸由亮氨酸变为脯氨酸(L463P)。50名健康对照者不存在此突变。羊水细胞DNA不存在此突变的胎儿,出生后未患大疱性表皮松解症。结论:KRT5第7外显子的突变是引起该家系临床症状的特异性突变。     

New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of Siemens

The intermediate filaments of epithelial cells are formed by keratins, a family of structurally related proteins, which are expressed in pairs of acidic (type I) and basic (type II) polypeptides in a tissue- and differentiation-specific manner. Mutations in the genes encoding several keratins have been implicated in the pathogenesis of diseases of keratinization. We report molecular analysis of two patients with the rare autosomal dominant disorders bullous congenital ichthyosiform erythroderma (BCIE) and ichthyosis bullosa of Siemens (IBS). Previous studies have shown that these genodermatoses are due to mutations in the KRT1 and KRT2E genes, respectively. We report a new amino acid substitution mutation in codon 155 of KRT1 (valine to aspartic acid) in the conserved H1 domain of the protein in the patient with BCIE. We also report a novel amino acid substitution mutation in codon 192 of KRT2E (asparagine to lysine) in the conserved 1A helix initiation peptide of the protein in the patient with IBS. Our results demonstrate that these mutations are deleterious to keratin filament network stability and lead to specific clinical inherited disorders of keratinization.     

An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13

A new variant of congenital exfoliative ichthyosis in two related Bedouin families is reported. The ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the palms and soles. The prominent well-demarcated areas of denuded skin in moist and traumatized regions resembled the 'mauserung' phenomenon of ichthyosis bullosa of Siemens (IBS). Unlike in IBS, epidermolysis is absent on histological examination. Electron microscopy revealed a prominent intercellular oedema and numerous aggregates of keratin filaments in basal keratinocytes. Abnormal keratin (K) 1 expression was seen in the affected epidermis; however, all other keratins, including K2e, had a distribution comparable to that seen in normal controls. A maximum two-point LOD score of 2.53 and multipoint LOD score of 3.76 were obtained for marker D12S390, suggesting linkage to the type II keratin cluster on chromosome 12q13. Sequencing of both the K1 gene, the promotor and the 3' calcium regulatory region did not reveal a mutation. K2e and K5 genes, as well as the genes harboured within the minimal region, such as retinoic acid receptor gamma, sterol O-acyltransferase 2, integrin beta7 and insulin-like growth factor binding protein-6, were also excluded. This combination of clinical, histological, ultrastructural and genetic features has not been previously reported in other congenital exfoliative ichthyoses. We therefore suggest that it represents a new form of exfoliative ichthyosis.     

Epidermolysis bullosa nevus arising in a patient with Dowling–Meara type epidermolysis bullosa simplex with a novel K5 mutation

We report herein a 4-year-old girl with Dowling–Meara type epidermolysis bullosa (EB) who presented with peculiar pigmented nevi. Blister formation had repeatedly occurred on the erythematous plaques in a circinate fashion since birth, and marked hyperkeratosis was observed on the palms and soles associated with nail deformity. Her mother and maternal grandmother also had similar symptoms. In addition to the blistering lesions, the patient had three large, asymmetrical, pigmented plaques with color variegation. Light and electron microscopic findings of the blistering lesions showed a subepidermal blister with intracytoplasmic granules in keratinocytes as well as degeneration of basal cells and aggregation of tonofilaments. The pigmented lesions revealed histopathological features of compound nevus without malignant changes. Gene analysis revealed an E478K (Glu to Lys) mutation in exon 5 of the keratin 5 ( K5 ) gene. These findings, together with clinical features, were consistent with those of Dowling–Meara type EB associated with so-called EB nevus.     

Ichthyosis Bullosa of Siemens: Report of a Sporadic Case

We report a sporadic case of ichthyosis bullosa of Siemens occurring in a Korean boy. In this report, the varied findings of the clinical features in one subject over five years are presented along with an investigation of the ultrastructural alteration. The patient had suffered from blistering, superficial peeling, and dark-grey colored lichenified patches on the extremities since infancy. As he grew older, the lesions were more localized to the elbows, knees, buttock and the dorsal aspects of the hands and feet, and were replaced by yellowish, lichenified plaques. Since the original report of Siemens in 1937, nine families including one sporadic case have been reported in the literature. To our knowledge, this is the second report of sporadic case of IBS.     

Ichthyosis bullosa of Siemens: its correct diagnosis facilitated by molecular genetic testing

Ichthyosis bullosa of Siemens (IBS, MIM 146800) is a unique congenital ichthyosis characterized by mild epidermal hyperkeratosis over flexural areas, blister formation and the development of superficially denuded areas of hyperkeratotic skin. It is clinically difficult to distinguish severe IBS from mild bullous congenital ichthyosiform erythroderma (BCIE, MIM 113800). In the current literature, 19 IBS families with keratin 2e (K2e) mutations have been reported, despite only five IBS families having been reported before the first identification of K2e mutation in 1994. We studied four patients from three Japanese IBS families. They had previously been misdiagnosed as having BCIE before the correct diagnosis was made after mutation detection. To detect the pathogenic mutations, we performed direct sequencing of the entire coding regions of KRT2E encoding K2e in the patients and healthy family members. K2e mutations, a 1469T-->C transition (L490P) and a 1477G-->A transition (E493K) within the conserved 2B helix termination motif of the rod domain were detected in the families and the definite diagnosis of IBS was made in the four cases. The present results indicate that IBS is not such a rare entity as was previously thought, and accurate diagnosis is now available by mutation analysis.     

Atypical epidermolysis bullosa simplex with a missense keratin 14 mutation p.Arg125Cys

Epidermolysis bullosa (EB) is a group of hereditary autosomal dominant bullous diseases. EB is divided into four major phenotypes: intraepidermal EB (or EB simplex), junctional EB, dermolytic EB and mixed EB (Kindler syndrome). EB simplex is further divided into three subtypes: localized EB simplex, Dowling-Meara EB simplex and other generalized EB simplex. We report a 28-year-old man with EB simplex with a missense keratin 14 mutation p.Arg125Cys associated with clumping of keratin filaments and acantholysis in mainly the spinous cells and basal cells. Immunohistochemistry revealed that the broader expression of keratin 5 and 14 was observed in the epidermis, while the expression of keratin 1/10 was quite normal. Dysregulated expression of keratin 5/14 may hinder some functions or roles of keratin 1/10, namely filament assembly of keratin 1/10 in spinous cell integrity, although the expression of keratin 1/10 was not affected and this has not been demonstrated before.