四种遗传性鱼鳞病基因型与临床表型的相关性分析

目的对四种鱼鳞病(寻常型鱼鳞病;X性-联鱼鳞病;板层状鱼鳞病;大疱性鱼鳞病)的致病基因进行精细定位,并分析其基因型与临床表型的关系。方法对四种鱼鳞病各1例患者进行临床表型分析以及外周血DNA直接测序检测鱼鳞病FLG基因、STS基因、TGM1基因和K1,K10角蛋白基因的突变位点。结果①寻常型鱼鳞病患者在FLG基因的外显子5的第278位有G-T突变,613位有G-A突变。②板层状鱼鳞病患者TGM1基因外显子3的第504位碱基有C-T突变,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位碱基有C-T突变,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。③X-性联鱼鳞病患者STS基因完全缺失。④大疱性鱼鳞病患者外显子5的第242碱基存在A-C突变,外显子6的第599位碱基均存在A-G突变,导致K1蛋白第633位氨基酸由赖氨酸(Lys)变为精氨酸(Arg)。结论鱼鳞病患者临床表型的不同与致病基因的突变位点密切相关。     

儿童寻常性鱼鳞病并发银屑病1例

1 病历患儿女,8岁.因全身皮肤干燥、脱屑7年伴丘疹、斑块、鳞屑2 周于2012年2月23日来我院门诊就诊.患儿自1岁起双下肢皮肤干燥、脱屑,后逐渐发展至全身,四肢皮损较严重,每年夏季皮损自行消退,冬季复发,在当地医院确诊为寻常性鱼鳞病,予以尿素软膏外用治疗有效.2 周前无明显诱因双小腿出现十余个绿豆大淡红色丘疹,迅速增多、增大,发展至全身,部分皮损融合,鳞屑明显伴瘙痒.患儿既往体健,无慢性病史,患儿父亲有鱼鳞病史.     

四种遗传性鱼鳞病临床表型和组织病理的比较研究

目的：比较四种鱼鳞病（寻常型鱼鳞病；X-连锁鱼鳞病；板层状鱼鳞病；大疱性鱼鳞病）临床表型和组织病理的差异。方法：对鱼鳞病患者进行临床表型分析、皮损组织病理和电镜检测。结果：1．寻常型鱼鳞病：浅褐色多角形鳞屑，组织病理角化过度伴局灶性角化不全，颗粒层变薄；电镜示透明角质颗粒数量减少且结构异常。2．X-连锁鱼鳞病：粗大深褐色鳞屑，组织病理中度角化过度，颗粒层正常或稍增厚。3．板层状鱼鳞病：粗大黑色板样鳞屑，组织病理致密板层状角化过度伴灶性角化不全，局灶颗粒层增厚，棘层不规则增生肥厚；电镜示角质包膜异常。4．大疱性鱼鳞病：棕色疣状鳞屑，组织病理致密角化过度，颗粒层显著增厚，颗粒层及棘层中上部细胞核周空泡改变。电镜可见异常角蛋白分布于基底层以上全部表皮，棘细胞松解，颗粒层细胞核周围有异常聚集的角蛋白丝。结论：四种鱼鳞病患者临床表型、组织病理和严重程度有明显差异。     

银屑病和鱼鳞病患者血清必需脂肪酸分析

为了探讨必需脂肪酸与鳞屑性皮肤病的关系,用气相质谱法分析了寻常型银屑病,性联隐性鱼鳞病,寻常型鱼鳞病和正常对照组的血清和血清磷脂脂肪酸的组成,结果：银屑病组Ｃ＾４２０、Ｃ＾４２２、Ｃ＾５２２显著低于正常,而Ｃ＾２１８、Ｃ＾３１８及Ｃ＾３２０明显升高。     

性联鱼鳞病分子发病机制的研究进展

性联鱼鳞病是一种遗传性皮肤病,一般在出生时或生后不久即发病。它不仅累及皮肤,而且累及其他系统。该病是由类固醇硫酸酯酶基因缺失或突变引起的,目前已发现一些不同的部分缺失形式或点突变,对发病机制有了较深入的了解,在药物和基因治疗方面取得了一定进展,为将来预防和治愈本病打下基础。     

内皮蛋白、兜甲蛋白及角蛋白2e在三种鱼鳞病表皮中的表达

目的 比较角蛋白鱼鳞病(KPI)与寻常型鱼鳞病(IV)和板层状鱼鳞病(LI)内皮蛋白(involucrin)、兜甲蛋白(loricrin)及角蛋白2e(K2e)的表达是否存在差异,与角化过度程度不一是否存在一定关系。方法 以正常人为对照组,利用免疫组化半定量分析检测KPI、IV、LI三组患者表皮involucrin、loricrin及K2e的表达,并进行统计学分析。结果 involucrin阳性细胞PU值：IV组(0.221±0.012)高于正常对照(0.144±0.011),其次是LI(0.128±0.008),KPI(0.113±0.008)最低,差异有统计学意义(P<0.01)。loricrin阳性细胞PU值：IV组(0.251±0.011)高于正常对照(0.207±0.030),其次是LI(0.170±0.012),KPI组(0.152±0.009)最低,差异有统计学意义(P<0.01)。K2e阳性细胞PU值：IV(0.241±0.013)高于KPI(0.130±0.021),两者均高于正常对照(0.115±0.008)和LI(0.114±0.008),差异有统计学...     

性联隐性鱼鳞病和常染色体显性遗传鱼鳞病的Southern杂交分析

用类固醇硫酸醋酶(Steroid sulfatase, STS)基因的cDNA为探针对19例性联隐性鱼鳞病和11例常染色体显性遗传(常显)鱼鳞病分别进行Southern杂交,发现84%性联隐性鱼鳞病患者有ST5基因缺失,且为全长STS基因缺失,常显鱼鳞病组均正常.此实验室检查对鱼鳞病的基因诊断、携带者检测及产前诊断有较大的意义.     

汉族寻常型鱼鳞病丝聚合蛋白基因突变的研究

目的:检测汉族寻常型鱼鳞病(IV) 丝聚合蛋白基因的突变.方法:提取65例IV患者及70例健康对照者的基因组DNA,采用MassARRAY(r)分子量阵列技术分析丝聚合蛋白基因5个突变位点(3321delA,441delA,1249 insG,E1795X和S3296X).结果:34例(52.31%)IV患者发现丝聚合蛋白3321delA基因突变,对照组有4例(5.71%)发生该基因突变;1例(1.54%)患者发现丝聚合蛋白441delA基因突变,对照组没有发现该基因突变.患者组及对照组均未见丝聚合蛋白1249insG, E1795X及S3296X基因突变.结论:丝聚合蛋白基因突变可能与汉族人群IV易感性相关.丝聚合蛋白3321delA基因突变可能是汉族IV主要的突变位点.     

寻常型鱼鳞病患者皮损中间丝聚合蛋白及其基因的改变

【摘要】 目的 探讨寻常型鱼鳞病患者中间丝聚合蛋白（FLG）基因突变与FLG及兜甲蛋白在寻常型鱼鳞病患者皮损组织中的表达及其临床意义。 方法 采用SP免疫组化方法检测10例汉族寻常型鱼鳞病患者皮损及14例健康对照皮肤组织内FLG及兜甲蛋白的表达,用图像分析软件ImagePro plus（IPP）判定FLG及兜甲蛋白在寻常型鱼鳞病患者皮损及正常皮肤组织中表达的阳性单位（PU值）。提取10例汉族寻常型鱼鳞病患者及100例健康对照者的基因组DNA,采用PCR及直接测序法,对FLG基因已报道的13个突变位点（3321delA、441delA、1249insG、E1795X、S3296X、R501X、2282del4、R2447X、S2889X、7945delA、3702delG、Q2417X、R4307X）进行测序。 结果 FLG在寻常型鱼鳞病皮损及健康对照皮肤角质层、颗粒层、棘层及基底层细胞均有表达,胞质染色多见;寻常型鱼鳞病皮损阳性染色PU值明显低于健康对照皮肤（分别为0.2082 ± 0.0080和0.2300 ± 0.0228,两组比较,t = 3.30,P < 0.01）。兜甲蛋白在寻常型鱼鳞病皮损及健康对照皮肤颗粒层、棘层及基底层细胞均有表达,胞质及胞核染色多见;寻常型鱼鳞病皮损表达的PU值明显低于健康对照皮肤（分别为0.1370 ± 0.0112和0.1493 ± 0.0073,两组比较,t = 3.07,P < 0.01）。7例寻常型鱼鳞病患者检测到FLG 3321delA突变位点,2例检测到FLG 441delA突变位点,健康对照组未检测到FLG基因突变位点。 结论 FLG（3321delA,441delA）可能是汉族寻常型鱼鳞病患者的突变位点之一。FLG及兜甲蛋白表达下降可能与寻常型鱼鳞病患者皮肤屏障功能障碍有关。     

Hypoplastic thyroid,growth hormone deficiency,corneal opacities,cataract and hyperkeratotic skin disease: a possible new ichthyosis syndrome associated with endocrinopathies

A 56 year old man presented with ichthyosis vulgaris since early childhood, clinically characterised by fine scaling of the trunk and hyperkeratotic scales on the exterior surfaces of the upper and lower extremities. The patient also showed hypothyroidism due to hypoplastic thyroid, cataract, hypercholesterinemia with concommitant arcus cornealis and biliary concrements. Renal lithiasis caused by calcio-oxalate was additionally present. Endocrinological screening revealed growth hormone deficiency in the 1.55 m tall man—(secondary) osteoporosis was observed. The clinical symptomatology indicates that this case cannot be considered as a subtype of the inherited ichthyosis group, but suggests a new syndrome as a separate nosologic entity.     

Excretion of (sulfated) steroids in the urine and excretion of cholesterol sulfate in the feces of boys with recessive X-linked ichthyosis

Summary The excretion of sulfated steroids was investigated in the urine and feces of six boys aged 9 months to 7 years and 10 months who had recessive X-linked ichthyosis. Profiles of urinary total steroids as well as sulfated steroids were normal. Cholesterol sulfate excretion in the urine was not elevated. In the feces 2–20% of total cholesterol was cholesterol sulfate, whereas in the feces of 28 healthy children no cholesterol sulfate was demonstrable. In the 6 patients total cholesterol excretion (500–2,500 mol/kg feces) was also elevated in comparison with the 28 healthy controls (150–700 mol/kg feces, mean 365 mol/kg feces)     

新发MBTPS2基因突变致毛囊性鱼鳞病、秃发、畏光综合征一例

【摘要】 本文首次报道1例MBTPS2基因c.1165C>T突变致毛囊性鱼鳞病、秃发、畏光综合征。先证者主要临床表现为皮肤干燥、先天性无头发、毛囊角化性丘疹、畏光,伴癫痫,智力、运动发育落后。应用二代测序及一代测序验证显示,先证者和其母亲在MBTPS2基因第9外显子区域存在c.1165C>T（p.pro389Ser）突变。根据患儿临床表现和MBTPS2基因突变遗传学特点,确诊为毛囊性鱼鳞病、秃发、畏光综合征。     

常染色体隐性遗传性鱼鳞病一家系表型、基因型与皮损超微结构研究

目的 探讨常染色体隐性遗传性鱼鳞病家系临床表型、基因型及超微结构。方法 观察常染色体隐性遗传性鱼鳞病患者临床表现。用PCR扩增TGM1基因15个外显子及其邻近剪切位点,双向直接测序;取先证者背部皮损做透射电镜观察,记录电镜表现特征。结果 先证者临床表现介于板层状鱼鳞病及非大疱性鱼鳞病样红皮病之间,其弟弟为火棉胶婴儿。先证者、其弟及父亲3号外显子第551位碱基胞嘧啶（C）→胸腺嘧啶（T）,其编码的第143位氨基酸由精氨酸变为半胱氨酸（R143C）;先证者、其弟及母亲4号外显子第759位胞嘧啶（C）→胸腺嘧啶（T）,使第212位氨基酸由丝氨酸转变为苯丙氨酸（S212F）。电镜观察发现,先证者皮损不仅有Ⅱ型结构表现,也同时存在Ⅲ型结构特征。结论 该家系患者携带复合杂合突变,R143C属于热点区,S212F为新发现的位点。携带TGM1基因突变的先证者皮损电镜表现为Ⅱ型,但同时发现有Ⅲ型结构存在。     

Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations

Background

X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema.

Objective

To test the hypothesis that co-inheritance of FLG mutations can act as a genetic modifier in XLI.

Methods

An unusually severe XLI phenotype in addition to eczema and mild childhood asthma was investigated in a female Indian patient by fluorescent in situ hybridization (FISH) for the common STS gene deletion. Direct sequencing of the entire FLG gene was also performed.

Results

FISH analysis revealed that the proband was homozygous for the common STS genomic deletion mutation. Further investigation revealed a frame-shift mutation 3672del4 in the gene encoding filaggrin (FLG), leading to premature termination of profilaggrin translation. Interestingly, her father, who had a very typical mild presentation of XLI, did not carry this FLG mutation in addition to his STS deletion. Her mother was a heterozygous carrier of the FLG mutation and consistent with this, had mild symptoms of ichthyosis vulgaris; she was also a heterozygous carrier of the STS deletion.

Conclusion

This is the second reported case of the modifying effects of FLG null alleles on XLI and strengthens the hypothesis that filaggrin defects can synergize with STS deficiency to exacerbate the ichthyosis phenotype.