全外显子测序诊断不典型Netherton综合征伴水疱
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摘要
报告1例Netherton综合征(NS)。患儿女,14岁。出生后即无诱因进行性头颈、躯干红斑、水疱,环形双边状红斑鳞屑,反复发作14年伴全身干燥。全外显子高通量测序SPINK5基因染色体chr5:147470777发生c.652C>T(E8)截断性杂合突变,氨基酸改变p.218,R>X(877),其无义突变可能会导致蛋白翻译提前终止和染色体chr5:147503528位点发生IVS27+5G>A剪切位点杂合突变,其mRNA剪接可能会受影响。皮损组织病理改变类似银屑病样表现。免疫组化法检测LEKTI蛋白的表达与正常对照无显著差异。扫描电镜下未见特异性结节性(套叠性)脆发。患儿COL17A1、ITGB4、PLEC、CDSN、KRT1、KRT10、KRT2及DSG1基因均未见致病性突变。通过一代基因检测验证该患儿诊断为NS,基因检测是不典型NS的主要诊断方法。
A 14-year-old Han female with Netherton's syndrome is reported. There were erythemas and blisters on the head, neck and torso, double ring-shaped erythemas with scales and dry skin since birth. High-throughput sequencing of all coding exons of SPINK5 genes showed truncating mutation on chromosome chr5:147470777 c.652 C>T(E8) replaced by p.218,R>X(877). This nonsense mutation may lead to early termination of protein translation and heterozygous mutations on chromosome chr5:147503528 locus IVS27+5 G>A, possibly affecting m RNA splicing. The pathological changes of skin lesions were similar to that of psoriasis. Immunohistochemistry showed no differences in expression of LEKTI protein between patient and normal control. No specific fragile nodular hair-shaft deformities were observed under scanning electron microscope. No pathogenic mutation was found in COL17 A1, ITGB4, PLEC, CDSN, KRT1, KRT10, KRT2 and DSG1 genes. The patient was diagnosed with Netherton's syndrome by a generation of gene tests. Genetic examination is the main diagnostic method for atypical Netherton's syndrome.
A 14-year-old Han female with Netherton's syndrome is reported. There were erythemas and blisters on the head, neck and torso, double ring-shaped erythemas with scales and dry skin since birth. High-throughput sequencing of all coding exons of SPINK5 genes showed truncating mutation on chromosome chr5:147470777 c.652 C>T(E8) replaced by p.218,R>X(877). This nonsense mutation may lead to early termination of protein translation and heterozygous mutations on chromosome chr5:147503528 locus IVS27+5 G>A, possibly affecting m RNA splicing. The pathological changes of skin lesions were similar to that of psoriasis. Immunohistochemistry showed no differences in expression of LEKTI protein between patient and normal control. No specific fragile nodular hair-shaft deformities were observed under scanning electron microscope. No pathogenic mutation was found in COL17 A1, ITGB4, PLEC, CDSN, KRT1, KRT10, KRT2 and DSG1 genes. The patient was diagnosed with Netherton's syndrome by a generation of gene tests. Genetic examination is the main diagnostic method for atypical Netherton's syndrome.
引文
[1]闫薇,薛晓东,李薇,等. Netherton综合征[J].临床皮肤科杂志,2010,39(2):102-104.
[2] Wilkinson RD, Curtis GH, Hawk WA. Netherton's Disease:Trichorrhexis Invaginata(Bamboo Hair), Congenital Ichthyosiform Erythroderma and the Atopic Diathesis. A Histopathologic Study[J]. Arch Dermatol, 1964, 89(1):46-54.
[3] Sprecher E, Chavanas S, Digiovanna J, et al. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome:implications for mutation detection and first case of prenatal diagnosis[J]. Journal of Investigative Dermatology, 2001,117(2):179-87.
[4] Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5,encoding a serine protease inhibitor, cause Netherton syndrome[J].Nature Genetics, 2000, 25(2):141.
[5] Bitoun E, Micheloni AL, Bonnart C, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome[J]. Human Molecular Genetics, 2003, 12(19):2417.
[6] Leclercmercier S, Bodemer C, Furio L, et al. Skin Biopsy in Netherton Syndrome:A Histological Review of a Large Series and New Findings[J]. Am J Dermatopathol, 2016, 38(2):83-91.
[7]唐新平,刘乐斌,杨小红,等.不伴套叠性脆发的2例NS致病基因突变检测[J].临床皮肤科杂志,2015(9):539-542.
[8]赵邑,马志红,汪旸,等. NS及红斑型天疱疮表皮中激肽释放酶相关肽酶和丝氨酸蛋白酶抑制物的检测[J].中国皮肤性病学杂志,2009,23(9):544-546.
[9] Bitoun E, Chavanas S, Irvine AD, et al. Netherton syndrome:disease expression and spectrum of SPINK5 mutations in 21families[J]. Journal of Investigative Dermatology, 2002, 118(2):352-361.
[10] Bitoun E, Micheloni AL, Bonnart C, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome[J]. Human Molecular Genetics, 2003, 12(19):2417.
[11] Chao S, Richard G, Lee JY. Netherton syndrome:report of two Taiwanese siblings with staphylococcal scalded skin syndrome and mutation of SPINK5[J]. Digest of the World Core Medical Journals, 2005, 152(1):159-165.
[12] Raghunath M, Tontsidou L, Oji V, et al. SPINK5 and Netherton syndrome:novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases[J]. Journal of Investigative Dermatology, 2004, 123(3):474-483.
[13] Shimomura Y, Sato N, Kariya N, et al. Netherton syndrome in two Japanese siblings with a novel mutation in the SPINK5 gene:immunohistochemical studies of LEKTI and other epidermal molecules[J]. British Journal of Dermatology, 2005, 153(5):1026-1030.
[14] Fontao L, Laffitte E, Briot A, et al. Infliximab Infusions for Netherton Syndrome:Sustained Clinical Improvement Correlates with a Reduction of Thymic Stromal Lymphopoietin Levels in the Skin[J]. Journal of Investigative Dermatology, 2011, 131(9):1947.
[15] Renner ED, Hartl D, Rylaarsdam S, et al. Comèl-Netherton syndrome defined as primary immunodeficiency[J]. Journal of Allergy&Clinical Immunology, 2009, 124(3):536.
[2] Wilkinson RD, Curtis GH, Hawk WA. Netherton's Disease:Trichorrhexis Invaginata(Bamboo Hair), Congenital Ichthyosiform Erythroderma and the Atopic Diathesis. A Histopathologic Study[J]. Arch Dermatol, 1964, 89(1):46-54.
[3] Sprecher E, Chavanas S, Digiovanna J, et al. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome:implications for mutation detection and first case of prenatal diagnosis[J]. Journal of Investigative Dermatology, 2001,117(2):179-87.
[4] Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5,encoding a serine protease inhibitor, cause Netherton syndrome[J].Nature Genetics, 2000, 25(2):141.
[5] Bitoun E, Micheloni AL, Bonnart C, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome[J]. Human Molecular Genetics, 2003, 12(19):2417.
[6] Leclercmercier S, Bodemer C, Furio L, et al. Skin Biopsy in Netherton Syndrome:A Histological Review of a Large Series and New Findings[J]. Am J Dermatopathol, 2016, 38(2):83-91.
[7]唐新平,刘乐斌,杨小红,等.不伴套叠性脆发的2例NS致病基因突变检测[J].临床皮肤科杂志,2015(9):539-542.
[8]赵邑,马志红,汪旸,等. NS及红斑型天疱疮表皮中激肽释放酶相关肽酶和丝氨酸蛋白酶抑制物的检测[J].中国皮肤性病学杂志,2009,23(9):544-546.
[9] Bitoun E, Chavanas S, Irvine AD, et al. Netherton syndrome:disease expression and spectrum of SPINK5 mutations in 21families[J]. Journal of Investigative Dermatology, 2002, 118(2):352-361.
[10] Bitoun E, Micheloni AL, Bonnart C, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome[J]. Human Molecular Genetics, 2003, 12(19):2417.
[11] Chao S, Richard G, Lee JY. Netherton syndrome:report of two Taiwanese siblings with staphylococcal scalded skin syndrome and mutation of SPINK5[J]. Digest of the World Core Medical Journals, 2005, 152(1):159-165.
[12] Raghunath M, Tontsidou L, Oji V, et al. SPINK5 and Netherton syndrome:novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases[J]. Journal of Investigative Dermatology, 2004, 123(3):474-483.
[13] Shimomura Y, Sato N, Kariya N, et al. Netherton syndrome in two Japanese siblings with a novel mutation in the SPINK5 gene:immunohistochemical studies of LEKTI and other epidermal molecules[J]. British Journal of Dermatology, 2005, 153(5):1026-1030.
[14] Fontao L, Laffitte E, Briot A, et al. Infliximab Infusions for Netherton Syndrome:Sustained Clinical Improvement Correlates with a Reduction of Thymic Stromal Lymphopoietin Levels in the Skin[J]. Journal of Investigative Dermatology, 2011, 131(9):1947.
[15] Renner ED, Hartl D, Rylaarsdam S, et al. Comèl-Netherton syndrome defined as primary immunodeficiency[J]. Journal of Allergy&Clinical Immunology, 2009, 124(3):536.