小儿Sjögren-Larsson综合征临床特征及基因突变分析

目的 分析4例 Sjögren-Larsson 综合征 （Sjögren-Larsson syndrome, SLS）患儿临床特征及ALDH3A2基因突变, 以明确诊断, 并为遗传咨询和产前诊断提供依据。方法 收集 2008—2013 年中国人民解放军总医院儿童医学中心收治的 4 例 Sjögren-Larsson 综合征患儿的临床资料。抽取外周静脉血各3 mL, 应用二氧化硅法提取基因组DNA。采用聚合酶链反应（PCR）扩增ALDH3A2基因的11个外显子及其与内含子的连接区。PCR产物直接测序法检测基因突变。结果 来自3个家系的4例患儿均存在先天性鱼鳞病、智力低下、痉挛性截瘫或四肢瘫等典型临床表现。3例患儿 ALDH3A2基因测序均检出基因突变。分别为：例1, IVS5-1del G, c.1157A＞G（p.Asn386Ser）; 例2和例3, c.1157A＞G （p.Asn386Ser）纯合突变; 例4基因检测未发现编码区致病突变。结论 明确了 4 例 Sjögren-Larsson综合征患儿的基因诊断, 发现 2个ALDH3A2基因突变位点,其中 IVS5-1del G为新发突变。     

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??Objective??Testicular adrenal rest tumors??TARTs?? are common in males with congenital adrenal hyperplasia??CAH?? due to 21-hydroxylase deficiency and 11-β hydroxylase deficiency. It’s rare to find TARTs in CAH due to 3β-hydroxysteroid dehydrogenase deficiency. We present rare cases of two brothers with nonclassic CAH due to 3β-hydroxysteroid dehydrogenase deficiency??who presented with TARTs. The clinical characteristics and mutation ofHSD3B2geneof the two patients were analyzed. Methods??The clinical data of the two brothers with TARTs in nonclassic CAH were collected. HSD3B2 genes were amplified with polymerase chain reaction and screened for mutations by sequencing. Results??Both of the two brothers were admitted into our hospital presenting bilateral testicular irregular lump with significantly high ACTH??DHEAS level??and increased An??T and 17-OHP level. The HSD3B2 gene analysis revealed that two patients carried C.776 C??T??p. Thr259Met?? and C.674 T??A??p.Val225Asp?? heterozygous missense mutation??which were inherited from parents respectively. The C.674 T??A??p.Val225Asp?? mutation, inherited from mother??was not reported untill now. After treatment with hydrocortisone, TARTs decreased and the markers of adrenal function were improved. Conclusion??The study shows??for the first time??that TARTs in nonclassic CAH in these two brothers is due to 3β-hydroxysteroid dehydrogenase deficiency. A new HSD3B2 gene mutation??C.674 T??A??p.Val225Asp????is reported here. The presence of TARTs is a known factor for infertility??however??if given early diagnosis and appropriate management??TARTs could be reduced and the fertility will be improved. It is important for pediatricians to screen for TARTs in CAH males.     

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??Objective??To summarize and analyze the clinical characteristics??diagnosis and treatment of children with Major Histocompatibility Complex Class ??MHC-?? deficiency??in order to promote the awareness of this disease. Methods??Retrospectively analyze the clinical features??immunological functions??protein expressions and genetic profiles of 2 children with MHC-?? deficiency identified from Children’s Hospital of Fudan University??and discuss the method of diagnosis and treatment by reviewing related literatures. Results????1??Both of the patients were male and had a history of recurrent infection??and the age of onset was 4 years and 2 months??respectively??the age of diagnosis was 8 years and 3 months.Both had pulmonary infection??one had diarrhea and one was infected after BCG vaccination. Both were susceptible to fungi and virus??and even under the treatment of broad spectrum antibiotics and antifungal drugs??they were both dead from severe infection at the age of 8y and 3m??respectively. ??2??One had neutropenia??two developed anemia??one had hypogammaglobulinemia?? and both had severe CD4 T-cell lymphopenia. ??3??Genetic analysis of CIITA showed that P1 had compound heterozygous mutations??with c.531C??A mutation in exon 7??inherited from father?? and c.2408C??A mutation in exon 11??inherited from mother????P2 carried a homozygous nonsense mutation??with c.1161G??A in exon 11 as well. ??4??Due to severe infection??both patients failed to undergo the HSCT. Conclusion??Patients with MHC?? deficiency usually experience early onset and are susceptible to various pathogens. Conventional anti-infection treatment is not effective for them. Early diagnosis and HSCT is the only effective way for them to survive??gene therapy is still in the research stage.     

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??Objective To analyze thecauses ofinfantsalt losing syndrome and theapplication value of gene detection inthe diagnosis of the cause. Methods Four cases ofsalt losingsyndrome withlow sodium and highpotassium admitted from 2010 to 2014in Shanghai Children’s Medical Center?? Affiliated to Shanghai Jiaotong University School of Medicine wereincluded and clinicaldata??therapy and follow-up were collected. DNA of childrenandtheir parentsin thefour cases were detected. Results There were different degrees ofsalt losingsituation in the fourcases. It found that the patients had different gene mutations through genetic testing??mutations of splicing site??c.293-13A??G??heterozygous???? andsmallduplication??c.923dupT?? p.Leu308Phefs*6??heterozygous???? were detected in CYP21A2?? mutation of small deletion??c.1334delC?? p.Ala445Valfs*17??hemizygous???? was detected in DAX1?? mutation of splicing site??c.del1311G?? p.Arg438Glyfs*43??heterozygous???? and point mutation??c.1439+1G??C??heterozygous???? were detected in SCNN1A and mutation of splicing site??c.240-1G??A??heterozygous???? and nonsensemutation??c.1009C??T??p.Gln337*??heterozygous???? were detected in CYP11B2?? respectively. The four cases werediagnosed asfour differentdiseases??congenitaladrenal hyperplasia??21-hydroxylase deficiency????congenital adrenal hypoplasia??pseudohypoaldosteronismtype I and hypoaldosteronism. Conclusion The cause of infant salt losing syndrome is complex and is misdiagnosed easily. Gene analysismay be helpful for early diagnosis and treatment.     

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??Abstract??Objective??To first diagnose and fine map the chromosome deletion regions of two children with Jacobsen syndrome by Affymetrix SNP 6.0 chip in China and roughly analyze the correlation between phenotype and genotype. Methods??Genomic DNA of each index patient and his/her parents was extracted from peripheral blood. Screening of subtelomeric rearrangements was carried out in all patients by MLPA??P070??. For each patient with a positive result??a subsequent second-stage test was performed with another MLPA kit ??P036??. The parents of patients who had positive results confirmed by the second kit were tested to assess whether the genetic aberrations were de novo or inherited. If the subtelomeric aberrations were de novo??then we used the Affymetrix genome-wide human SNP array 6.0 to confirm and accurately define the exact size of each subtelomeric aberrant region. Results??We found that two patients presented with severe DD??microcephaly??and facial dysmophism. Patient 1 had low birth weight and white matter with delaying of myelinization??and patient 2 had congenital heart disease and skeletal deformity. No patient was with thrombocytopenia. We found that the sizes of the deletions were 4.1 Mb and12.8 Mb respectively. The 4.1 Mb deletion was smaller than any other region previously reported for this syndrome. Conclusion??The critical region underlying DD/MR is probably distal part within 4.1Mb to the telomere??and SNX19??THYN1??OPCML??NCAPD3 and NTM might be candidate genes. One of the critical regions for craniofacial abnormalities may be within 130.3-134.4Mb in chromosome 11q. ??3?? The critical region related to congenital heart malformations may be within 125.8Mb-130.4Mb in chromosome 11q. However??we realize that this study is limited by the small sample of cases presented and hope that in the future more Chinese JBS patients will be reported to elucidate the spectrum and relationship of the phenotype and genotype of JBS in China.     

苍白球黑质变性2个家系的临床和基因诊断

目的 对苍白球黑质变性(HSD)2个家系进行泛酸激酸2(PANK2)基因突变位点的筛查.方法 分别抽取2个家系 4名成员外周静脉血各2 mL,盐析法提取2个家系成员基因组DNA,用PCR方法扩增PANK2基因的全部编码外显子,纯化后直接测序.结果 在1号先证者的PANK2 基因上发现2个杂合的错义突变:外显子2上核苷酸序列第970位G>T突变(c.970G>T),导致编码的第324位氨基酸由天门冬氨酸(D)变成酪氨酸(Y)(D324Y);患儿母亲是这一突变的杂合携带者,具有正常表型.外显子3上核苷酸序列第1133位A>G突变(c.1133A>G),导致编码的第378位氨基酸从天门冬氨酸(D)变成甘氨酸(G) (D378G);患儿父亲是这一突变的杂合携带者,具有正常表型.在2号先证者的PANK2 基因上发现2个杂合的错义突变:外显子2上核苷酸序列第808位C>G突变(c.808C>G),导致编码的第270位氨基酸由亮氨酸(L)变成缬氨酸(V)(L270V);外显子3上核苷酸序列第1103位A>G突变(c.1103A>G),导致编码的第368位氨基酸从天门冬氨酸(D)变成甘氨酸(G) (D368G);该患儿为抱养儿,无法检测其父母的基因型.这4个错义突变均能引起PANK2 基因编码氨基酸的改变,从而引起蛋白质结构和功能的异常.结论 在这2个家系中,c.970G>T、c.1133A>G、c.808C>G和c.1103A>G错义突变导致2个先证者出现HSD的表型.实用儿科临床杂志,2011,26(16 ):1276-1278     

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??Objective??To study the clinical features and SCN1A gene mutation in a familial inherited Dravet syndrome family with dizygotic twins. Methods??The clinical manifestations of dizygotic twins with Dravet syndrome and GEFS + mother were summarized and SCN1A gene was sequenced. The relationship between genotype-phenotype of SCN1A gene and Dravet syndrome was analyzed by literature. Results??The dizygotic twins and their mother have de novo SCN1A gene mutant c.3624A??T??p.R1208S?? at the second loop of Na+ channel α subunit. This is very rare compared to the usual mutation domain at S4 or S5-S6. It is the first report in China that Dravet syndrome dizygotic twins inherited SCN1A gene mutation from their mother who was diagnosed as GEFS+. Point mutations of SCN1A were more common??accounting for 93.8%. The relationships between phenotype-genotype were very complex??since other pathogenic factors may be involved in. Conclusion??It is the first report in China that SCN1A gene mutation in a familial inherited Dravet syndrome with dizygotic twins and found a de novo SCN1A gene mutation of c.3624A??T??p.R1208S????which is located at the very rare region of the protein.     

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??Objective??To investigate diagnosis of children’s neuronal ceroid lipofuscinosis??NCL????especially the significance of gene diagnosis. Methods??The clinical data of 5 cases of suspected NCL in our hospital from January 2013 to January 2017 were retrospectively analyzed. There were 3 boys and 2 girls??2 of whom were sister and brother. The age of onset ranged from 3 years and 4 months to 8 years and 1 month?? averaged 5 years and 9 months. The first visit to our hospital ranged from 3 years and 6 months to 14 years?? with an average of 8 years and 1 month. DNA of peripheral blood was extracted from 4 children with abnormal imaging and their parents and brothers??and the related genes were detected. Results??Four cases of children were diagnosed with NCL??and 1 case was diagnosed with hysteria??gene detection showed??case 1?? TPP1 gene c.887-17A??G was a shearing variant??and c.646G??A was a missense mutation??case 2?? TPP1 gene c.1015_1016 del was frameshift mutation??and c.640C??T was nonsense mutation??the nucleotide of case 3?? CLN6 gene changed to c.158T??C??p.L53P?? and c.889C??T??p.P297S??. The parents of the 3 cases only carried one of the heterozygous variants??and the brother of case 3 had no mutation. Heterozygous mutation existed in case 4?? CLN3 gene??c.1160_1169 delCAGCCTACGTinsGC??which was not detected in the mother??and there was the deletion of the paternal sample??there was loss of heterozygosity in the exon E3-E8 of the CLN3 gene??which was the true missing from mother. Five cases were followed up for 15-60 months and there was no death. Conclusion??Suspected NCL patients should be checked head MRI??electroencephalogram and gene. The gene mutation leads to NCL??such as TPP1??c.887-17A??G??c.1015_1016 del????CLN3??c.1160_1169 delCAGCCTACGTinsGC????CLN6???c.158T??C??p.L53P?? and c.889C??T??p.P297S?????are reported for the first time. Genotype is very important for NCL classification and prognosis.     

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??Abstract?? Objective To investigate the different clinical and immune features of variable phenotypes of severe combined immunodeficiency caused by RAG 1 mutations.Methods From 2012.9 to 2013.04?? three patients were included in the study??and records of clinical details were reviewed. Results The phenotypes of three patients were typical SCID for patient 1??Omenn syndrome for patient 2 and atypical SCID complicated with recurrent autoimmune hemolytic anemia for patients 3??respectively.RAG 1 mutations were compound heterozygous allele 1??1870 C??T/Arg624Cys??allele 2??2005 G??A/Glu669Lys??allele 1 was published mutation??allele 2 was de novel mutation?? for patient 1??compound heterozygous allele 1??994 C??T/Arg332X??allele 2??1439 G??A/Ser480Asn??both mutations were de novel mutations??for patient 2??homozygous 2095 C??T/R699W for patient 3 and was published mutation. First two patients died soon after discharge.Patient 3 was treated for recurrent autoimmune hemolytic anemia in our ward.Conclusion RAG1 mutations can lead to variable SCID phenotypes.Patients with typical SCID and Omenn syndrome were with poor prognosis??which need transplantation treatment.     

3例Fanconi-Bickel综合征SLC2A2基因分析

Fanconi-Bickel 综合征(FBS, OMIM 227810)是一种常染色体隐性遗传的罕见糖代谢异常疾病,致病基因为SLC2A2。该文报道3 例经SLC2A2 基因分析确诊的FBS 病例。3 例患儿表现为典型的糖原累积症及近端肾小管功能障碍表现。基因测序显示1 例为纯合剪接突变IVS8+5G>C(c.1068+5 G>C);1 例为纯合无义突变c.1194T>A(p.Tyr398X);1 例为错义突变c.380C>A(p.Ala127Asp)和重复突变c.970dupT(p.324TyrfsX392),其中c.970dupT(p.324TyrfsX392)非经父母遗传,为新生突变。该4 种突变中,除IVS8+5G>C 外,其余3 种为中国人种FBS 新突变,而c.970dupT(p.324TyrfsX392)可能为世界首例FBS 新生突变报道。