以先天性甲状腺功能减退为表现的14q12q13.3微缺失综合征患儿1例的临床及遗传学分析

目的分析1例以先天性甲状腺功能减退症(CH)为表现的14q12q13.3微缺失综合征患儿的临床表型与遗传学病因。方法以1例因先天性甲状腺功能减退就诊于临沂市人民医院的新生儿作为研究对象, 对其进行全外显子组测序(WES)、深度基因组拷贝数变异(CNV)和染色体微阵列分析(CMA), 分析其临床资料并进行文献复习。结果患儿于新生儿期起病, 主要表现为特殊面容、外阴水肿、肌张力低下、精神运动发育迟缓、反复呼吸道感染伴喉喘鸣和喂养困难等, 实验室检测显示甲状腺功能减退。WES和深度基因组CNV分析检测提示患儿染色体14q12q13.3区可能存在拷贝数缺失, CMA证实其14q12q13.3区(32649595₃6769800)存在4.12 Mb的片段缺失, 共涉及22个基因, 包含CH的致病基因NKX2-1, 患儿父母均未发现同样的片段缺失。结论综合其临床表型及基因检测的结果, 确诊患儿为14q12q13.3微缺失综合征。     

Silver-Russell综合征病例报道一例并文献复习

目的通过报道罕见的Silver-Russell综合征病例1例,并文献复习,了解该疾病的研究进展。方法对1例Silver-Russell综合征患儿的临床表现、实验室检查进行观察与分析并复习相关文献。结果确诊Silver-Russell综合征1例。结论 Silver-Russell综合征临床极少见,临床有遇到（1）宫内及生后生长发育迟缓;（2）典型面部特征：相对巨颅、三角脸等;（3）躯体不对称畸形;（4）喂养困难的患儿应警惕本病可能。本疾病临床表现非特异性,临床诊断困难,对高度可疑本病的患儿应行基因检查,一旦确诊应尽早采取重组人生长激素（GH）替代治疗等综合治疗,以改善患儿生存质量。     

产前诊断人体鱼序列综合征一例并文献复习

目的探讨人体鱼序列综合征的产前诊断及临床特征。方法对1例人体鱼序列征病例进行产前诊断及分析,结合文献讨论该综合征的产前超声、脐血Array-CGH、尸体病理解剖结果及临床特点。结果本例主要表现胎儿双下肢并腿畸形,双肾脏发育不良及外生殖器未发育等畸形,其染色体未见异常。结论人体鱼序列综合征的特点为多发畸形,通常在孕期可以通过超声诊断。     

单中心174例原发性免疫缺陷病临床预警症状的初步探讨

目的分析并总结原发性免疫缺陷病（PID）患儿的临床感染特征和预警症状,了解预警症状对PID早期识别的应用价值。方法参考2011年免疫学会国际联合会（IUIS）PID分类委员会公布的方案、泛美免疫缺陷病组（PAGID）和欧洲免疫缺陷病协会（ESlD）提出的PID诊断和分类标准,在首都医科大学附属北京儿童医院2000年10月至2011年11月病例检索系统检索出院诊断中含有上述PID分类疾病的病历,对于诊断低丙种球蛋白血症和联合免疫缺陷的患儿除外继发性免疫缺陷病,逐份查阅病历重新诊断,并做出明确、可以和可能诊断,以明确、可以诊断的病例进行预警症状的分析。结果①174例PII）患儿进入分析,男女比例为4．4：1,其中抗体缺陷为主的免疫缺陷101例（58．0％）,严重联合免疫缺陷病（SCID）34例（19．5％）,吞噬细胞功能缺陷19例（10．9％）,定义明确的免疫缺陷综合征10例（5．7％）,免疫失调性疾病10例（5．7％）。渤5例（43．1％）存在反复呼吸道感染,以抗体缺陷为主的免疫缺陷最为常见,与SCID间差异有统计学意义;卡介苗接种后异常反应在慢性肉芽肿病（CGD）中最多见,与抗体缺陷为主的免疫缺陷和SCID比较差异有统计学意义;腹泻病在定义明确的免疫缺陷综合征中较常见,败血症在SCID和CGD患儿中较常见,但PID各类型间比较差异无统计学意义。③72例（41．4％）患儿存在营养发育落后,PID各类型间差异无统计学意义;淋巴结、肝和脾肿大以CGD和免疫失调性疾病最为常见;鹅口疮在SCID中常见,与抗体缺陷为主的免疫缺陷差异有统计学意义;肛周脓肿以CGD多见,与其他PID类型比较差异有统计学意义。107例（61．5％）有明确微生物学证据。④PID患儿共电话随访到85例（48．8％）,其中死亡28例（32．9％）。⑤124例为明确和可以诊断PID,其中106例（85．5％）具备〉12条预警症状。静脉应用抗生素清除病灶（96．0％）、体重不增或生长发育极度迟缓（41．1％）、反复呼吸道感染（41．9％）和P1D家族史（22．6％）在不同类型PID中均占有较高的比例。结论预警症状对PID有着很好的提示作用,需要静脉应用抗生素清除病灶、体重不增或生长发育极度迟缓和PID家族史对PID有预警意义,中耳炎、中枢神经系统感染和反复呼吸道感染在抗体缺陷为主的免疫缺陷中较为多见,深部脓肿、卡介苗接种后异常反应对CGD有预警意义。慢性反复发作性腹泻对PID预警作用值得进一步关注。     

Snijders Blok-Campeau综合征患儿1例的临床特征及基因变异分析

目的探讨Snijders Blok-Campeau综合征(SBCS)患儿的临床表型和基因变异特点。方法选取2017年6月于河南省儿童医院被确诊为SBCS的1例患儿为研究对象。收集患儿的临床病例资料, 采集患儿及其父母的外周血样提取基因组DNA, 进行家系全外显子组测序(trio-WES)及基因组拷贝数变异(CNV)检测, 针对可疑致病变异位点, 应用Sanger测序进行家系验证。结果患儿主要临床表现为语言障碍、智力障碍和运动发育迟缓, 伴特殊面容(前额宽、面部呈倒三角状、眉毛稀疏、眼距宽、眼裂小、鼻梁宽、面中部凹陷、上唇薄、尖下颌、耳位低且耳壳后旋)。trio-WES和Sanger测序结果提示患儿存在CHD3基因c.4073-2A>G杂合剪接变异, 其父母均为野生型, CNV检测未发现致病性CNV。结论该SBCS患儿临床特征为语言和智力障碍、运动发育迟缓, 伴特殊面容。CHD3基因剪接变异可能为导致该患儿罹患SBCS的遗传学病因。     

Kartagener综合征一例并文献复习

目的探讨Kartagener综合征的临床特点、诊断标准,以提高对Kartagener综合征认识。方法 Kartagener综合征1例。患儿,女,10岁余。因反复咳嗽1年,咯血4次入院。回顾性分析该患儿临床资料,检索国内外文献,进行总结分析。结果患儿隐匿起病,主要表现为反复咳嗽,咳脓痰,伴咯血。CT示双肺支扩伴感染,全内脏反位,鼻窦炎。经抗感染对症治疗1周后,临床症状消失出院。检索国内外文献发现,Kartagener综合征以全内脏反位,支气管扩张,副鼻窦炎三联征为诊断标准。治疗以对症治疗为主。结论 Kartagener综合征是一种罕见的常染色体隐性遗传病,加强对该病的认识,有利于提高对该病的诊断率,减少误诊率。对该病的致病基因、机制的进一步研究,可能提供更好的诊断和治疗方法。     

CHAMP1基因变异所致常染色体显性智力障碍40型患儿1例的分析

目的探讨1例CHAMP1基因变异所致常染色体显性智力障碍40型(MRD40)患儿的临床表型和遗传学特征。方法选取2019年10月至2020年9月于郑州大学第一附属医院就诊的1例MRD40型患儿为研究对象。采集患儿的临床资料, 用低深度高通量全基因组拷贝数变异测序(CNV-seq)和全外显子组测序(WES)对其进行遗传学分析, 并回顾文献报道的CHAMP1基因变异所致MRD40病例的临床表型和遗传学特征。结果患儿, 女, 11月龄, 表现为全面发育迟缓合并特殊面容。CNV-seq检测未见异常, WES结果提示其携带CHAMP1基因c.1908C>G(p.Y636*)新发杂合变异。连同12篇文献报道的33例患儿, 除发育迟缓、智力障碍外, 大多存在肌张力减退(94.1%)、说话和/或行走时间延迟(85.2%, 82.4%)及眼部异常(79.4%)。共检出CHAMP1基因变异26个, 大多为功能缺失变异, 位于第3外显子且为新发。结论 CHAMP1基因c.1908C>G(p.Y636*)杂合变异可能是本例患儿的致病原因。对于全面发育迟缓/智力障碍、肌张力减退伴特殊面容的患儿, 应...     

12p部分三体综合征的临床研究进展

12号染色体由130万个碱基编码的1100多个基因组成,占人类基因组的大约4．5％。12号染色体短臂三体综合征是一种罕见的染色体异常。其表现多具有特殊面容、低耳位、发育迟缓、肌张力低下等畸形。不同的染色体橡型其畸变的发生和临床严重程度存在差别。     

气管炎菌苗、酮替芬联用防治反复呼吸道感染120例临床分析

反复呼吸道感染是儿科常见病,如果不及时治疗,使其迁延不愈、反复发作,严重影响患儿的发育,致免疫功能低下[1]．对于反复呼吸道感染患儿无特殊治疗方法．我院气管炎菌苗、酮替芬联用防治反复呼吸道感染,取得较好的疗效,现报告如下．1临床资料1．1对象选择1995年以来在我院门诊就诊的反复呼吸道感染患儿120例,均符合1987年全国小儿呼吸道疾病会议制订的反复呼吸道感染的诊断标准．男69例,女sl例,年龄最小6个月,最大12岁．其中6个月至1岁4冽,l岁至3岁42例,3岁至7岁67例,7岁至12岁7例．病程最长45年,平均病程1．9年．每年最多门…     

Phelan-McDermid综合征1例

目的 探讨Phelan-McDermid综合征（PMS）患者的临床表型和基因型特点。方法 回顾性分析华中科技大学附属协和医院儿科确诊的1例PMS患儿的临床和遗传学资料，并结合文献对其基因型和表型进行详尽分析。结果 患儿，男，3岁5个月，全面性发育迟缓，自闭症样行为，既往有反复呼吸道感染。全外显子拷贝数变异检测：染色体22q13.31～q13.33区域杂合缺失，缺失大小为6.7 Mb，确诊为PMS。结论 PMS较为罕见，临床表型和基因型复杂多变，易引起误诊。本研究丰富了PMS的临床及遗传学特征，为临床诊断和遗传咨询提供重要依据。     

Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations

Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum.We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.     

Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho‐reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC ?10.1 s.d., height ?5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype–phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.     

Ligase IV syndrome

Ligase IV (LIG4) syndrome belongs to the group of hereditary disorders associated with impaired DNA damage response mechanisms. Subjects affected with this rare autosomal recessive disease exhibit microcephaly, unusual facial features, growth retardation, developmental delay, skin anomalies, and are typically pancytopenic. The disease is characterized by pronounced radiosensitivity, genome instability, malignancy, immunodeficiency, and bone marrow abnormalities. LIG4 syndrome results from mutations in the DNA ligase IV gene encoding an enzyme that plays a pivotal role in repairing double strand DNA breaks and V(D)J recombination. Since LIG4 null-mutant mice are embryonic lethal and biallelic null mutations have not been described to date in LIG4-deficient patients, viability of the DNA ligase IV deficiency syndrome appears to require at least one allele with a hypomorphic mutation. Mutations R278H, Q280R, H282L, M249E located in the vicinity of the active site are typical hypomorphic because they do not affect ligase expression and retain residual albeit reduced activity of the enzyme at levels of 5–10% of that for the wild-type ligase. Carriers heterozygous for those mutations usually develop moderate defects in V(D)J recombination, mild immune abnormalities and malignancy. In contrast, mutations resided in OBD, i.e. in the C-terminal subdomain of the catalytic domain, and in XRCC4-binding domain more dramatically inhibit the ligase function and also greatly decrease its expression. A truncating mutation R580X and a frameshift mutation K424FS resulting in loss of the C-terminal XRCC4-binding domain have deleterious effect on both expression and function of LIG4 and represent a null allele.     

657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family

We report on a consanguineous Turkish family whose first son died of anal atresia and whose second son presented with severe pre- and post-natal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosomal instability and rhabdomyosarcoma in the anal region. The proband was found to carry the homozygous 657del5 mutation in the NBS1 gene, which is responsible for Nijmegen breakage syndrome (NBS) in most of the Slav populations. Our family, the first diagnosed with NBS in the Turkish population, represents one of the most severely affected examples of the syndrome, with profound pre- and post-natal growth retardation associated with structural abnormalities, and expands the clinical spectrum of this rare disorder.     

Microcephaly is not mandatory for the diagnosis of mosaic variegated aneuploidy syndrome

The phenotype of mosaic variegated aneuploidy (MVA) syndrome is characterized by severe microcephaly, growth deficiency, mental retardation, and mild physical anomalies. The MVA syndrome is associated with mosaicism for several different aneuploidies involving many different chromosomes with or without premature centromere division (PCD). To date 28 cases of MVA syndrome have been reported. We report the first case of MVA syndrome without microcephaly. The clinical features in our patient included craniofacial dysmorphic features, growth retardation, and developmental delay. Cytogenetics analyses and FISH studies showed multiple aneuploidy with trisomy 18, 19, and 8, respectively in blood lymphocyte and fibroblasts without PCD. This case is compared with the other of MVA syndrome previously reported in literature. From this case report, we suggest that microcephaly is not mandatory for the diagnosis of MVA syndrome.     

Cohen syndrome in the Ohio Amish

We describe eight members from two large Amish kindreds who share a phenotype characterized by early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, common facial appearance, and friendly disposition. Several of the children had intermittent granulocytopenia. The phenotypic occurrence in three siblings coupled with the increased coefficient of inbreeding in the Amish suggested that this disorder is autosomal recessive and due to a single founder allele. Despite similarity to the clinical features of Cohen syndrome, experienced dysmorphologists attending the 23rd David W. Smith Workshop suggested the facial gestalt of the Amish children was inconsistent with this diagnosis. We mapped the locus responsible for these individuals' phenotype to chromosome 8q22-q23, which contains the recently discovered Cohen syndrome gene, COH1. Complete sequencing of the COH1 gene identified a likely disease-causing frameshift mutation and a missense mutation in the Amish patients. A comparison of features among different Cohen syndrome populations with shared linkage to the COH1 locus or known COH1 gene mutations may allow for the determination of improved clinical criteria on which to suspect the diagnosis of Cohen syndrome. We conclude that facial gestalt seems to be an unreliable indicator of Cohen syndrome between ethnic populations, although it is quite consistent among affected individuals within a particular ethnic group. Other features common to almost all individuals with proven COH1 mutations, such as retinal dystrophy, myopia, microcephaly, mental retardation, global developmental delay, hypotonia, and joint hyperextensibility appear to be better clinical indicators of this disorder.     

Epstein-Barr virus-associated B-cell lymphoma in a patient with DNA ligase IV (LIG4) syndrome

A 14-year-old Japanese girl with a progressing combined immunodeficiency had developed non-Hodgkin's diffuse large B cell lymphoma. Her molecular analysis showed a compound heterozygote of novel mutations in the LIG4 gene, M249V substitution and a five nucleotides deletion from nucleotide position 1,270-1,274. She had also a set of characteristic clinical features of LIG4 syndrome. Mutations in the LIG4 gene, which plays a critical role in the repair of DNA double-strand breaks, imply a correlation with malignancies and several cases with leukemia or lymphoma have already been reported. We report here on a case of LIG4 syndrome complicated with distinct EBV-associated B-cell lymphoma.     

Combined immunodeficiency, chromosomal instability, and postnatal growth deficiency in a Japanese girl

We report on an 11-year-old Japanese girl with combined immunodeficiency and chromosomal instability. She had postnatal growth deficiency and microcephaly, preaxial polydactyly of the left hand, and susceptibility to infections. Immunological studies showed marked lymphocytopenia (around 500/ll), reduced lymphocyte response to various mitogens, and reduced or absent serum IgA, IgG, and IgM. Cell biological studies of her primary skin fibroblasts demonstrated spontaneous chromosome aberrations and radiation hypersensitivity. The combination of immunodeficiency, chromosomal instability, and radiation hypersensitivity as seen in the girl is present in both ataxia-telangiectasia and Nijmegen breakage syndrome. Ataxia-telangiectasia was excluded because of differences in clinical features and laboratory data. Likewise, Nijmegen breakage syndrome is unlikely to be the case because the characteristic face, hyperpigmented spots, and mental retardation present in the syndrome were missing in the girl. Sequence analysis of a Nijmegen breakage syndrome responsible gene, NBS1, revealed no mutations. A normal NBS1 product was also demonstrated by immunoblot analysis using an anti-NBS1 antibody. We propose that the disorder in the girl represents a new combination of combined immunodeficiency and chromosomal instability.     

Achalasia and microcephaly

The authors report the combination of achalasia, microcephaly, and mental retardation in three surviving sisters and similar manifestations in a brother who died after recurrent vomiting and respiratory infections. The achalasia in the females was relieved with an operation. There was no demonstrable chromosomal abnormality. In this family achalasia, microcephaly, and mental retardation occurred together as an apparent autosomal recessive syndrome.     

Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity,Primordial Dwarfism,and Neurological Abnormalities

DNA double‐strand break repair via non‐homologous end joining (NHEJ) is involved in recombination of immunoglobulin and T‐cell receptor genes. Mutations in NHEJ components result in syndromes that are characterized by microcephaly and immunodeficiency. We present a patient with lymphopenia, extreme radiosensitivity, severe dysmaturity, corpus callosum agenesis, polysyndactily, dysmorphic appearance, and erythema, which are suggestive of a new type of NHEJ deficiency. We identified two heterozygous mutations in LIG4. The p.S205LfsX29 mutation results in lack of the nuclear localization signal and appears to be a null mutation. The second mutation p.K635RfsX10 lacks the C‐terminal region responsible for XRCC4 binding and LIG4 stability and activity, and therefore this mutant might be a null mutation as well or have very low residual activity. This is remarkable since Lig4 knockout mice are embryonic lethal and so far in humans no complete LIG4 deficiencies have been described. This case broadens the clinical spectrum of LIG4 deficiencies.