CXCR4基因突变致WHIM综合征3例报告并文献复习

目的探讨CXCR4基因突变导致WHIM综合征的临床特征及基因变异特点。方法回顾性分析3例CXCR4基因突变致WHIM综合征患儿的临床资料和全外显子组测序（WES）结果,并行系统检索和文献复习,收集诊断明确的WHIM综合征患者,总结临床特征和基因突变信息。结果3例WHIM综合征患儿均为男性,确诊年龄分别为11岁、13月和5岁。3例均有反复感染,均无皮肤疣表现,1例发生糖尿病。3例患儿多次查血常规示淋巴细胞及中性粒细胞减少,但无周期性特征;3例患儿免疫球蛋白均减低。2例行骨髓穿刺检查,其中1例有典型无效生成性慢性粒细胞缺乏样表现。2例患儿经集落刺激因子治疗后,WBC可升至正常,但易反复。WES结果显示,3例患儿均为CXCR4基因第2外显子C端杂合突变,在该基因第2外显子剪切位点发生碱基替换突变（1000C>T）,造成氨基酸R334X改变。共检索到46篇WHIM综合征文献（45篇英文,1篇中文）,共报告WHIM患者74例（包括本文3例）。74例患者中,男32例,女42例,成人36例,儿童38例。出现皮肤疣的起病中位年龄为6.5岁;65例（87.8%）患者表现为反复感染;60例（81.1%）报告基因检测结果,共检测到9个突变,均为CXCR4基因突变。结论WHIM综合征为罕见的常染色体显性遗传病,可表现为粒细胞减少、低丙种球蛋白血症、疣状物、反复感染（尤其对人乳头状瘤病毒易感）及无效生成性慢性粒细胞缺乏。小年龄患儿可无皮肤疣,临床发现上述表现应考虑该病,并行基因检测以明确诊断。     

1个Alagille综合征家系中JAG1基因新突变的识别

Alagille综合征 （ALGS）是一种主要由JAG1基因突变导致的常染色体显性遗传病,可累及肝脏、心脏、骨骼、眼和面部等多器官。本文报道1例ALGS患儿的临床和遗传学特征。患儿,男,2岁9个月,因发现肝功能异常及心脏杂音2年余就诊。查体：发育营养稍差,皮肤巩膜无黄染。前额突起,左眼内斜视,鼻梁低平,小下颌。双肺呼吸音清,胸骨左缘2~3肋间可闻及2/6级收缩期杂音,肝脾不大。血生化发现胆汁酸、胆红素、转氨酶等均升高。心脏彩超提示房间隔缺损 （静脉窦型）和左肺动脉狭窄;脊柱正位片发现第6、8胸椎蝴蝶椎畸形。患儿明显左眼内斜,眼科诊断眼球后退综合征。因此,该患儿符合ALGS在肝脏、心脏、脊柱和面部的特殊表现,且DNA直接测序发现JAG1基因存在一个新突变c.2419delG （p.Glu807AsnfsX819）,ALGS诊断明确。确诊后予以对症支持治疗。目前已随访至4岁2个月,病情平稳,但面部畸形、左眼内斜视、心脏杂音和肝功能异常持续存在,其远期预后有待观察。     

发热、头痛、皮肤紫癜2例

该研究2例学龄期患儿于春季急性起病,表现为发热、头痛、呕吐、意识障碍,以及皮肤紫癜、脑膜刺激征阳性。外周血白细胞及中性粒细胞均增高、血红蛋白及血小板不同程度降低;CRP明显增高;脑脊液白细胞数增高达数百或上千、且以中性粒细胞为主,脑脊液蛋白增高,糖、氯化物正常。其中1例头颅CT示右侧小脑、双侧大脑多发血肿。骨髓细胞学提示感染性骨髓象,血培养、骨髓培养均提示金黄色葡萄球菌(MRSA)。患儿抗感染治疗过程中出现心脏杂音,并且血红蛋白及血小板进行性下降,心脏彩超发现主动脉瓣赘生物形成,确诊为感染性心内膜炎(IE)。根据药敏试验改为万古霉素抗感染治疗,1例6周后痊愈,1例放弃治疗死亡。儿童IE起病隐匿,临床表现多样,建议对于不明原因发热患儿要注意动态观察心脏杂音,及时行心脏彩超排除IE;以化脑为表现的患儿伴有难以用血小板减少解释的皮肤、黏膜出血时,也应警惕IE。     

纤维支气管镜下介入治疗婴儿严重气管软化狭窄

1 病例摘要 患儿,女,4个月,主因"发现心脏杂音3月余,咳嗽10 d,加重3 d"于2011年2月25日入院.患儿1月龄时于外院检查发现心脏杂音,查心脏彩超提示先天性心脏病:室间隔缺损(膜周部+肌部),房间隔缺损(继发孔),二尖瓣关闭不全伴轻度反流,三尖瓣关闭不全伴中度反流,肺动脉高压.     

Kabuki综合征2例报告

目的分析2例Kabuki综合征患儿的临床特征及基因诊断结果。方法回顾分析2例Kabuki综合征患儿的临床资料。结果 2例均为1岁余男性患儿,有特殊面容、发热惊厥表现,基因检测均提示KMT2D(或MLL2)基因突变,但临床表型仍有差异。结论临床疑似Kabuki综合征的患儿可进行基因检测明确诊断。     

左室假腱索的临床意义探讨：附24例报告

本文报告因心律不齐和心脏杂音作二维超声心动图检查发现左室假腱索24例,其中心律不齐(过早搏动)18例,检出纵向型假腱索15例(80.5%),横向型假腱索3例(19.5%);心脏杂音6例中纵向型假腱索2例(33.3%),横向型假腱索4例(66.7%);提示纵向型假腱索易激发过早搏动,横向型假腱索易产生心脏杂音。测量24例左室假腱索患儿左心功能参数(射血分数和心脏指数),除1例持续7年频发过早搏动患儿轻度降低外,余23例左心功能参数均正常,提示左室假腱索对左心功能无明显影响。     

GATA4基因在汉族先天性房室间隔缺损患者中的突变分析(英文)

目的通过检测GATA4基因在房室间隔缺损(AVSD)患儿中的突变情况,探讨其在房室间隔缺损发病机制中的作用。方法收集94例汉族AVSD患儿(包括合并21三体综合征23例,散发病例71例)的血液标本,PCR方法扩增GATA4基因全部编码序列后,对扩增产物进行测序,然后与GenBank人中GATA4基因编码序列进行比对,并以100例健康汉族儿童为对照。结果在94例患儿中检出4例错义突变(碱基变化为C106G、C259T、C504A、A1079G,氨基酸改变分别为P36A,P87S,D168E,E360G),前三者为散发的非综合征完全性AVSD患儿,第4例为完全性AVSD伴21-三体综合征患儿;6例患者发现多态性(rs56166237,碱基变化为G99T,氨基酸编码A33A)。结论 GATA4基因作为心脏发育的重要转录因子,其基因突变可能导致GATA4蛋白功能的改变,从而导致AVSD的发病;GATA4基因在合并21-三体综合征抑或散发的AVSD患者中突变率均不高,提示AVSD可能是一个多基因的遗传性心脏疾病。     

Alagille 综合征合并肝细胞癌1 例报告并文献复习

目的探讨儿童Alagille综合征合并肝细胞癌的临床表现、影像学检查、治疗及预后。方法分析1例Alagille综合征合并肝细胞癌患儿的临床表现、辅助检查、诊断,并复习相关文献。结果患儿,女,6岁,因反复皮肤黄染入院,曾有心脏手术史。入院后查体有特殊面容(前额突出、眼眶深陷、尖下颌、鼻前端肥大)。血生化提示存在肝内胆汁淤积,甲胎蛋白升高;影像学腹部B超示肝内弥漫性多发实性占位,肝脏磁共振提示肝大,肝脏多发占位。Jagged 1基因检测为c.1205delC,杂合型。结论儿童期Alagllie综合征合并肝细胞癌极为罕见,早期诊断和长期随访对治疗及预后具有积极意义。     

肉眼血尿,心脏杂音,赘生物

患儿为学龄期女性,因发现肉眼血尿1d入院.入院后迅速完善检查,明确了系统性红斑狼疮诊断.治疗后病情好转,但病程中出现心脏杂音,行心脏彩超提示赘生物.为儿童罕见病例,经过会诊,诊断Libman-Sacks心内膜炎.总结:重视临床体检,注意病情的变化;重视多学科的合作.     

20p12.2缺失致Alagille综合征患儿临床和肝脏病理分析

目的分析20p12缺失致Alagille综合征(ALGS)患儿的临床表现和肝脏病理。方法回顾分析1例20p12微缺失致ALGS患儿的临床资料。结果患儿,男,1月龄起病,以胆汁淤积为首发表现,伴特殊面容,蝶形椎,肾脏和心脏病变;肝脏穿刺术病理学检测提示肝脏淤胆改变,肝细胞中度损害(G2S3),无胆管减少表现。采集患儿及父母血标本,采用二代基因测序检测发现chr20p12.2:(9288462-10654178)处1.36 Mb的杂合缺失,缺失片段中包含JAG1基因,为新发突变。确诊后予以对症支持治疗,随访半年,患儿生长发育无异常,黄疸仍迁延不退,远期预后有待进一步随访。结论ALGS是一种常染色体显性遗传病,临床表现多样,基因检测和肝活检有助于诊断。     

Tetralogy of Fallot is an Uncommon Manifestation of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder. We report three patients with WHIM syndrome who are affected by Tetralogy of Fallot (TOF). This observation suggests a possible increased risk of TOF in WHIM syndrome and that birth presentation of TOF and neutropenia should lead to suspect WHIM syndrome.     

A case of WHIM syndrome associated with diabetes and hypothyroidism

Abstract: The WHIM syndrome is a rare immunological disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. We hypothesized that immunological or genetic mechanisms may link WHIM syndrome and type 1 diabetes. We report that the young girl with WHIM syndrome developed diabetes and transient hypothyroidism. A nonsense mutation (C→T) truncating the CXC chemokine receptor 4 (CXCR4) C-terminal cytoplasmic tail domain occurred at nucleotide position 1000(R334X) of the CXCR4 gene in one allele of the patient was identified, and the person was diagnosed as having WHIM syndrome. Recent observation suggested that the CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, might be involved in the pathogenesis for type 1 diabetes. Taken into consideration the concurrent prevalence of the two disorders and the speculated common pathogenesis associated with the CXCR4, our patient may enable us to understand the genetic damage related to accelerated apoptosis.     

Congenital nephrotic syndrome of NPHS1 associated with cardiac malformation

Congenital nephrotic syndrome (CNS) is a rare disease inherited as an autosomally recessive trait and defined as proteinuria manifesting at birth or in the first 3 months of life. The classical form is the Finnish type of CNS (CNF), which is caused by mutations in the nephrin gene (NPHS1). The classical findings include prematurity, large placenta and massive proteinuria. Minor cardiac findings have been reported as a minor functional disorder but CNS with major cardiac malformation is rare. Here we report the case of a Turkish child with CNS with small indel mutation (c.614_621delCACCCCGGinsTT) in exon 6 of NPHS1 and also major cardiac malformation who did not develop end‐stage renal disease until the age of 5 years.     

Association of severe bronchial disease (bronchial casts, bronchiectasis) and partial abnormal pulmonary venous drainage in 2 children with Turner's syndrome]

The prevalence of cardiovascular malformation is high in Turner's syndrome. We report two cases of partial anomalous pulmonary venous drainage associated with a severe bronchial disease. CASE REPORTS: Case 1: a 5-year-old girl with monosomy X presented with acute respiratory failure. The chest X-ray showed an atelectasis of the left lower lobe. The patient improved following bronchoscopic removal of a bronchial cast. During hospitalization, an anomalous pulmonary venous drainage of the right lung was discovered. In spite of complete surgical repair of the cardiac malformation, several episodes of respiratory failure occurred several years after the operation. Case 2: a 9-year-old girl with monosomy X and coarctation of the aorta underwent pre-operative cardiac catheterization. She had a history of bronchiectasis, leading to a lobectomy. Her respiratory condition improved following surgery. A partial anomalous pulmonary venous return was discovered during the cardiac angiography. The coarctation was repaired surgically. The correction of the left-to-right shunt was not necessary. CONCLUSION: The partial anomalous pulmonary venous return is frequently reported in Turner's syndrome. The possible respiratory disease associated with this cardiac malformation is usually described as a consequence of the increase in pulmonary blood flow. Our two cases did not match this hypothesis.     

Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: A prospective study

Recent molecular studies have revealed that a 22q11 deletion is frequently detected in DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and conotruncal anomaly face syndrome (CTAFS). As one of the major clinical manifestations in these three syndromes is conotruncal cardiac malformation, we prospectively studied the frequency of a 22q11 deletion in a group of patients with conotruncal cardiac malformation. Fluorescence in situ hybridization (FISH) analyses using N25 (D22S75) DiGeorge Chromosome Region probe were performed on 64 patients with conotruncal cardiac malformation, who visited our clinic from October 1993 to January 1994. Of the 64 patients studied, a 22q11 deletion was detected in 5 patients (7.8%): 3 out of 30 patients with tetralogy of Fallot, one of three with interruption of the aortic arch, and one hemitruncus patient. No deletion was found in 16 patients with complete transposition of the great arteries, 8 with double outlet right ventricle and 2 with aortopulmonary window. In these five patients with 22q11 deletion, patient 1 was clinically diagnosed as having DGS, patients 2 and 3 had CTAFS, and patient 4 had VCFS. Patient 5 could not be dysmorphologically evaluated. It was noteworthy that all patients with a 22q11 deletion, except a non-evaluated patient, had some symptoms of syndromes DGS, CTAFS or VCFS, and that we failed to identify a non-syndromic 22q11 deletion positive patients in the present series of 64 patients.Conclusion This study suggests that it is advisable to bear 22q11 deletion in mind when a patient with conotruncal cardiac anomalies has some other features of DGS, VCFS or CTAFS.     

Early diagnosis of congenital heart disease

Routine examination of apparently healthy newborn babies detects less than half of those with congenital cardiac malformations because they are asymptomatic and without signs. More severe cardiac malformations are not detected more easily. A normal clinical examination does not exclude serious congenital cardiac malformation. Left heart obstruction is easily overlooked but often causes serious deterioration in less than 3 weeks. It is important to arrange early echocardiography of babies with signs and to consider cardiac malformation in a sick baby even if a previous routine examination was normal. All babies with Down syndrome should have early expert cardiological assessment.     

Aortic arch interruption type A with aortopulmonary fenestration in an offspring of a chronic alcoholic mother ("fetal alcohol syndrome")

A case is described of a newborn infant, small for gestational age, with the features of the "fetal alcohol syndrome", who presented a murmur within the first few days of life, and died at age 7 days in heart failure. Autopsy revealed interruption of the aortic arch, type A, an aortopulmonary window and intact interventricular septum. The association of "fetal alcohol syndrome" and cardiac malformation is discussed, with reference to other cases described in the literature.     

Complex cyanotic heart defect in a newborn infant with cat eye syndrome

In a cyanotic newborn with characteristic features of Cat-Eye-Syndrome, cytogenetic examination disclosed a supernumerary small bisatellited chromosome. Angiography showed Tetralogy of Fallot with pulmonary atresia and a narrow patent ductus arteriosus with additional stenosis of the bifurcation of the pulmonary artery. At an age of 14 weeks, the patient died after the attempt of corrective cardiac surgery. Congenital cardiac malformation is present in more than one third of patients with cat-eye-syndrome and is usually the lifelimiting malformation in this syndrome.     

Familial interruption of the aortic arch

Summary Interruption of the aortic arch (IAA) is an important congenital cardiac malformation occurring in 1.4% of cases with a congenital cardiac malformation. Only two reports have described IAA in siblings, each with type B and an anomalous right subclavian artery. We report the occurrence of IAA type B with an anomalous right subclavian artery in two siblings and their half-sibling, each of whom had additional conotruncal cardiac malformations. Recent evidence suggests that conotruncal cardiac malformations, including IAA type B, are related to abnormalities of neural crest cell migration. Thus, the family reported herein may manifest a syndrome related to alterations in mesenchymal tissue/neural crest cell migration.