1 例多发先天畸形- 肌张力低下- 癫痫综合征1 临床及遗传学分析

目的分析多发先天畸形-肌张力低下-癫痫综合征1(MCAHS1)的临床及遗传学特征。方法回顾2018年4月确诊的1例MCAHS1患儿的临床资料;应用全外显子测序及Sanger验证行基因检测;采用流式细胞术分析患儿外周血粒细胞表面糖基磷脂酰肌醇(GPI)锚定蛋白FLAER、CD16、CD24、CD58、CD59表达量。结果男性患儿,4月龄,因阵发性双眼上翻,发育落后就诊;患儿有特殊面容、肌张力低下。全外显子测序发现患儿PIGN基因存在2个杂合变异,c.343G>C和c.1694G>T,分别来自于临床表型正常的母亲和父亲,为复合杂合变异。该变异尚未见报道,经美国医学遗传学与基因组学学会(ACMG)指南评级为疑似致病性变异。该复合杂合变异导致粒细胞表面GPI锚定蛋白的表达量下降。随访发现患儿10月龄出现发热抽搐,15月龄出现癫痫,口服丙戊酸钠后发作控制。经康复治疗患儿仍发育缓慢。文献检索已经报道MCAHS1患者18例,基因变异以错义变异最常见,多数患儿预后不佳。结论该MCAHS1患儿的基因测序扩充了MCAHS 1基因变异谱。     

钼辅因子缺乏症1 例临床及遗传学分析

目的探讨钼辅因子缺乏症的临床及遗传学特征。方法回顾分析1例确诊钼辅因子缺乏症患儿的临床资料。结果女性患儿,6月龄,生后即出现喂养困难、抽搐,并逐渐出现小头畸形、痉挛型四肢瘫等。全外显子测序发现患儿MOCS2基因存在c.473TG(p.Leu158*)和c.472_477del(p.Leu158_Lys159del)复合杂合变异,分别遗传自父亲和母亲。按照美国医学遗传学学会指南,c.473TG为致病变异,c.472_477del为可能致病变异。结论患儿被确诊为MOCS2基因杂合变异所致的钼辅因子缺乏症。     

Menkes 病二家系遗传学分析

目的分析Menkes病基因变异特征。方法回顾分析2例Menkes病患儿的临床资料以及ATP7A基因检测结果。结果例1患儿为男性,2月龄,ATP7A基因第21外显子存在c.4077dupT的纯合变异。例2患儿为男性,4月龄,ATP7A基因第10外显子存在c.2354delC的纯合变异,2例患儿家系验证父母均为野生型。这2种变异在HGMD数据库中均未报道,根据ACMG指南划分为致病变异。结论对2例患儿家系的遗传学分析丰富了中国人ATP7A基因的变异谱,也为临床医师早期诊断和遗传咨询提供帮助。     

RARS2 基因变异一家系报告并文献复习

目的探讨RARS2基因变异的临床特点。方法回顾分析一家系2例RARS2基因变异患儿的临床资料,并复习相关文献。结果 2例患儿为姐妹,均于4月龄起病,表现为喂养困难、顽固性局灶性癫痫发作、四肢肌张力减低、小头畸形,血乳酸一过性升高;头颅磁共振示双侧大脑半球萎缩,右侧颅板下出血,右侧基底节区异常信号。先证者检测到RARS2基因复合杂合变异,NM_020320 c.1157GT(p.R386L),NM_020320 c.1210AG(p.M404V)。先证者姐姐首次基因检测无发现,再次分析发现RARS2基因同样变异,并于1岁4月龄死亡。检索到相关文献19篇,包括本家系2例共37例患儿。其中男37.2%、女62.8%,大多在6月龄内起病;临床表现有癫痫发作,精神运动发育停滞或倒退,喂养困难,肌张力减低,小头畸形;大部分患儿血、脑脊液乳酸增高及脑桥小脑发育不良。共发现RARS2基因33个变异位点。结论 RARS2基因变异的临床表现有顽固性癫痫发作、喂养困难、精神运动发育迟滞或倒退、小头畸形、肌张力减低,部分患儿无桥脑小脑发育不良,预后差。     

严重表型心- 面- 皮肤综合征2 例临床特征和基因突变分析

目的探讨心-面-皮肤综合征严重表型患儿的临床特征和基因变异。方法回顾分析2例具有心-面-皮肤综合征严重表型患儿的临床资料,以及高通量测序技术检测的基因分析结果。结果 2例男性患儿,生后即出现喂养困难及精神运动发育迟缓,除有颅面部和心脏畸形外,还伴喉气管畸形,均在6月龄内死亡。基因检测发现2例患儿的BRAF基因存在新生变异c.1783TC(p.F595L)、c.770AG(p.Q257R)。结论发现2例国内未见报道的BRAF基因变异致心-面-皮肤综合征严重表型患儿。     

先天性肌营养不良1A型患儿临床特征及LAMA2变异分析：病例报告1例及文献复习

LAMA2双等位基因致病性变异导致先天性肌营养不良1A型（CMD1A）。该研究患儿为19月龄男孩，临床表现为运动发育落后，伴血清肌酸激酶、转氨酶及乳酸脱氢酶升高。遗传学分析发现患儿LAMA2基因存在复合杂合变异，其中母源性c.7147C > T （p.Ala2383Ter）为已报道的无义变异，而父源性c.8551_8552insAA （p.Ile2852ArgfsTer2）为未报道的移码变异，且根据ACMG指南确定为致病性变异。该患儿最终确诊为CMD1A。国内外文献复习发现：该病患儿多在生后6个月内起病，以严重的运动发育落后为特点，伴有血清肌酸激酶升高，可有脑白质受累的影像学改变；LAMA2基因变异具有明显的异质性，且绝大部分属于零效变异；目前CMD1A患儿无特异性治疗，远期预后不良。     

COA6 基因新发变异致婴儿细胞色素c 氧化酶缺陷致心脑肌病4 型 1 例报告并文献复习

目的提高对婴儿细胞色素c氧化酶缺陷致心脑肌病4型(CEMCOX 4)临床表型及基因型的认识。方法回顾分析1例婴儿CEMCOX4患儿的临床资料并复习相关文献。结果女性患儿,5日龄,出生后即出现呼吸困难;多次血气分析示乳酸增高;心脏彩超示肥厚型心肌病,双侧心室流出道梗阻。全外显子测序发现患儿COA6基因存在c.411_412insAAAG纯合变异,导致从第140个赖氨酸开始的氨基酸合成发生改变,并在改变后的第4个氨基酸终止(p.Lys 140 ArgfsTer 4),可能致蛋白质功能受到严重影响。家系验证示父母均携带c.411_412 insAAAG杂合变异。该变异未曾见报道。文献复习提示婴儿CEMCOX4多表现为乳酸性酸中毒、肌张力低下及肥厚性心肌病,致病基因的纯合变异较复合杂合变异预后更差。结论报道婴儿CEMCOX4病例,并发现新的COA6基因变异,扩充了COA6基因变异谱。     

MOCS1基因突变致钼辅酶缺乏症1例

患儿男,1月龄时因左手抖动1周就诊。血尿酸降低,头颅MRI示脑软化、萎缩、囊变,婴儿期出现小头畸形、特殊面容（长脸、长额头、前额隆起、长人中、低鼻梁、颜面部浮肿、厚下嘴唇）、下肢肌张力增高及严重全面发育迟缓。患儿行全外显子组测序示MOCS1基因存在c.217C > T （p.R73W）纯合变异,来源于父母,该变异判定为“可能致病的”。根据患儿临床表现及基因检查明确诊断为钼辅酶缺乏症A型,该病为国内首次报道。     

泛酸激酶相关神经变性病2 例报告并文献复习

目的探讨泛酸激酶相关神经变性病(PKAN)的临床特征及遗传学特点。方法总结分析2例PKAN患儿的临床资料及基因检测结果,并以"Hallervorden-Spalz"、"脑组织铁沉积"、"NBIA"和"PKAN"、"PANK2"为检索词,检索2019年3月前的PubMed、人类基因组突变数据库(HGMD)、中国知网数据库(CNKI)和万方数据库,进行文献复习。结果 2例患儿均为男性。例1患儿为7 岁2月龄,肌张力升高3年余,加重2周;头颅磁共振成像示苍白球病变;全外显子基因检测发现PANK2基因杂合变异C.515-527del、C.644-645delGAinsAT,其母亲携带杂合致病变异,父亲携带可疑杂合致病变异。例2患儿为14岁9月龄,走路不稳8年、加重1年;全外显子基因检测发现PANK2基因纯合变异c.397AG(p.Met133Val),其母亲为杂合变异,父亲未检测到变异。结论杂合和纯合PANK2基因变异均可导致发病。     

天冬酰胺合成酶缺乏症1例报告并文献复习

目的探讨天冬酰胺合成酶缺乏症(ASNSD)的临床及基因变异特征。方法分析1例ASNSD患儿的临床资料,并复习相关文献。结果患儿女性,5岁3月龄,主要表现为严重的精神运动发育迟缓、反复癫痫发作。头颅磁共振提示幕上脑室扩张,脑萎缩,胼胝体菲薄。全外显子测序显示患儿ASNS基因存在复合杂合变异,分别为源自父亲的整码变异c.1503_1505delAGC,及母亲的错义变异c.776G>C。该变异为首次报道,生物信息学软件(Provean、mutationtaster)均预测其致病。结论基因检测有助于ASNSD诊断,该例患儿扩充了ASNSD的基因变异谱。     

Bibliometric data: a disaster for many non-American biomedical journals

Bibliometric data published by the Institute of Scientific Information in Philadelphia (ISI), and which was previously discussed in Acta Paediatrica , has increasingly been used despite all the relevant and severe criticism that has been raised against this method of evaluating individual research results and grading scientific journals. It is obvious that the present trend regarding the use of bibliometric data as a basis for priorities and funding of research and for the promotion of individual scientists favours American-oriented research projects at the expense of those that are based on concepts of predominantly European relevance.

Conclusion: For the future of non-American research, it is important that no single super-power, i.e. the USA, should dominate scientific priorities. The condition for efficient European competition is that European Centres with high levels of competence for creative research and training of scientists from all over the world are established. In addition, it is important that the results of European research are published in prestigious European journals, as was the situation before World War II.     

alpha -SMOOTH MUSCLE ACTIN DISTRIBUTION IN THE PULMONARY VASCULATURE COMPARING HYPOPLASTIC AND NORMAL FETAL LUNGS

We investigated the intra-acinar pulmonary vascular muscularization in the developing human fetal lung between the 17th and 24th gestational weeks, that is, during the canalicular phase of lung development. Fifteen hypoplastic and 25 normal developed lungs were included in this study using monoclonal alpha -smooth muscle (sm) actin antibodies for smooth muscle detection. Computer-aided image analysis was performed for morphometrical measurements and statistical evaluation. Alphasm-actin-immunoreactive intra-acinar vessels down to a luminal diameter of less than 10 mu m were detected in hypoplastic as well as in normally developed lungs. Crucial differences presented as follows: significantly higher density of intra-acinar vessels, especially due to alpha -sm-actin-negative vessels less than 30 mu m in luminal diameter, in the control group; significantly higher alpha -sm-actin immunoreactivity per section unit as well as per vessel in the hypoplastic lung group. As suggested by others, alpha-sm-actin-positive cells of the intra-acinar vessel wall in the developing human lung were demonstrated to be smooth muscle cells, their immediate precursors, and pericytes. We conclude that the increased alpha -sm-actin immunoreactivity represents muscularization of the vessel wall in functional terms and may be regarded as one structural cause among others for the establishment of persistent fetal circulation in hypoplastic lungs.     

Whole-body mineral measurements in Swedish adolescents at 17 years compared to 15 years of age

Aim: To provide reference data for bone mineral variables in 15- and 17-y-old adolescents and to analyse the relationships between these variables and measures of bone and body size, gender, puberty, growth, various lifestyle and environmental factors and socioeconomic background.

Methods: In the same 321 randomly selected adolescents (147 boys and 174 girls) living in two different regions of Sweden, the total bone mineral content (TBMC), bone area (BA) and total bone mineral density (TBMD) were assessed by dual-energy X-ray absorptiometry at ages 15 and 17 y. The effects of bone and body size, gender, growth, sexual maturity, physical activity, region of domicile, social conditions, food habits, smoking and alcohol intake on TBMC and TBMD were examined in multivariate analyses.

Results: In the 15-y-old adolescents, BA, height, gender, physical activity, maturity and weight explained 91% and 48%, of the variance in TBMC and TBMD, respectively. In similar analyses in the 17-y-olds, the corresponding figures were 92% and 62%, respectively, when BA, height, growth, physical activity, gender and region emerged as significant in the model. In all these analyses, BA explained most of the variance in TBMC and TBMD. No significant reduction of variance was found when different measures of social conditions, smoking, food habits, alcohol or dietary intakes of energy, calcium or vitamin D were included in the models. The reason why region of domicile had a significant impact on TBMC in the 17-y-olds is not known. The fact that the normal fluoride concentration in drinking water (1.1 mg/L) is 10 times higher in the region where TBMC was higher than in the other region is an interesting observation.

Conclusion: Almost 90% of the variance in TBMC and 50% of that in TBMD was explained by measures of bone and body size and only a few percent by gender, physical activity, Tanner stage, growth and region of domicile.     

The potential role of rapamycin in pediatric transplantation as observed from adult studies

Although pediatric patient and renal graft survival rates have shown marked improvements during the past decade, the persistent toxicities of immunosuppressive drugs and chronic allograft attrition remain major obstacles in transplant therapy. Results in adult patients suggest that complete steroid withdrawal is possible in the majority of recipients under treatment with a cyclosporin A-rapamycin (CsA RAPA) regimen. Furthermore, preliminary studies suggest that a marked reduction in the dose of CsA may be possible under the umbrella of RAPA coverage. The gain in immunosuppressive efficacy afforded by RAPA has not only been obtained without an increased morbidity owing to infectious or neoplastic causes, but also with the potential for reducing the incidence and/or progression of chronic rejection.     

VARICELLA ZOSTER VIRUS INFECTIONS IN THE PEDIATRIC STEM CELL TRANSPLANT PATIENT

Varicella zoster virus (VZV), a member of the human herpesvirus family, causes the clinical syndromes of chickenpox during primary infection and shingles on later reactivation. In immunocompromised patients, including those undergoing hematopoietic stem cell transplantation, VZV can produce life-threatening infections. The most serious forms of VZV infection involve hematogenous dissemination of the virus to vital organs, such as the lung, brain, and liver. Advances in immunoprophylaxis, antiviral chemotherapy, and vaccine development have provided effective tools to limit the morbidity and mortality previously associated with VZV infection in hematopoietic stem cell transplant patients. In this review, we discuss virologic aspects of VZV, pathogenesis of VZV infection, methods of viral diagnosis, clinical manifestations of infection in both normal and immunocompromised patients, and available preventative and therapeutic measures.     

Génétique des schizophrénies : mise en perspective des schizophrénies à début précoce et autres pathologies du développement

Schizophrenia (SCZ) is a severe brain disorder characterized by hallucinations, delusions, flat and/or inappropriate affect and cognitive impairment. The lifetime risk is about 0.5% with heritability of 65–85%. The prevalence of early-onset schizophrenia (defined here as before 15 years of age) has not been well studied, but is likely to be 5–10% of all cases. The rarity of early-onset SCZ has made it difficult to study. We focus on genetic studies of adults with schizophrenia, highlighting results for early-onset schizophrenia where available. Prior to the past 5 years, studies failed to find replicable association or linkage between SCZ and specific genes when appropriate statistical corrections for multiple testing were used. Many false positive results were probably reported using the candidate gene approach. Recently, the development of single nucleotide polymorphism (SNP) “chips” has permitted large genome-wide association study (GWAS) analyses that suggest that across all age groups, a proportion of genetic risk can be attributed to a large number of common SNP, each with a very small effect on risk (odds ratios of 1.1 or less). The greatest known genetic effect is conferred by the 1.5–3 Mb 22q.11.2 deletions, which occurs in ∼ 1/4000–1/6000 births with SCZ developing in 20–30% of carriers. Large SNP and aCGH microarray studies have now identified associations between SCZ and other rare, large copy number variations (CNV, insertions and deletions) with high odds ratios (5–10), including deletions of 1q21, 2p16.3 (neurexin-1 gene), 3q29 and 15q13.3, and duplications of 16p11.2. Some of these CNV are also associated with autism or other developmental disorders as well as epilepsy or intellectual deficiency, suggesting some overlap in the mechanisms that contribute to risks of these disorders. Based on preliminary data from larger-scale analyses in progress, approximately 1–2% of cases carry a CNV that has been clearly associated with SCZ (ORs 4–12). Whole exome and genome sequencing studies of large adult samples will be the next steps to identify rarer SCZ-associated mutations, including point mutations and smaller as well as rarer CNV. Genetic findings are beginning to contribute to an understanding of biological mechanisms of SCZ risk and may lead to new approaches to treatment.     

INACTIVATION OF PULMONARY SURFACTANT AND THE TREATMENT OF ACUTE LUNG INJURIES

Inactivation of pulmonary surfactant may be important in acute lung injury and acute respiratory distress syndrome. Treatment of surfactant dysfunction by instilling exogenous surfactants may improve gas exchange and pulmonary mechanics. Surfactants used for treatment vary in their attributes and effects, so when various surfactants are considered for therapy, resistance to inactivation is an important consideration. Animal models of acute lung injury exist in which the relative merits of surfactants can be compared. We hypothesize that the surfactants most resistant to inactivation in vitro will be the ones that are most effective in treatment of animal models of acute lung injury. Surfactants with higher concentrations of surfactant proteins (specifically A, B, and C) are more resistant to inactivation. Nonionic polymers mimic surfactant proteins in preventing surfactant inactivation under some conditions. Adding nonionic polymers to surfactant containing minimal amounts of SP-B and SP-C markedly improves lung function of animals with lung injury. Making surfactants more "inactivation-proof" may improve surfactant therapy of acute lung injuries.     

Plasma Proinsulin and C-Peptide Concentrations in Children with Hyperinsulinaemic Hypoglycaemia

ABSTRACT. Plasma concentrations of proinsulin and C-peptide were measured in five children presenting with svere hypoglycaemia associated with elevated plasma levels of immunoreactive insulin (IRI) in order to determine whether the profile of circulating B-cell products related to the underlying pathophysiology of the pancreas. Results were compared with data from 13 normal infants. Four children, three neonates and a nine year old girl, were subjected to partial or total pancreatectomy. The neonates had nesidioblastosis, nesidioblastosis with a microadenoma, and a functional abnormality without histological derangement respectively; the older child had a localised adenoma. The remaining child, a neonate, had transient hypoglycaemia and elevated IRI levels associated with hyperlactataemia and hyperalaninae-mia. All the children had markedly elevated plasma proinsulin concentrations; the highest levels were seen in the child with an isolated adenoma and in the neonate with nesidioblastosis and a microadenoma. Both of these children also had substantially elevated plasma C-peptide concentrations. The remaining three neonates had plasma C-peptide levels, which although in the normal range for normoglycaemia were inappropriately elevated during hypoglycaemia. It is concluded that elevated proinsulin and C-peptide concentrations are seen in children with hypoglycaemia associated with increased plasma IRI levels and that the profile of the concentrations does not provide a reliable marker for the nature of the underlying pancreatic abnormality.     

Growth tracks in early childhood

Aim: Child growth is modulated by numerous factors and, particularly in infancy and early childhood, often tends to follow apparently irregular patterns, with many centiles crossed before the later growth channels are reached. The aim of this study was to visualize the diversity of individual growth. Design: The study investigated 333 girls and 329 boys without chronic illnesses from four paediatric practices in Kiel, Germany. The children were measured on natural     

Residual pulmonary hypertension in children after treatment with inhaled nitric oxide: a follow-up study regarding cardiopulmonary and neurological symptoms

Inhaled nitric oxide is a potent vasodilator in acute severe pulmonary hypertension and is increasingly used as rescue treatment in intensive care algorithms aiming at reducing severe hypoxaemia in neonates and children. Although the immediate effects may seem impressive, longterm outcome regarding residual pulmonary hypertension and other sequelae has been studied in only a very few patients. The aim of the present study was to evaluate residual pulmonary hypertension, cardiopulmonary or neurological symptoms in children after treatment with inhaled nitric oxide in severely hypoxaemic and/or pulmonary hypertensive mechanically ventilated children. The study was performed in four paediatric intensive care units in university hospitals in Sweden, Norway and Australia. Patients who had received inhaled nitric oxide as part of their intensive care treatment for severe hypoxaemia and/or pulmonary hypertension, and in whom 6 mo had elapsed since treatment, were included for evaluation. Thus 36 paediatric or neonatal patients were examined for circulatory, respiratory or neurological disorders with clinical examination, echocardiography, chest X-ray and a capillary blood sample. Four patients with congenital heart disease had residual pulmonary hypertension. Nine patients were receiving bronchodilators. Sixteen patients had minor (n = 15) or moderate (n = 1) changes on a chest X-ray. One patient had a possible delay in psychomotor development. Conclusions: In spite of the severity of their primary illness, we found that the overwhelming majority of the surviving children were asymptomatic and doing well. The few residual circulatory and respiratory symptoms could be related to the initial condition.