新生儿葡萄糖/半乳糖吸收不良症2例病例报告并文献复习

目的 探讨以新生儿反复腹泻为主要临床表现的SLC5A1基因致病变异所致葡萄糖/半乳糖吸收不良症的临床特征及其遗传学特点。方法 报告2例新生儿SLC5A1基因复合杂合变异致葡萄糖/半乳糖吸收不良症患儿的临床表现、实验室检查及基因检测结果,并对国内外数据库中有具体临床信息和基因检测结果的相关文献进行复习。结果 2例患儿生后即出现反复腹泻,伴脱水、高钠血症和代谢性酸中毒。全外显子组测序检测到2例患儿均携带SLC5A1基因的复合杂合变异,例1(男)为c.325dupG和c.1107_1109delAGT变异,例2(女)及有相似病史的哥哥均为c.781G>A和c.1298T>C变异。检索PubMed、中国知网、万方和维普数据库,共检索到具有临床资料和基因突变分析的18篇病例报道,与本文合并后共报道74例葡萄糖/半乳糖吸收不良患者。新生儿期最显著的临床表现为腹泻(100%)和脱水(89.2%),换果糖基质奶粉或无碳水化合物配方奶喂养后大便正常。该病患儿通常生后2~5 d即出现腹泻症状,但是亦存在家族内异质性及较晚发病的病例。结论 对于生后不久出现水样便和脱水的患儿,需考虑葡萄糖/半乳糖吸收不良症的可能,并尽早完善基因检测,有助于早期诊断和治疗。     

先天性葡萄糖- 半乳糖吸收不良症1 例临床及基因分析

目的分析1例先天性葡萄糖-半乳糖吸收不良症患儿的临床和SLC5A1基因突变特点。方法收集2016年11月诊治的1例先天性葡萄糖-半乳糖吸收不良症患儿的临床资料,应用家系单基因病全外显子组测序分析方法进行SLC5A1基因突变检测。结果男性患儿,生后第3天开始出现腹泻,黄色稀水样便,伴发热,无寒战;多次电解质检查提示血钠明显升高,最高162 mmol/L。全基因外显子检查发现SLC5A1基因2个与葡萄糖-半乳糖吸收不良症(OMIM:606824)相关性较高的变异,c. 406(外显子5) delT、c. 92 TA(外显子1),患儿父母亲表型均正常,母亲c. 92 TA杂合。行葡萄糖、果糖激发试验,提示糖吸收不良,确诊葡萄糖-半乳糖吸收不良症。10月龄予去碳水化合物液态奶及果糖喂养,半天后患儿大便即转成形便,随访情况良好。结论先天性葡萄糖-半乳糖吸收不良症是临床罕见的常染色体隐性遗传性疾病,出生早期出现持续水样腹泻,基因分析可明确诊断。早期诊断及去碳水化合物液态奶及果糖喂养对预后至关重要。     

A20单倍剂量不足合并甲基丙二酸尿症1例

患儿男, 6月龄, 因"反复发热2个月余"就诊, 基因检测发现同时存在2个基因缺陷。TNFAIP3基因存在c.1243₁247del杂合变异, 为未报道的新发变异;MMACHC基因存在c.349G>C和c.482G>A复合杂合变异。确诊A20单倍剂量不足及甲基丙二酸尿症2种罕见遗传病, 给予羟钴胺、左卡尼汀、沙利度胺等治疗。随访3年, 患儿生长发育正常, 腹泻好转, 仍有反复发热。     

婴儿失盐综合征4例病因分析及基因诊断应用价值探讨

目的 探讨婴儿失盐综合征的病因及基因检测在病因诊断中的应用价值。方法　收集2010-2014年上海交通大学附属上海儿童医学中心收治的4例表现为低钠高钾血症的失盐综合征患儿的临床资料、治疗随访情况,并采集该4例患儿及其父母的DNA进行基因检测。结果　4例患儿存在不同程度的失盐。通过基因检测,明确了其存在不同的致病基因突变：分别为CYP21A2基因存在剪接位点变异c.293-13A＞G（杂合）,小的重复c. 923dupT,p.Leu308Phefs*6（杂合）; DAX1 基因存在小的缺失c.1334delC, p.Ala445Valfs*17（半合子）; SCNN1A基因存在小的缺失c.del1311G, p.Arg438Glyfs*43（杂合）, 剪接位点变异c.1439+1G＞C（杂合）; CYP11B2基因存在剪接位点变异c.240-1G＞A（杂合）, 无义变异c.1009C＞T, p.Gln337*（杂合）。结合临床表现, 分别诊断为： 先天性肾上腺皮质增生症（21-羟化酶缺乏症）; 先天性肾上腺发育不良; 假性醛固酮减少症I型; 醛固酮减少症。结论　婴儿失盐综合征病因复杂,容易误诊,基因检测有助于早期明确诊断,进行针对性治疗。     

新生儿血友病A 11例病例系列报告

目的 探讨新生儿血友病A的临床表现、诊治及预后。方法 对复旦大学附属儿科医院2016年2月1日至2019年6月30日收治的11例新生儿血友病A临床资料进行回顾性分析。结果 11例新生儿血友病患儿均为男性,3例有明确血友病家族史。2例无出血表现,2例仅表现为皮肤瘀点瘀斑,7例有出血表现。出血部位包括硬膜下、颅内、皮下、消化道。11例活化部分凝血酶时间(APTT)均延长,均为凝血因子Ⅷ缺乏,中间型9例,重型和轻型各1例。5例行基因检测者证实FⅧ基因突变,缺失2例,点突变3例。血友病A确诊后予静脉输注Ⅷ因子。随访至2019年6月9~10日,1例失访,4例无出血表现,1例有踝关节自发出血表现,5例表现为外伤后皮肤瘀点/皮下血肿。结论 新生儿期多次凝血功能异常,以APTT延长为主,特别是延长＞3倍者有或无出血表现均应考虑血友病可能,应行凝血因子活性水平测定及基因检测及早确诊,早期诊断和预防性输注凝血因子可改善预后。     

头颅超声对4例FGFR2基因缺陷新生儿胼胝体形态的评估

目的 通过已经建立的头颅超声胼胝体形态评估模型,对FGFR2基因缺陷新生儿进行胼胝体表型评估,探索该疾病的新生儿期头颅影像可识别表型。方法 纳入2016年1月至2017年12月复旦大学附属儿科医院新生儿基因组计划中高通量测序检测到FGFR2基因致病变异或可疑致病变异的新生儿,收集临床及影像信息;利用头颅超声技术,二维测量胼胝体嘴部、膝部、体部、压部厚度,利用计算机辅助分析构建胼胝体虚拟三维结构并计算容积,行胼胝体形态评估。结果 6例FGFR2基因缺陷新生儿进入本文分析,均存在不同程度颜面部发育异常,其中有4例有完整影像学资料的进入进一步评估:3例经MRI及超声评估,一致诊断为胼胝体发育异常,1例未行MRI检查,但超声评估为胼胝体发育异常。结论 鉴于FGFR2基因缺陷表型的多样性,将胼胝体形态评估模型应用于此类疾病,有助于建立头颅影像可识别表型,而且有望能将该超声可识别的表型用于围产期筛查,为FGFR2基因突变的遗传干预、咨询提新的思路。     

头颅超声对4例FGFR2基因缺陷新生儿胼胝体形态的评估

目的 通过已经建立的头颅超声胼胝体形态评估模型,对FGFR2基因缺陷新生儿进行胼胝体表型评估,探索该疾病的新生儿期头颅影像可识别表型。方法 纳入2016年1月至2017年12月复旦大学附属儿科医院新生儿基因组计划中高通量测序检测到FGFR2基因致病变异或可疑致病变异的新生儿,收集临床及影像信息;利用头颅超声技术,二维测量胼胝体嘴部、膝部、体部、压部厚度,利用计算机辅助分析构建胼胝体虚拟三维结构并计算容积,行胼胝体形态评估。结果 6例FGFR2基因缺陷新生儿进入本文分析,均存在不同程度颜面部发育异常,其中有4例有完整影像学资料的进入进一步评估:3例经MRI及超声评估,一致诊断为胼胝体发育异常,1例未行MRI检查,但超声评估为胼胝体发育异常。结论 鉴于FGFR2基因缺陷表型的多样性,将胼胝体形态评估模型应用于此类疾病,有助于建立头颅影像可识别表型,而且有望能将该超声可识别的表型用于围产期筛查,为FGFR2基因突变的遗传干预、咨询提新的思路。     

WT1基因检测时机对Wilms肿瘤合并慢性肾脏疾病预后影响的回顾性队列研究

目的 分析在Wilms肿瘤合并慢性肾脏疾病(CKD)的患儿中WT1基因检测对诊断和长期预后的影响。方法 检索上海市肾脏发育与儿童肾脏病研究中心儿童肾脏病基因检测数据库,2001年1月1日至2018年12月31日明确WT1基因突变、年龄<18岁患儿,或Wilms肿瘤合并CKD 2~5期或肾病综合征或有蛋白尿的连续病例。按进展为终末期肾衰竭(ESRD)之前是否明确WT1基因突变分为早诊断组和晚诊断组,以ESRD为终点比较两组的预后。结果 22例患儿明确WT1基因的常染色体显性遗传突变,分别位于第8~9外显子/内含子。依据临床分型,10例为Denys-Drash综合征,3例为Fraiser综合征,9例表型为孤立型肾病综合征,5例合并假两性畸形。随访终点进入ESRD有15例,7例进入CKD 2~4期。应用生存曲线分析证实,早诊断组较晚诊断组进入ESRD病程显著延迟(P=0.011)。结论 在儿童Wilms肿瘤、肾病综合征/蛋白尿、慢性肾功能损害的患儿中,在肾功能进展恶化之前及早明确WT1基因突变,不仅有助于临床诊断分型,还能显著延缓进入ESRD病程。     

WT1基因检测时机对Wilms肿瘤合并慢性肾脏疾病预后影响的回顾性队列研究

目的 分析在Wilms肿瘤合并慢性肾脏疾病(CKD)的患儿中WT1基因检测对诊断和长期预后的影响。方法 检索上海市肾脏发育与儿童肾脏病研究中心儿童肾脏病基因检测数据库,2001年1月1日至2018年12月31日明确WT1基因突变、年龄<18岁患儿,或Wilms肿瘤合并CKD 2~5期或肾病综合征或有蛋白尿的连续病例。按进展为终末期肾衰竭(ESRD)之前是否明确WT1基因突变分为早诊断组和晚诊断组,以ESRD为终点比较两组的预后。结果 22例患儿明确WT1基因的常染色体显性遗传突变,分别位于第8~9外显子/内含子。依据临床分型,10例为Denys-Drash综合征,3例为Fraiser综合征,9例表型为孤立型肾病综合征,5例合并假两性畸形。随访终点进入ESRD有15例,7例进入CKD 2~4期。应用生存曲线分析证实,早诊断组较晚诊断组进入ESRD病程显著延迟(P=0.011)。结论 在儿童Wilms肿瘤、肾病综合征/蛋白尿、慢性肾功能损害的患儿中,在肾功能进展恶化之前及早明确WT1基因突变,不仅有助于临床诊断分型,还能显著延缓进入ESRD病程。     

干扰素基因刺激蛋白相关婴儿期发病血管病变1例并文献复习

目的 探讨干扰素基因刺激蛋白(STING)相关婴儿期发病血管病变(SAVI)的临床特点、诊断和治疗。方法 对1例SAVI患儿的临床表型及基因型进行分析,并通过复习相关文献,分析和总结有关国内外SAVI的文献报道,总结SAVI的临床特征及遗传学特点。结果 男,11岁4个月,为反复呼吸道感染、咳嗽、活动耐力下降,查体可见杵状指(趾),实验室检查提示ESR异常升高、ANA及抗心磷脂抗体阳性,肺部高分辨CT提示间质性病变。全外显子测序提示患儿TMEM173基因新生杂合突变:c.463G>A,p.V155M。予托法替尼(每次5 mg,每天2次)治疗有效。文献复习目前国内外已报道SAVI病例31例(包括本文1例),SAVI男性多发,以婴幼儿为主。首发症状以皮疹(58.0%)、呼吸急促(41.9%)及活动受限(48.3%)为主。实验室检查64.5%伴有ESR增快或CRP升高,64.5%出现自身抗体阳性。70.9%患儿肺部影像学提示为间质性肺炎改变。基因检查可明确诊断,SAVI相关的基因突变位于第5号染色体上的TMEM173基因,74.1%为新发突变。Janus激酶抑制剂治疗有效。结论 SAVI为一种罕见的自身炎症性疾病,为TMEM173基因变异,临床上以活动耐力下降、生长受限及间质性肺疾病为主要表现。Janus激酶抑制剂对该病治疗有效。     

CARD11基因非经典区域突变所致免疫缺陷2例的临床和免疫特征

目的 报道2例CARD11基因非经典区域突变所致免疫缺陷的临床和免疫特征.方法 总结2例CARD11突变患儿的临床特征;采用全外显子组测序及Sanger测序技术寻找其基因突变,采用体外实验进行致病性验证,探讨其致病机制;采用流式细胞术等技术分析其免疫特征.结果 2例患儿均表现为反复呼吸道感染和过敏性疾病.例1主要表现为...     

Shwachman-Diamond综合征8例病例系列报告

背景 Shwachman-Diamond综合征(SDS)主要表现为骨髓衰竭、胰腺外分泌功能不全、骨骼异常三联征.约90％SDS患儿为SBDS基因突变,EFL1、DNAJC21、SRP54基因突变也可导致SDS样综合征.既往报道SBDS基因型与血液表型无明显相关性.目的 总结SDS患儿的临床特征,探究SBDS基因型与表型...     

Congenital glucose–galactose malabsorption: a novel deletion within the SLC5A1 gene

Glucose–galactose malabsorption (GGM) is an autosomal recessive disease caused by mutations in the Na⁺/glucose cotransporter gene SLC5A1 (OMIM 182380, phenotype number 606824). Patients with GGM present with neonatal onset of severe life-threatening diarrhoea and dehydration. We describe a 5-day-old girl with the typical clinical course of GGM. Our clinical diagnosis was confirmed by an abnormal chromatography of the stool and normal small bowel biopsies. Mutation analysis revealed a novel, homozygous deletion within exon 10 of the SLC5A1 gene, i.e. c.1107_1109 del AGT.     

Mucoid presentation of acute enterocolitis in children: a hospital-based case-control study

A hospital-based case-control study was carried out to clarify the characteristics of mucoid presentation of acute enterocolitis in children. One hundred sixty-eight cases of acute mucoid enterocolitis (study population) were compared with 200 cases of watery diarrhoea and 118 cases of blood dysentery (control groups) on the basis of clinical characteristics and findings on stool examination. Study and control groups were comparable with respect to age, body weight and nutritional status. There was no significant difference in clinical characteristics (duration of diarrhoea, stool frequency, presence of vomiting, fever and dehydration) between patients suffering from mucoid enterocolitis and blood dysentery. However, watery diarrhoea patients had significantly high frequencies of vomiting (p = 0.00001) and dehydration (p     

ZMPSTE24基因突变致限制性皮病1例病例报告并文献复习

目的 报告1例ZMPSTE24基因突变致胎儿死亡的限制性皮病(RD)病例,总结临床特征及基因突变的特点,为产前咨询提供依据。方法 对1例ZMPSTE24基因突变的RD患儿的临床资料和测序结果进行分析,结合人类基因突变数据库(HGMD)和PubMed,对ZMPSTE24基因突变所致疾病临床表型进行文献复习。结果 男,死胎,G1P1。母亲孕27周行超声检查,胎儿臀位、羊水过少、羊水指数1.9 cm、胎儿右侧胸腔少量积液。孕31⁺³周因胎膜早破入院,伴妊娠期糖尿病,超声示胎儿宫内重度生长受限。孕32⁺²周娩出一男死胎,具有典型RD表型。为明确病因诊断行新生儿panel测序并行Sanger测序验证,检测到ZMPSTE24基因的一个纯合移码突变(c.1085dupT,p.Leu362PhefsTer19),为已报道的RD热点突变,突变频率达57.14%。检索HGMD和PubMed,共检索到ZMPSTE24基因的32种致病突变(63例),导致4种不同的疾病表型。检索万方、中国知网和PubMed数据库,检索时间从建库至2019年7月25日,共有49例(包括本文1例)ZMPSTE24突变导致RD。ZMPSTE24突变的临床表型严重程度与锌金属蛋白酶活性和核纤层蛋白前体蛋白的堆积程度相关。结论 本例检测到的Leu362PhefsTer19突变为ZMPSTE24基因热点突变,ZMPSTE24基因型与临床表型呈高度相关。本研究提示妊娠期胎儿发育异常应注意RD可能,基因检测可明确诊断。早期基因诊断可为临床及时干预和遗传咨询提供依据。     

ZMPSTE24基因突变致限制性皮病1例病例报告并文献复习

目的 报告1例ZMPSTE24基因突变致胎儿死亡的限制性皮病(RD)病例,总结临床特征及基因突变的特点,为产前咨询提供依据。方法 对1例ZMPSTE24基因突变的RD患儿的临床资料和测序结果进行分析,结合人类基因突变数据库(HGMD)和PubMed,对ZMPSTE24基因突变所致疾病临床表型进行文献复习。结果 男,死胎,G1P1。母亲孕27周行超声检查,胎儿臀位、羊水过少、羊水指数1.9 cm、胎儿右侧胸腔少量积液。孕31⁺³周因胎膜早破入院,伴妊娠期糖尿病,超声示胎儿宫内重度生长受限。孕32⁺²周娩出一男死胎,具有典型RD表型。为明确病因诊断行新生儿panel测序并行Sanger测序验证,检测到ZMPSTE24基因的一个纯合移码突变(c.1085dupT,p.Leu362PhefsTer19),为已报道的RD热点突变,突变频率达57.14%。检索HGMD和PubMed,共检索到ZMPSTE24基因的32种致病突变(63例),导致4种不同的疾病表型。检索万方、中国知网和PubMed数据库,检索时间从建库至2019年7月25日,共有49例(包括本文1例)ZMPSTE24突变导致RD。ZMPSTE24突变的临床表型严重程度与锌金属蛋白酶活性和核纤层蛋白前体蛋白的堆积程度相关。结论 本例检测到的Leu362PhefsTer19突变为ZMPSTE24基因热点突变,ZMPSTE24基因型与临床表型呈高度相关。本研究提示妊娠期胎儿发育异常应注意RD可能,基因检测可明确诊断。早期基因诊断可为临床及时干预和遗传咨询提供依据。     

Effect of feeding yogurt versus milk in children with acute diarrhea and carbohydrate malabsorption

BACKGROUND: The aim of this study was to compare the effect of infant formula and the same formula subjected to microbial fermentation (yogurt) on the duration of diarrhea in young children with acute watery diarrhea, with or without reducing substances in stools. METHODS: One hundred twelve well-nourished children, aged 3 to 24 months, who were admitted to the hospital with acute watery diarrhea were included in a randomized trial. After appropriate rehydration, they were fed either an infant formula (group M, n = 56) or the same formula fermented with Lactobacillus bulgaricus and Streptococcus thermophilus (group Y, n = 56). The two feedings were comparable in lactose concentration (40 to 42 g/L), pH 4.5, flavor, and texture. The groups were subdivided into those with or without reducing sugars in stools at presentation. The presence of reducing sugars in stool was used as a marker of carbohydrate malabsorption. RESULTS: Group M and group Y had comparable clinical characteristics at admission, including the number of patients with reducing sugars in stools (n = 31 in group M and 27 in group Y). The success rate (cessation of diarrhea and appropriate weight gain 7 days after enrollment into the study) was similar in both groups (82% in group M vs. 84% group Y). Clinical failure was 3.6% in both groups. The percentage of patients withdrawn from the study for medical reasons (5.4% in group M vs. 7.1% in group Y) or withdrawn at the parents' request (8.9% in group M vs. 5.4% in group Y) was similar. Duration of diarrhea and number of stools were significantly less in group Y compared with group M. Forty-eight hours after inclusion, diarrhea was still present in 62% of group M versus in 35% of group Y (P < 0.002). In children with reducing sugars in stools, the rate of success (82%) was similar in groups M and Y, but the duration of diarrhea and number of stools per day were significantly decreased in group Y. Forty-height hours after inclusion, diarrhea was still present in 75% of group M patients and in 20% of group Y patients who had reducing substances in the stool. CONCLUSION: Young children with acute watery diarrhea, without malnutrition or associated disease, can be equally well treated with feeding of either infant formula or yogurt. Yogurt feeding is associated with a clinically relevant decrease in stool frequency and duration of diarrhea in children who have reducing sugars in stools.     

Congenital selective malabsorption of glucose and galactose

We review here the case histories and results of in vivo and in vitro tests for eight children with congenital selective glucose and galactose malabsorption (GGM) whom our laboratory has followed up since 1971. Clinically, GGM was manifested by intractable, acidic, sugar-containing diarrhea that started during the neonatal period. Diarrhea only abated when glucose and galactose were removed from the diet. The disease was notable for the absence of other symptoms, although mellituria was a common finding. Defective sugar transport was permanent, but sugar tolerance appeared to increase with age. In vitro, intracellular mucosal glucose concentration (C) was significantly below control level in GGM intestinal tissue for concentrations (M) of 10 and 0.1 mM glucose in the medium. C/M for galactose also decreased, while the C/M ratios for alanine and xylose were within the control range. Glucose influxes across the luminal membrane, net glucose transepithelial fluxes, and electrical parameters were all consistent with defective sodium and glucose cotransport at the brush border membrane of jejunal epithelial cells. However, the present results are also consistent with a small residual active transport system observed only at low glucose concentration in the medium. Further observations are needed to establish the role of glucose transport systems in absorption of other monosaccharides, the relationship between kidney and intestinal sodium-glucose cotransport systems, and their genetic control.     

KMT2D基因致病变异致Kabuki综合征新生儿14例病例系列报告并文献复习

背景 Kabuki综合征(KS)是一种罕见的多发畸形综合征,主要临床表现为特殊面容、骨骼异常、智力障碍等.KMT2D基因致病变异所致KS占75％.目前KS诊断标准用于新生儿期诊断较为困难.目的 提出KMT2D基因突变所致KS在新生儿期的遗传筛查指征.设计病例系列报告.方法 回顾性分析复旦大学附属儿科医院(我院)KMT2...