NPHP不同基因变异进展为终末期肾病的肾单位肾痨3例

目的分析不同NPHP变异导致肾单位肾痨的临床特征。方法回顾分析3例NPHP变异致肾单位肾痨患儿的临床资料。结果 3例患儿均为女性,且均有贫血表现。例1存在内脏反位、肝功能异常等肾外表现;例2、例3的肾脏病理均示肾小球纤维化,肾小管基底膜完整性破坏,小管萎缩,肾脏间质炎症细胞浸润。例1、例2家族中有肾脏病史患者,例3弟弟有相同基因变异,暂无表现。基因检测显示3例患儿均存在NPHP基因变异。例1在NEK8/NPHP9基因存在c.388AC p.K130Q杂合变异以及c.1465GA,p.V489M杂合变异,均为新发现的变异;例2为NPHP1全基因缺失;例3的NPHP3基因存在c.3218TG,p.L1073*纯合变异,其弟弟存在相同的纯合变异位点。3例患儿均已行肾脏移植治疗,门诊随访中。结论肾单位肾痨是一类临床和遗传异质性疾病,临床表现无特异性,基因检测有助于诊断。肾移植是NPHP进展为终末期肾病的有效治疗手段。c.388AC p.K130Q杂合错义变异和c.1465GA,p.V489M杂合变异是新发现的NPHP基因变异。     

1例肾单位肾痨12型的临床特点及TTC21B基因型研究

肾单位肾痨（NPHP）是一组常染色隐性遗传，主要累及肾小管间质的囊性肾病。该文报道1例TTC21B基因突变所致的NPHP 12型。患儿女，起病隐匿，3岁6个月首次就诊时即存在中量蛋白尿、肾功能损害、高血压2期，并伴有内脏反位、短指/趾，4岁前进展到终末期肾病。尿蛋白电泳以肾小球性蛋白尿为主。尿β2-微球蛋白、尿α1-微球蛋白等肾小管指标均明显增高。基因检测显示TTC21B基因存在c.1552T > C （p.C518R）、c.752T > G （p.M251R）复合杂合突变，前者来自父亲，后者来自母亲。c.752T > G为新发突变。TTC21B基因突变患儿的肾脏病理除了NPHP典型的肾小管改变外，多同时存在显著的肾小球损害。     

NPHP3基因突变致婴幼儿期进展为终末期肾病的肾单位肾痨2例并文献复习

摘要目的：总结2例在婴幼儿期进展为终末期肾病（ESRD）的NPHP3基因突变致肾单位肾痨（NPHP）患儿的临床特征及基因突变的特点。方法：收集患儿的一般情况、肾活检、影像学、实验室检查和基因测序结果,并行文献复习。结果：①2例均为男性,发病年龄3和17个月,均以黄疸、肝功能异常为首发症状,2例进展至ESRD的年龄分别为11和35个月。例1肾活检病理肾小管间质炎,肾小球轻度病变,未见囊肿;肝脏活检肝细胞弥漫性变性,间质纤维组织增生。未发现家族中有类似疾病。②行高通量测序结果显示,例1存在NPHP3基因 C.2369A>G (p.L790P)、c.1358A>G (p.L453P)杂合错义突变,例2存在c.1174C>T(p.R392X)无义突变和IVS26 3A>G剪切突变。2例均为复合杂合突变,均分别来自患儿父母。p.L453P和p.L790P错义突变及IVS26 3A>G剪切突变经软件预测为有害突变。除IVS26 3A>G外均为新发现的突变。③共检索到18篇文献1 504例NPHP患者行NPHP3测序,79例检测到NPHP3纯合突变或复合杂合突变。其中19例在新生儿期进展为ESRD,需要肾脏替代治疗,常伴有肺发育不良和胰腺囊肿,在胎儿期表现为羊水少,超声提示双肾增大,伴有囊性改变,常被诊断为常染色体隐性遗传多囊肾;余20例（含文2例）在5岁前进展为ESRD,以肝功能异常和贫血为主要表现,常伴肝脏纤维化和胆管发育异常;42例在5岁后进展为ESRD,以贫血、肾功能异常和高血压等肾脏表型为主。 结论：NPHP3基因突变所致NPHP并非传统意义上的青年型NPHP,约半数在5岁前进展为ESRD,故婴幼儿期不明原因的黄疸和肝功能异常应警惕NPHP3基因突变可能。本研究发现的c.1358A>G、C.2369A>G和c.1174C>T突变为新发现的NPHP3基因突变类型。     

丙酮酸脱氢酶复合物缺陷Leigh 综合征2 例临床及PDHA1基因分析

目的探讨PDHA1基因突变所致丙酮酸脱氢酶复合物E1α亚单位缺陷Leigh综合征的临床特点及诊断和治疗。方法回顾分析2例因发育落后就诊,磁共振扫描提示Leigh综合征,并经生化代谢及基因检测确诊患儿的临床资料。结果 2例男性患儿分别于1岁1个月、4个月就诊,发育落后,肌张力障碍,肌力低下;头颅磁共振检查发现双侧基底节区对称性损害;血清丙酮酸、乳酸明显增高,血氨基酸及酯酰肉碱谱无异常。基因分析发现2例患儿X染色体PDHA1基因分别存在c.615CG、c.605AG错义突变,均为未报道的新突变,证实为丙酮酸脱氢酶复合物E1α亚单位缺陷所致Leigh综合征。结论 PDHA1基因突变患儿临床表现复杂多样,对于不明原因的发育落后儿童,应注意线粒体病的可能,基因检测有助于诊断、治疗及遗传咨询。     

婴儿Sandhoff病临床特点及基因型分析

目的探讨婴儿Sandhoff病的临床和HEXB基因突变特点。方法回顾分析2例婴儿Sandhoff病先证者及其家系的临床资料。结果 2例患儿男女各1例,均在婴儿期起病,首发表现均为发育落后,有过度惊吓、癫痫、腱反射增强、眼底樱桃红斑等,均出现进行性发育倒退,2岁左右基本丧失一切运动和认知能力。头颅MRI检查男性患儿未见异常;女性患儿显示双侧基底节异常信号,小脑萎缩。2例患儿HEXB基因分别为杂合、纯合突变,突变位点系首次报道。男性患儿在学龄前期死亡,女性患儿仍在随访中。结论精神运动发育迟缓和倒退是婴儿Sandhoff病最早和最常见的表现,丘脑及基底节区异常信号可能是其特征性表现,髓鞘发育不良和脑萎缩也很常见。基因检测有助于确诊。     

Shwachman-Diamond 综合征1 例报告及文献复习

目的分析Shwachman-Diamond综合征(SDS)的临床和基因特征。方法回顾分析1例经基因检测明确诊断的SDS患儿的临床资料,并结合相关的文献资料总结SDS综合征的临床表现、基因特征及治疗。结果患儿,男,14月龄。以反复肝功能异常为首发临床表现,伴生长发育落后、外周血象中性粒细胞绝对计数1.5×10~9/L,无典型胰腺外分泌功能障碍,四肢长骨X线表现骨龄落后伴骨质密度异常,腹部CT无胰腺脂肪化。基因测序结果提示患儿SBDS基因c.258+2TC纯合变异。结论 SDS典型表现为胰腺脂肪化和外分泌不足,血象异常尤其是中性粒细胞减少和骨骼异常。对疑似患儿及时进行基因检测有助于早期诊断及治疗。     

儿童囊性肾瘤伴 DICER1基因突变1例并文献复习

目的分析1例儿童囊性肾瘤伴DICER1基因突变患儿的临床资料并复习相关文献, 以提高对此类疾病的认识。方法收集2020年11月1例儿童囊性肾瘤伴DICER1基因突变患儿的临床资料, 总结临床特点、影像学表现、手术经过、病理和基因结果。通过PubMed、中国知网、万方等数据库检索相关文献, 检索时间截至2021年5月。结果本例患儿术前B超、CT及MRI均提示左肾巨大囊实性肿块, 边界尚清, 患儿接受左瘤肾切除术, 术中未发现肿大淋巴结, 术后病理考虑囊性肾瘤, 患儿血液及肿瘤组织均发现DICER1基因突变, 随访6个月无肿瘤残余及复发。中文文献尚无儿童囊性肾瘤伴DICER1基因突变的病例报告, 英文文献中, 同时检测到胚系和体细胞突变的仅有6例报道。结论儿童囊性肾瘤较为少见, 其发生机制与DICER1基因突变有关, 手术切除是主要治疗方式, DICER1基因突变可致多种肿瘤, 术后长期随访监测非常重要。     

以无症状蛋白尿为突出表现的 LMX1B基因相关疾病北大核心CSCD

目的总结和分析3例以无症状肾小球性蛋白尿为突出表现的LMX1B基因相关疾病患儿临床资料, 以提高临床医师对基因突变致无症状蛋白尿的认识。方法回顾性分析2014年4月至2017年10月在北京大学第一医院儿科住院的3例以无症状蛋白尿为突出表现, 经目标区域捕获二代测序和Sanger测序确诊为LMX1B基因相关疾病的患儿为研究对象, 分析其临床资料, 包括肾脏和肾外表现、肾活检病理结果和家族史。结果 3例患儿均为女童, 分别于2岁、1岁和4岁起病, 明确诊断时的年龄分别为11岁、5岁和6岁。均有肾小球性蛋白尿, 其中1例患儿蛋白尿达肾病水平。2例患儿有镜下血尿。肾功能均正常。仅1例患儿行肾活检, 且为重复肾活检。第1次肾活检组织电镜下观察到肾小球基底膜节段变薄, 间隔4年后的第2次肾活检组织电镜下观察到肾小球基底膜不规则增厚伴"虫蚀样"改变和胶原纤维样物质沉积。体格检查示3例患儿均无指甲、四肢和关节异常。2例患儿有肾脏病家族史。结论儿童期隐匿起病, 临床未找到明确病因的无症状蛋白尿要警惕遗传因素, 通过基因检测有助于及早诊断并指导治疗。     

以肾脏损害为首发症状的儿童甲基丙二酸尿症9例分析

目的总结以肾脏损害为首发症状的甲基丙二酸尿症(MMA)患儿的临床特点,为提高临床诊断和治疗水平提供经验。方法选择2008年4月至2010年1月首都医科大学附属北京儿童医院肾脏科以肾脏损害为首发症状的MMA患儿为研究对象。从病案中采集患儿一般情况、临床表现、实验室检查、影像学检查、病理学检查结果、治疗和预后结局数据。结果 9例患儿进入分析,其中男5例,女4例,确诊年龄1个月至9.9岁。9例患儿均以肾脏损害为首发症状入院,主要表现为蛋白尿、血尿、水肿和高血压,其中2例患儿出现急性肾功能衰竭。9例患儿均无阳性家族史。9例患儿均经气相色谱-质谱联用尿有机酸测定确诊为MMA,其中8例患儿同时合并高同型半胱氨酸血症。尿液检查提示6例患儿尿微量蛋白升高。1例行肾穿刺活检提示轻度系膜增生性肾小球肾炎。肾外系统表现为精神、智力和发育落后、抽搐发作和贫血等。9例患儿确诊后均给予维生素B12等治疗。1例患儿合并溶血尿毒综合征并进展至多器官功能衰竭于住院期间死亡。余8例患儿经治疗尿甲基丙二酸浓度均较治疗前明显下降,精神状态和肾功能均明显好转。8例患儿随访1～6个月神经系统症状均明显改善,未再发现肾脏损害。结论 MMA可合并较严重肾脏损害,部分患儿以肾脏损害为首发症状,早期诊断和治疗能使病情得到及时、有效控制,并明显改善预后。     

儿童慢性马兜铃酸肾病3例临床病理分析及文献复习

目的通过报告3例慢性马兜铃酸肾病,增加对其临床与病理特征的认识。方法对北京大学第一医院儿科收治的3例慢性马兜铃酸肾病患儿进行回顾性分析,总结其临床和病理特点,并复习相关文献。结果3例慢性马兜铃酸肾病患儿,男1例,女2例,年龄为10岁、14岁和16岁;分别因乙型肝炎、颅咽管瘤术后脑水肿和紫癜性肾炎服用含马兜铃酸成分的中草药或中成药4～8个月,于开始服用2个月至6年后发病;3例患儿均以不同程度的肾功能损害伴近-远端肾小管受损为主要表现,其中2例以贫血为首发症状,肾功能损害严重,均已达到肾衰竭尿毒症期,另1例以糖尿为首发表现,肾功能损害较轻,同时表现继发性Fanconi综合征。3例肾病理均以广泛性或多灶状寡细胞性间质纤维化和肾小管萎缩为特征,肾小球病变轻微,免疫荧光除2例因基础疾病见IgA(++～+++)外,均未见明显免疫复合物沉积。2例患儿停用含有马兜铃酸的药物后肾功能仍呈不同程度的进行性恶化,其中1例放弃治疗半年后死于消化道大出血,1例等待肾替代治疗;另1例肾功能损伤较轻者,停用含有马兜铃酸的药物后经小剂量糖皮质激素和营养肾小管治疗病情改善,肾功能及肾小管功能恢复,仍在临床随访中。结论儿童慢性马兜铃酸肾病临床特点是渐进性肾功能损害和肾小管功能受损,肾脏病理特征为广泛的寡细胞性间质纤维化和肾小管萎缩;在停服含马兜铃酸药物后肾功能恶化常不可逆转,最终导致终末期肾病;小剂量糖皮质激素对于缓解早期轻症者的病情可能有益。预防该病的关键在于提高对含马兜铃酸中药肾毒性的认识。     

Leptospirosis in children in Mumbai slums

Objective : There is limited data available on symptomatic leptospirosis in Indian children. We report an outbreak of leptospirosis that occurred in children living in slums following heavy rainfall and flooding. This hospital — based prospective study was conducted from July to August 2001.Methods : Diagnosis of acute leptospirosis was suspected by following the Indian Leptospirosis Society working definition for leptospirosis. Diagnosis was confirmed by detecting anti —Leptospira antibodies, using either aLeptospira genus — specific latex agglutination assay or a dipstick assay or by a macroscopic slide agglutination test.Result : Thirty (32%) out of 93 children admitted had acute leptospirosis. Fever, bodyache, chills, abdominal pain, headache, vomiting, cough, hepatosplenomegaly, edema and crepitations were the common presenting signs and symptoms. Twenty — two children had anicteric leptospirosis and 8 had Weil disease. Response to penicillin treatment was good in all except in one child with Weil disease who died of renal failure within 3 hours of admission.Conclusion : Leptospirosis has emerged as an infectious disease in Mumbai. During monsoon, parents should ensure that their child does not have contact with the contaminated flood water.     

Renal transplantation: Experience in Australia

Objective : Outcome of renal transplantation in children under the age of 15 years, who received a renal allograft at The New Children’s Hospital between January 1983 to June 1997 was studied.Methods : Retrospective review of patients records and access to data collected from Renal Registry of the Hospital. 64 renal transplants were undertaken in 57 children during this period. Prednisone and Azathioprine were the mainstay of the immunosuppressive regimen up to 1983, then Cyclosporine A was introduced. Median age of first grafts was 10 years (range 1 month –14 years). There were 41 living related and 23 cadaveric grafts. 37 (64%) children had a congenital disorder as the cause of renal failure. Among them 14(37%) had congenital renal dysplasia/ hypoplasia, 20(36%) had primary glomerular disorder as the cause of renal failure.Results : Survival analysis at 12 month, 5 yr and 10 yr showed functioning grafts in 85%, 67% and 64% case respectively. Longest surviving transplant was 14 years. 6 children had died. Cumulative patient survival was 92.9% at 1 year, 90% at 5 year and 87% at 10 year. Sixteen primary grafts were lost with most common cause being chronic rejection accounting for 68% of all transplant lost. Recurrence of primary disease was the second most common cause of graft failure. There was one malignancy in this series. 25 of the 29 children of school age with functioning transplant attended school full time in a class appropriate for their age and nine of 13 years older patients were working full time, two worked part time.Conclusion : Renal transplantation is a successful treatment of end stage renal failure in children with high survival and normally functioning life. Chronic rejection remains a major cause of graft loss.     

Heparin prophylaxis of Henoch-Schoenlein nephropathy

Eighty eight children with extrarenal manifestations of Henoch-Schoenlein purpura received 120-150 IU/kg heparin in infusion for three days at onset and at relapses. Nephropathy developed in one child (1.1%), whereas renal involvement was noticed in 14 out the 67 control patients with Henoch-Schoenlein purpura (20.9%). The difference was highly significant (p less than 0.001).     

Renal Granulomatous sarcoidosis in childhood: a report of 11 cases and a review of the literature

We analysed retrospectively 11 children with renal granulomatous sarcoidosis confirmed by renal histology in order to describe the course and prognosis of the disease. Symptomatic sarcoidosis was diagnosed at a mean age of 10.1 years. Nine children had renal involvement at the time of diagnosis. In the course of the disease, nine patients developed renal failure and mild proteinuria, seven had transient sterile leucocyturia, four showed microscopic haematuria, seven had a urinary concentrating defect, and enlarged kidneys were seen in three patients. One child had hypercalcaemia and hypercalciuria, none had hypertension. Light microscopy of the kidney showed interstitial infiltration by mononuclear cells in all children, interstitial fibrosis in nine patients, epithelioid granulomas in seven, tubular involvement in eight, and mild glomerular involvement in seven patients. Renal immunofluorescence was negative. Ten children received prednisone for 1–11 years. After a mean follow up of 5.5 years, three patients had entered end-stage renal failure and one had chronic insufficiency after interruption of medical supervision and prednisone therapy. Conclusion Renal failure, proteinuria, leucocyturia, haematuria, and concentration defect are the prominent features of renal granulomatous sarcoidosis in children. Steroid therapy, adjusted according to disease activity, may prevent end-stage renal failure. Received: 4 December 1997 / Accepted in revised form: 22 June 1998     

An institutional experience of pre‐emptive liver transplantation for pediatric primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disease that culminates in ESRF. Pre‐emptive liver transplantation (pLTx) treats the metabolic defect and avoids the need for kidney transplantation (KTx). An institutional experience of pediatric PH1 LTx is reported and compared to the literature. Between 2004 and 2015, eight children underwent pLTx for PH1. Three underwent pLTx with a median GFR of 40 (30–46) mL/min/1.73 m² and five underwent sequential combined liver‐kidney transplantation (cLKTx); all were on RRT at the time of cLKTx. In one case of pLTx, KTx was required eight and a half yr later. pLTx was performed in older (median 8 vs. 2 yr) and larger children (median 27 vs. 7.75 kg) that had a milder PH1 phenotype. In pediatric PH1, pLTx, ideally, should be performed before renal and extrarenal systemic oxalosis complications have occurred, and pLTx can be used “early” or “late.” Early is when renal function is preserved with the aim to avoid renal replacement. However, in late (GFR < 30 mL/min/1.73 m²), the aim is to stabilize renal function and delay the need for KTx. Ultimately, transplant strategy depends on PH1 phenotype, disease stage, child size, and organ availability.     

Evaluation of children with urinary tract infection – Impact of the 2011 AAP guidelines on the diagnosis of vesicoureteral reflux using a historical series

ObjectiveTo clarify the impact of the updated American Academy of Pediatrics guidelines for the evaluation of children presenting with initial febrile urinary tract infection (UTI) on the diagnosis of vesicoureteral reflux (VUR) in children with normal renal sonograms.Materials and methodsChildren with VUR followed between 2002 and 2004 were evaluated using criteria specified in the AAP guidelines. A total of 49 children (42 girls) who were 2–24 months of age at diagnosis of VUR made following initial febrile UTI were included.Results40.8% of ultrasounds were abnormal. While children with abnormal ultrasounds were more likely to have scintigraphic evidence of renal damage than children with normal ultrasounds (50% vs 17%, p = 0.026), one third of the children with abnormal renal scans had normal RBUS. There was no statistically significant difference in diagnosis of grade 3 or higher VUR between groups (p = 0.136).ConclusionsMost children in this series would not have been diagnosed with VUR after initial febrile UTI. More worrisome, 17.2% of children with normal ultrasound had renal injury identified on renal scanning, and 62.1% had grade 3 or higher VUR. These findings reinforce concerns that the new guidelines may miss or delay diagnosis of clinically significant VUR.     

A pilot study on neurological manifestations and antibodies against antigens in children with hematological and other cancers

BackgroundParaneoplastic neurological syndromes (PNS) are most commonly recognized in adults with cancer and can often be identified by the presence of serum antibodies to neuronal proteins that are also expressed by the associated tumor. In children: (a) little emphasis is given to the possibility of paraneoplastic neurological involvement; and (b) few studies investigated the presence of anti-neuronal antibodies.ObjectiveTo run a pilot study on the spectrum of PNS and presence of antibodies to neural antigens in children with malignancies.Methods23 children (7 boys; 16 girls, aged 4 months to 16 years) with hematological or other cancers were examined for neurological manifestations and for antibodies to the neuronal antigens that are frequently detected in adult patients with PNS.ResultsTen of the 23 children had neurological symptoms (and/or positive antibodies): in 6/10 neurological manifestations could be explained by tumor invasion or chemotoxicity or were probably incidental; a child with neuroblastoma developed opsoclonus-myoclonus syndrome without detectable anti-neuronal antibodies; antibodies to a Tr-like cerebellar antigen [associated to no neurological signs and later enuresis], to voltage-gated potassium channels [associated to sensory signs] and to glutamic acid decarboxylase [associated to multifocal myoclonus] were found in one child each. Results were compared with age- and sex-matched control groups.ConclusionThese results suggest that PNS, though surprisingly not so uncommon in children, may be associated with immune responses to distinct neuronal antigens. Further work is needed to determine whether screening for new antibodies to neuronal antigens could be a useful aid in the diagnosis and prognosis of neurological syndromes in children.     

Laparoscopic treatment of renal cancer in children: A multicentric study and review of oncologic and surgical complications

ObjectiveThe aim was to report a multicentric study with a longer follow-up to evaluate the laparoscopic radical nephrectomy in children with renal cancer.Material and methodsThis was a retrospective multicentric study, from October 2005 to January 2012, of children who underwent a laparoscopic radical nephrectomy for small renal malignant tumors.ResultsSeventeen children were included in this study. Sixteen underwent chemotherapy before surgery according the SIOP (Société Internationale d'Oncologie Pédiatrique) protocol and one was treated by surgery only for a carcinoma. All except one could be treated by laparoscopy; the biggest tumoral size was 8 cm. The median hospital stay was 3 days (2–10). The pathologic examination showed 15 Wilms' tumors, one clear cell sarcoma and one TFE3 renal cell carcinoma. With a median follow-up of 42 months (range 12 and 77 months) after laparoscopic radical nephrectomy, 15 children had no oncological complications (port site or local recurrence, pulmonary metastasis) and one had a local recurrence without intraoperative tumoral rupture. The child with TFE3 renal cell carcinoma died 4 years after surgery from brain and lung metastases without local recurrence. No small bowel obstruction occurred.ConclusionsRadical nephrectomy in children for Wilms' tumor or other renal cancer can be safely performed laparoscopically and our indications can be summarized, for trained laparoscopic surgeons, by small tumors under about 8 cm diameter, especially without crossing the lateral edge of the vertebra on the CT scan at the time of surgery.     

儿童继发于甲基丙二酸血症的微血管性溶血及肾脏损伤病例分析

目的总结以微血管性溶血及肾脏损伤为主要表现的甲基丙二酸血症(MMA)患儿的临床特点。方法回顾性分析4例以微血管性溶血及肾脏损伤为主要表现的MMA患儿的临床资料。结果 4例患儿中,男女各2例,年龄为9个月到3岁7个月。2例确诊为MMA合并同型半胱氨酸血症;2例确诊为MMA,但未行同型半胱氨酸检查。4例患儿均表现为中重度贫血、蛋白尿、血尿、高血压,其中1例患儿肾功能异常且有血小板减低,表现为溶血尿毒综合征。2例患儿行肾脏穿刺活检,分别为肾小球增生硬化性病变伴肾小管坏死、系膜增生性肾小球肾炎。4例患儿均给予维生素B12等治疗,治疗后微血管性溶血指标及肾脏损伤指标明显好转。结论 MMA可出现微血管性溶血及肾脏损伤,甚至出现溶血尿毒综合征,需要及时诊断和治疗。