儿童原发性1型高草酸尿症1例并文献复习

目的 总结儿童原发性1型高草酸尿症 (PH 1)临床资料,提高对该病的认识。方法 采集1例PH 1患儿的临床特点、影像学表现,肾结石分析信息;进行家系调查;对该家系相关成员进行AGXT基因外显子及附近调控区域直接测序,分析突变位点;文献综述。结果 女童,3岁时起病,首发症状为肉眼血尿,继腰、背部疼痛,体外震波碎石、排石治疗后结石复发,7年内进展为终末期肾病。腹部B超、X线平片和CT均提示多发双肾脏和输尿管结石。肾结石成份为单水草酸钙。未发现患儿家族有相同疾病的患者。AGXT基因分析发现,患儿存在c.242C>A（p.Ser81X）和c.823_824dupAG（p.Ser275delinsArgAlafs）杂合突变,其父亲携带c.823_824dupAG杂合突变,其母亲携带c.242C>A杂合突变。患儿为AGXT基因复合杂合突变,其中c.242C>A无义突变为首次报道。结论 PH 1为罕见遗传性疾病。经影像学证实为多发和复发性双肾结石,排除其他原因所致,应该考虑原发性高草酸尿症,肾结石成份和AGXT基因分析是PH 1诊断的重要手段,尤其AGXT基因分析在某些情况下可以替代肝穿刺成为PH 1确诊的无创检查;PH 1早期诊断和干预将会延缓肾功能恶化,改善预后。     

儿童原发性1型高草酸尿症临床及AGXT基因突变分析

目的探讨儿童原发性1型高草酸尿症(PH1)的临床及基因变异特点。方法回顾分析5例确诊PH1型患儿的临床资料。结果 5例患儿,男3例、女2例,发病年龄2个月～4岁;均有顽固性代谢性酸中毒、高钾血症、低钙血症等非特异性临床表现,年长患儿有多发性肾结石的特异性表现。基因检测显示,5例患儿均有AGXT基因不同位点的变异,共发现6个突变位点,3例患儿有6号外显子c.679_680del缺失突变,其中2号外显子c.190AT突变为首次报道。结论 PH1患儿临床表现多样,基因检测有助于早诊断、早干预,可延缓终末肾的进展。     

儿童1型原发性高草酸尿症七例临床分析

目的探讨1型原发性高草酸尿症(PH1)患儿的临床、影像、分子生物学特征,及临床表型与基因型的相关性.方法回顾性分析2016年6月至2019年5月广州市妇女儿童医疗中心肾内科住院经基因检测确诊为PH1的7例患儿(男4例、女3例)病例资料,分子生物遗传学检测方法采用对先证者进行肾小管疾病相关靶向基因外显子测序并采用Sanger测序法对家系进行验证,采用非条件Logistic回归分析统计肾钙质沉着与肾功能的关系.结果共纳入来自6个家庭的7例患儿,发病中位年龄5月龄,确诊中位年龄8月龄,5例已进展至终末期肾病、1例为慢性肾脏病2期、1例为慢性肾脏病1期.死亡4例、维持性透析1例、非透析随访患儿2例.婴儿型PH1患儿4例,儿童及青少年型1例,家族型1例,分类不明1例.2例为胞生姐弟,其中弟弟为先证者,因尿毒症而被确诊,姐姐继而因家系验证被确诊,为轻度肾功能不全,两人均有延迟诊断,弟弟延迟5年、姐姐延迟3年.7例患儿均有不同程度的尿蛋白升高(随机尿蛋白与尿肌酐比值的平均值为1.1)及镜下血尿、无肉眼血尿,3例患儿出现高钙尿症.综合CT、磁共振成像、X线片及超声等多种影像学检查,确诊4例单纯肾钙质沉着症、1例肾钙质沉着症伴肾石症、1例单纯多发肾结石及1例肾髓质小结晶,但其中超声检查能明确肾钙质沉着症的只有1例,其余4例由CT等放射性影像检查确诊,而且肾钙质沉着是肾功能不全的独立危险因素(OR 2.5,95%CI 0.7~1.2,P<0.05).基因检测7例均为AGXT基因变异,其中纯合变异4例、复合杂合变异3例.共发现9个变异基因型,有4个基因型出现在6号外显子变异,其中c.679_680del缺失变异3例(2例为胞生姐弟),c.679_680+2del缺失1例.结论PH1患儿以婴儿型为多见,病情进展迅速甚至以肾功能不全起病预后极差,是临床表型与基因型高度异质性疾病;肾钙质沉着是导致肾功能衰竭的一个独立危险因素,放射性影像检查对于肾钙质沉着症的诊断具有较高特异性;国内儿科领域PH1的漏诊及延迟诊断仍较突出,普遍开展尿草酸定量测定对降低漏诊率及追踪评估疗效具有重要意义.     

儿童原发性Ⅰ型高草酸尿症2例报告及文献复习

目的探讨原发性Ⅰ型高草酸尿症(PH Ⅰ)的临床特点、诊断及治疗。方法回顾分析2例PH Ⅰ患儿的临床表现、实验室检查结果,并对家系成员进行全外显子测序。结果 2例患儿发病年龄分别为2个月和1岁5个月,均有肾衰竭,伴不同程度贫血、肾石症等。全外显子测序发现2例患儿分别为AGXT基因c.815_816GA纯合变异及c.25_26 insC、c.815_816 insGA复合杂合变异。确诊为PH Ⅰ后给予肾脏替代联合对症治疗。结论 PH Ⅰ无特异性临床表现,部分患儿肾衰竭进展迅速。     

线粒体3-羟基-3-甲基戊二酰辅酶A合成酶缺乏症1例分析及文献回顾

目的探讨线粒体3-羟基-3甲基戊二酰辅酶A合成酶缺乏症(HMCSD)的临床及遗传学特征。方法回顾分析1例HMCSD患儿的临床资料,并复习相关文献。结果女性患儿,9个月余,先后因呕吐、抽搐及发热、咳嗽就诊。血生化检查示低血糖、代谢性酸中毒、肝功能异常、凝血功能异常,尿筛查示双羧酸尿。基因检测发现HMGCS2基因存在6号外显子c.1187+1GC和3号外显子c.648GT复合杂合突变,确诊为HMCSD。此突变未见报道。患儿经积极抗感染、纠正代谢性酸中毒、维持血糖稳定及补充左卡尼汀等治疗后好转。随访半年智力运动发育正常。结论 HMCSD临床表现多样,基因检测可明确诊断,早期识别、早期诊治有助于改善预后。     

罕见病研究：CTNS基因突变致胱氨酸贮积症

1岁6月龄男性患儿,4月龄时发现持续尿糖阳性,伴多饮、多尿、生长迟缓,辅助检查提示患儿存在低比重尿、贫血、低钾血症、低钠血症、低镁血症、代谢性酸中毒、糖尿、氨基酸尿、钾排泄分数增高、肾小管磷重吸收率降低,头颅、胸部及右手腕X线提示肾性佝偻病改变,裂隙灯检查观察到角膜出现大量结晶,基因检查示CTNS基因存在可疑致病性纯合突变c.922G>A(p.Gly308Arg),该患儿最终诊断为胱氨酸贮积症。治疗初期予对症支持治疗,维持内环境稳定,确诊后特异性应用半胱胺酒石酸胶囊行清除胱氨酸治疗。该文报道了1例CTNS基因突变致胱氨酸贮积症患儿,对该病病因、临床特征、诊疗等进行归纳总结,为该病的早期诊断、治疗及后续研究提供参考依据。     

全羧化酶合成酶缺乏症 1 例报告

目的探讨儿童全羧化酶合成酶缺乏症(HLCSD)的临床表现、诊断、治疗及预后。方法回顾分析1例HLCSD患儿的临床表现、实验室检查,并通过二代基因测序分析患儿及家系成员外周血基因突变情况。结果患儿,女,4月龄起病,主要表现为反复顽固性皮疹。体液免疫检查示Ig系列全系下降,血串联质谱示3-羟基异戊酰基肉碱水平明显升高,尿气相质谱显示乳酸、3-羟基异戊酸、丙酮酸等明显升高。二代基因测序发现,患儿HLCS基因的第9号和第11号外显子上发现了突变位点c.1544GA(S515N),c.1993CT(R665X),为杂合突变,其中R665X为新发突变。其父母分别为基因突变携带者。结论 HLCSD临床表现不典型,对于难治性皮疹伴神经系统异常、生长发育障碍、持续性酸中毒、高乳酸血症等表现者,应考虑HLCSD可能,通过血串联质谱、尿气相质谱分析和基因筛查可尽早确诊。     

转录辅助调节因子HCFC1突变致罕见X连锁甲基丙二酸尿症CblX型一家系报告

目的探讨X连锁甲基丙二酸尿症CblX家系的临床及基因特点。方法回顾性分析1例经血液及尿液分析发现甲基丙二酸尿症,并采用靶向捕获二代测序进行HCFC1基因分析诊断的X连锁甲基丙二酸尿症患儿的临床资料。结果患儿,男,于2月龄时出现抽搐,智力运动障碍,5月龄时表现癫痫、重度发育落后,尿甲基丙二酸、血液丙酰肉碱增高,血浆总同型半胱氨酸增高,符合甲基丙二酸尿症合并同型半胱氨酸血症。甲基丙二酸尿症相关常染色体基因分析未见突变,X染色体转录辅助调节因子HCFC1第3外显子存在c.344C??T(p.Ala115Val)半合子突变,证实为CblX型甲基丙二酸尿症。患儿父母健康,曾有一子生后重度智力、运动障碍,合并难治性癫痫,于6月龄夭折。患儿母亲携带相同的突变,尿液可检出少量甲基丙二酸,血浆同型半胱氨酸轻度增高。患儿父亲未携带突变。结论以新一代测序技术首次确诊我国1例X连锁CblX型甲基丙二酸尿症家系。     

Barth综合征1例临床及基因突变分析

目的探讨Barth综合征(BTHS)的临床表现及遗传学特征。方法回顾分析1例BTHS患儿的临床资料。结果患儿,男,10月龄,以左室增大,爆发性心肌炎,心力衰竭,肌无力,单核细胞增多,低血糖,乳酸性酸中毒,腹泻,面部异常等为主要表现。基因测序显示TAZ基因存在一个错义突变(c.406CT,p.Cys136Arg),突变来自患儿母亲。结论扩充了中国BTHS的基因突变谱及临床特征。     

精氨酰琥珀酸尿症导致新生儿死亡1例报告

目的报道1例早发型精氨酰琥珀酸尿症病例。方法女性患儿,于出生第2天发病,入院后经临床及实验室检查、基因检测获得诊断。结果患儿血氨显著增高,肝功能异常,伴代谢性酸中毒,血钾、血钙降低。血液瓜氨酸显著增高(1 098.12μmol/L)、精氨酸降低,尿乳清酸、尿嘧啶、精氨酰琥珀酸显著增高。经精氨酸支持、低蛋白饮食治疗无效,病情进行性加重,于生后23 d死亡。基因分析证实精氨酰琥珀酸裂解酶ASL基因存在c.544CT(p.R182X)和c.706CT(p.R236W)复合杂合突变,父母各携带1个杂合突变。结论此例为国内首次报道的早发型精氨酰琥珀酸尿症,死亡后获得确诊。精氨酰琥珀酸尿症是严重的遗传代谢疾病,临床诊断困难,生化特点为血瓜氨酸及尿精氨酰琥珀酸显著增高,ASL基因检测是诊断的关键。     

Primary hyperoxaluria type 1 with a novel mutation

Primary hyperoxaluria type 1 [PH1] is an autosomal recessive disorder caused by a deficiency of alanine-glyoxylate aminotransferase AGT, which is encoded by the AGXT gene. We report an Indian family with two affected siblings having a novel mutation in the AGXT gene inherited from the parents. The index case progressed to end stage renal disease at 5 months of age. His 4 month old sibling is presently under follow up with preserved renal function.     

Primary hyperoxaluria: an important cause of renal failure in infancy

All 25 infants with primary hyperoxaluria type I (PH) so far reported in detail (including one own observation) presented in renal failure (RF) whereas urolithiasis has conspiciously been absent. Diagnosis of PH was often delayed due to nonspecific symptoms of RF: Vomiting, anemia and severe metabolic acidosis. However, demonstration of increased renal echodensity at ultrasound examination should allow early diagnosis. A flecked retina has been noted in several infants. In contrast, our patient had black retinal pigmentations which have only once been reported in PH. Prognosis in untreated patients has so far been poor: 67% died within the first 6 months of life. It is likely that early diagnosis and treatment will improve prognosis in the future.     

Combined liver‐kidney transplantation for primary hyperoxaluria type I in children: Single Center Experience

Primary hyperoxalurias are rare inborn errors of metabolism with deficiency of hepatic enzymes that lead to excessive urinary oxalate excretion and overproduction of oxalate which is deposited in various organs. Hyperoxaluria results in serious morbid‐ity, end stage kidney disease (ESKD), and mortality if left untreated. Combined liver kidney transplantation (CLKT) is recognized as a management of ESKD for children with hyperoxaluria type 1 (PH1). This study aimed to report outcome of CLKT in a pediatric cohort of PH1 patients, through retrospective analysis of data of 8 children (2 girls and 6 boys) who presented by PH1 to Wadi El Nil Pediatric Living Related Liver Transplant Unit during 2001‐2017. Mean age at transplant was 8.2 ± 4 years. Only three of the children underwent confirmatory genotyping. Three patients died prior to surgery on waiting list. The first attempt at CLKT was consecutive, and despite initial successful liver transplant, the girl died of biliary peritonitis prior to scheduled renal transplant. Of the four who underwent simultaneous CLKT, only two survived and are well, one with insignificant complications, and other suffered from abdominal Burkitt lymphoma managed by excision and resection anastomosis, four cycles of rituximab, cyclophosphamide, vincristine, and prednisone. The other two died, one due to uncontrollable bleeding within 36 hours of procedure, while the other died awaiting renal transplant after loss of renal graft to recurrent renal oxalosis 6 months post‐transplant. PH1 with ESKD is a rare disease; simultaneous CLKT offers good quality of life for afflicted children. Graft shortage and renal graft loss to oxalosis challenge the outcome.     

原发性高草酸尿症3型8例病例系列报告并文献复习

背景：原发性高草酸尿症（PH）是一种罕见的由于先天性肝内乙醛酸代谢异常导致的遗传性肾结石/肾钙质沉着症,既往多关注1型和2型PH,PH3的致病基因HOGA1发现较晚,报告不多。 目的：总结PH3临床表型,探讨不同种族人群的PH3热点变异。 设计：病例系列报告。 方法：纳入2015年1月至2021年12月复旦大学附属儿科医院经HOGA1基因变异确诊为PH3的连续病例。从住院病史中采集临床和生物学检测信息,在PubMed、Embase、万方数据库和中国知网数据库中检索PH3病例的中、英文文献,采集病例来源（国家）、例数、性别、起病年龄、诊断年龄、起病临床表现（尿石症、肾钙质沉着症、高钙尿症、高草酸尿症）、随访时间、肾功能（慢性肾脏病2期、3期、4~5期）、随访年龄、尿路结石转归 (活动性结石、无症状结石或结石消失)、HOGA1基因变异位点。 主要结局指标：临床表型和不同种族人群的热点变异。 结果：纳入8例PH3患儿,男7例,女1例;起病年龄中位数10月龄,诊断年龄中位数16月龄。3例以肉眼血尿起病,5例以泌尿道感染起病。影像学均提示肾结石,均无肾钙质沉着表现。3例检测了24 h尿草酸,1例提示高草酸尿症;6例检测了尿钙,5例提示高钙尿症。1例失访,7例随访中位时间25个月,肾小球滤过率均维持稳定,3例肾结石消失。8例均检出HOGA1基因变异（共10个变异位点）,其中复合杂合变异5例,纯合变异3例,经ACMG分级判定6个位点为可能致病变异,4个位点为致病变异。中英文数据库共检索到82篇文献,筛选后23篇文献中321例PH3患者进入本文分析,中国36例（包括本文8例）,欧美293例。中国和欧美PH3患者：起病表现为尿石症的比例分别为83%(30/36)和85%(195/230),肾钙质沉着症分别为3%(1/29)和8%(20/261),高草酸尿症分别为90%(26/29)和96%(66/69),差异均无统计学意义;高钙尿症分别为44%(11/25)和23%（34/150),差异有统计学意义;末次随访时肾功能：中国1例PH3患者25岁时进展至终末期肾病,欧美2例PH3患者分别在8岁和33岁进展至终末期肾病;活动性结石：中国和欧美PH3患者分别为13%(3/23)和37%(22/59),差异有统计学意义。中国PH3患者热点变异为c.834G>A (splice site)、c.834_c.834+1GG>TT (splice site)和c.769T＞G (p.C257G),分别占28%(20/72)、21%(15/72)和11%(8/72);欧美PH3患者热点变异为c.700+5G>T (splice site)和c.944_946delAGG(p.E315del),分别占40%(236/586)和12%(73/586)。 结论：PH3起病年龄和诊断年龄较早,整体预后较PH1和PH2良好,中国与欧美PH3患者HOGA1基因突变可能存在不同的热点变异位点。     

Failure of isolated kidney transplantation in a pediatric patient with primary hyperoxaluria type 2

PH type 2 is caused by decreased activity of GRHPR enzyme that eventually leads to ESRD and systemic oxalosis. Here, we describe an Iranian pediatric patient with PH2 and early ESRD development who received recommended treatment by undergoing isolated kidney transplantation. Diagnosis criteria included a history of reoccurring calcium oxalate renal stones and elevated oxalate levels combined with liver biopsy and decreased enzymatic activity at age five. ESRD prompted transplantation and was performed at age nine. On Day 12 post‐op, his serum creatinine level increased. A graft biopsy showed calcium oxalate crystal deposits in renal tubes with no evidence of acute rejection, which resolved with intensive hydration and administration of a potassium citrate solution. Subsequent biopsies confirmed results found in first biopsy. Despite the immunosuppressive therapy, his serum creatinine level increased again after 11 months. Renal tubular obstruction then led to graft nephrectomy. Pathological analysis of tissue confirmed findings of past biopsies. This was a very rare case of early ESRD in PH2 resulting in a failed isolated kidney transplant. As the GRHPR enzyme is predominantly expressed in liver, we suggest a combined liver‐kidney transplant may be beneficial in patients with PH2.     

Bortezomib use in a pediatric cardiac transplant center

Data are limited on the efficacy and safety of bortezomib for the treatment of AMR following OHT for pediatric acquired or CHD. Retrospective chart review identified patients who received bortezomib for acute (n = 3, within two wk of diagnosis) and chronic (n = 1, three months after diagnosis) AMR or as part of a desensitization regimen (n = 1). Bortezomib was associated with a 3–66% reduction in class I DSA and a 7–82% reduction in class II DSA. Two of the three acute AMR cases resolved by the first follow‐up biopsy. Two patients with AMR resolution are currently well. One patient developed a second episode of AMR, which was unresponsive to bortezomib therapy and required retransplantation for progressive coronary allograft vasculopathy. One patient died shortly after the third cycle from multi‐organ failure. The desensitization patient showed transient HLA reduction with two cycles, but died five months after transplant from sepsis. Complications included infection (3/5), peripheral neuropathy (2/5), AKI (2/5), and thrombocytopenia (3/5). Adverse events appear more common in critically ill patients. Bortezomib therapy resulted in variable DSA reduction and AMR resolution in AMR in OHT secondary to pediatric acquired or CHD.     

Allogeneic bone marrow transplantation in the treatment of acute leukemias of children. Study of 26 patients

Twenty-six children with acute leukemia were treated with allogeneic marrow transplantation from HLA identical siblings after a conditioning regimen with Cyclophosphamide-total body irradiation (19 patients), Melphalan-total body irradiation (6 patients) or Busulfan-cyclophosphamide (1 patient). Eighteen were transplanted in complete remission (4 with acute non lymphoblastic leukemia in first remission, 14 with acute lymphoblastic leukemia: 6 in first, 6 in second and 2 in subsequent remission): 2 died of cytomegalovirus pneumoniae, 1 relapsed and 15 survive in continuous complete remission from 5 to 42 months after transplantation (median = 22 months). Eight were transplanted in relapse, 7 achieve complete remission, 5 of them relapsed, 1 died of G.V.H. and 1 survives in continuous complete remission 46 months after transplantation. Actuarial analysis shows a disease free survival rate at 3 years of 82% for patients transplanted in remission and 12% for patients transplanted in relapse (p less than 0.01).     

Two-step transplantation for primary hyperoxaluria: Cadaveric liver followed by living donor related kidney transplantation

Abstract:  In PH, PLTX, although ideal in theory, is rarely achieved. Patients usually have reached end-stage kidney disease while requiring combined liver and kidney transplantation. In this combined procedure, the sudden high oxalates mobilization from blood and tissue stores jeopardizes the success of the kidney graft, with a high risk of post-transplant early kidney necrosis or chronic graft damage. Here, we report the case of a three-yr-old girl with PH and ESRF in whom we performed sequentially deceased donor liver transplantation followed four months later by living donor kidney transplant, after normalization of blood oxalate levels and improvement of urinary oxalate output. After this two-step transplantation, our patient showed normalization of renal function with good urinary output and maintained normal blood oxalate levels. This strategy seems to be a reasonable approach in order to avoid acute renal tubular injury because of oxalate excretion in these patients.