SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant
SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant
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DOI：
10.1016/j.nefro.2019.10.009
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发表时间：
2020-07-01
期刊：
影响因子：
2.6
通讯作者：
Podkrajsek, Katarina Trebusak
中科院分区：
文献类型：
--
作者：
Meglic, Anamarija;Debeljak, Marusa;Podkrajsek, Katarina Trebusak
背景：遗传性球形细胞增多症是一种临床和遗传异质性疾病，其临床特征为球形细胞增多症、贫血、黄疸和脾肿大。病因学与基因编码蛋白参与红细胞膜和脂质双分子层之间的相互作用有关。在美国和欧洲，表现为轻度至中度严重疾病的β - I-spectrin （SPTB）基因的致病变异导致了大约25%的病例。在肾脏疾病中，SPTB缺乏患者中曾报道过膜增生性肾小球肾炎引起的肾病综合征和IgA肾病引起的肉眼血尿伴蛋白尿的孤立病例。目的：对来自同一家庭的7例球形红细胞增多症患者进行评估，以评估所有受影响的成年患者的肾功能衰竭。方法：通过临床、放射学和实验室检查，对球形红细胞增多症和肾脏疾病进行评价。在选定的患者中，我们还对遗传性球形细胞增多症、遗传性肾小球疾病和小管间质肾病相关基因进行了下一代测序遗传学检测。结果：在球形细胞增多症的家族成员中，2名成人患有终末期肾病，1名慢性肾病4期，组织病理学表现为间质纤维化/小管萎缩和肾小球硬化。当时，四名儿科患者没有出现肾脏疾病的迹象。SPTB基因新无义变异（NM 001024858; c.4796G>A; p.Trp1599Ter）在所有球形红细胞增多症家族成员中被检测到，并被预测为致病基因。此外，所有成年肾衰竭患者和指标患者的两个儿科表兄妹都是UMOD基因变异（NM 003361.3:c）的杂合。552G>C, NP 003352.2:p；Trp184Cys)先前在小管间质肾病患者中报道。在索引患者中不存在UMOD变异。结论：任何两种罕见的遗传性疾病同时发生都是极其罕见的，而据我们所知，遗传证实的HS和常染色体显性小管间质肾病（ADTKD）同时发生以前尚未有报道。由于与UMOD相关的ADTKD特征在总体上和本研究中呈现的家族是非常可变的，因此不可能评估HS引起的溶血危象是否影响UMOD相关肾脏疾病的进展。尽管如此，在该家族中观察到的肾脏疾病要求对该家族中UMOD阳性的儿科患者进行定期肾脏检查，以便识别高尿酸血症并尽早治疗。这强调了血清尿酸检测在儿科患者常规实验室筛查中的重要性，以便识别可能提示ADTKD的肾小管损伤的早期迹象。(C) 2020西班牙神经科学学会。Elsevier Espana， S.L.U.出版
Background: Hereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in beta I-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency.Objective: Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients. Methods: Clinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease.Results: Among the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM 001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM 003361.3:c.552G>C, NP 003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients.Conclusions: The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD. (C) 2020 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U.