University Medical Centre Ljubljana, University Children's Hospital, Department of Nephrology, Ljubljana, Slovenia.
University Medical Centre Ljubljana, University Children's Hospital, Institute for Special Laboratory Diagnostics, Ljubljana, Slovenia.
Nefrologia (Engl Ed). 2020 Jul-Aug;40(4):421-428. doi: 10.1016/j.nefro.2019.10.009. Epub 2020 Feb 26.
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 βI-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.
Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients.
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.
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.
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.
遗传性血影细胞增多症是一种临床表现和遗传异质性疾病，其临床特征为血影细胞、贫血、黄疸和脾肿大。病因与编码参与红细胞膜与脂质双层相互作用的蛋白的基因有关。βI- spectrin（SPTB）基因的致病变异导致约 25%的美国和欧洲患者出现轻度至中度严重疾病。在肾脏疾病中，先前曾报道过 SPTB 缺陷患者因膜增生性肾小球肾炎导致孤立性肾病综合征和因 IgA 肾病导致大量血尿伴蛋白尿。
评估来自同一家庭的 7 名患有血影细胞增多症的患者，以评估所有受影响的成年患者的肾衰竭情况。
对临床、影像学和实验室检查进行评估，以评估血影细胞增多症和肾脏疾病。在选定的患者中，我们还进行了下一代测序相关基因的基因检测，这些基因与遗传性血影细胞增多症、遗传性肾小球疾病和肾小管间质肾脏疾病有关。
在患有血影细胞增多症的家庭成员中，有 2 名成年人患有终末期肾病，1 名成年人患有慢性肾脏病 4 期，伴有间质纤维化/肾小管萎缩和肾小球硬化的非特异性组织病理学发现。当时，4 名儿科患者均无肾脏疾病的迹象。在所有患有血影细胞增多症的家庭成员中均检测到 SPTB 基因（NM_001024858；c.4796G>A；p.Trp1599Ter）的新型无义变异，该变异被预测为致病。此外，所有肾衰竭的成年患者和 2 名先证者的表亲均为 UMOD 基因变异（NM_003361.3：c.552G>C，NP_003352.2：p.Trp184Cys）的杂合子，该变异先前曾在肾小管间质肾脏疾病患者中报道过。在先证者中未发现 UMOD 变异。
两种罕见遗传性疾病同时发生的情况极为罕见，而据我们所知，遗传性血影细胞增多症和常染色体显性肾小管间质肾脏疾病（ADTKD）的基因确认同时发生以前尚未报道过。由于 HS 引起的溶血性危象是否影响 UMOD 相关肾脏疾病的进展尚不清楚，因此我们无法评估。一般来说，并且在本研究中介绍的家族中，UMOD 相关 ADTKD 的特征是极其多变的。然而，家族中的观察到的肾脏疾病需要对家族中的 UMOD 阳性儿科患者进行定期的肾脏检查，以便及早发现高尿酸血症并进行治疗。这强调了在儿科患者的常规实验室筛查中检测血清尿酸的重要性，以便早期发现可能的 ADTKD 肾小管损伤的迹象。
