SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant / Esferocitosis relacionada con SPTB en tres generaciones de una familia con insuficiencia cardíaca en la edad adulta debido a la presentación conjunta de la variante de UMOD causante de la enfermedad

ABSTRACT

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 BetaI-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_003361.3c.552G > C, NP_003352.2p.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

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