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      Hemolytic Uremic Syndrome in an Infant with Primary Hyperoxaluria Type II: An Unreported Clinical Association

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          A 6-month-old boy presented with acute renal failure, thrombocytopenia, and severe non-immune hemolytic anemia. Infection by Shiga-like toxin-producing Escherichia coli and other causes of microangiopathic hemolysis were ruled out, leading to a diagnosis of atypical hemolytic uremic syndrome (aHUS). Neither pathogenic variants in HUS-associated genes nor anti-factor H antibodies were identified. Copy number variation analysis uncovered 4 copies of complement factor H related genes, CFHR1- CFHR4, conceivably leading to higher than normal levels of the corresponding proteins. However, this abnormality was also found in the healthy relatives, neither explaining the disease nor the excessive complement deposition on endothelial cells detected by an ex-vivo test. Whole-exome sequencing revealed a pathogenic homozygous variant in GRHPR encoding the glyoxylate and hydroxypyruvate reductase. Recessive GRHPR mutations cause primary hyperoxaluria type 2 (PH2). The presence of renal calculi in the patient and elevated oxalate levels in the urine were consistent with the genetic diagnosis of PH2. We hypothesize that, in this patient, hyperoxaluria caused by the GRHPR genetic defect triggered endothelial perturbation and complement activation, which was amplified by impaired factor H regulatory activity due to the increased ­ CFHR1-CFHR4 copy numbers, resulting in aHUS.

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          Author and article information

          S. Karger AG
          July 2019
          19 March 2019
          : 142
          : 3
          : 264-270
          aIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
          bDepartment of Pediatric Hematology and Oncology, Süleyman Demirel University Medical Faculty, Isparta, Turkey
          cPediatric Nephrology, Karadeniz Technical University, Trabzon, Turkey
          dDepartment of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy
          Author notes
          *Marina Noris, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, IT–24020 Bergamo (Italy), E-Mail
          497823 Nephron 2019;142:264–270
          © 2019 S. Karger AG, Basel

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          Page count
          Figures: 3, Tables: 1, Pages: 7
          Experimental Nephrology and Genetics: Case Study of Genetic Interest


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