A Heterozygous CFHR3-CFHR1 Gene Deletion in a Pediatric Patient With Transplant-associated Thrombotic Microangiopathy Who was Treated With Eculizumab

Nozawa, Akifumi; Ozeki, Michio; Hori, Tomohiro; Kawamoto, Norio; Hirayama, Masahiro; Azuma, Eiichi; Fukao, Toshiyuki

doi:10.1097/mph.0000000000000986

Cited by 11 publications

(4 citation statements)

References 16 publications

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“…Studies carried out to investigate risk factors of TMA in the pediatric patient population undergoing autologous or allogeneic stem cell transplant identified a high frequency (83%) of heterozygous CFHR3-CFHR1 deletions, which are involved in complement overactivation and TMA development [ 23 , 34 ]. The authors suggest that deletions in CFHR3-CFHR1 genes, despite being common in the general population, might influence recipients susceptibility to endothelial injury from high-dose chemotherapy or viral infections after HSCT [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy

et al. 2023

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Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical hemolytic uremic syndrome (aHUS) and TMA in the setting of allogeneic stem cell transplant in pediatric patients. We hypothesized that germline mutations in the complement alternative pathway may similarly predispose MM patients to carfilzomib-associated TMA. We identified 10 MM patients with a clinical diagnosis of TMA in the context of carfilzomib treatment and assessed for the presence of germline mutations in the complement alternative pathway. Ten, matched MM patients exposed to carfilzomib but without clinical TMA were used as negative controls. We identified a frequency of deletions in the complement Factor H genes 3 and 1 (delCFHR3-CFHR1) and genes 1 and 4 (delCFHR1-CFHR4) in MM patients with carfilzomib-associated TMA that was higher as compared to the general population and matched controls. Our data suggest that complement alternative pathway dysregulation may confer susceptibility to vascular endothelial injury in MM patients and predispose to development of carfilzomib-associated TMA. Larger, retrospective studies are needed to evaluate whether screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use.

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Section: Discussionmentioning

confidence: 99%

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy

et al. 2023

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“…Interestingly, a high prevalence of deletions in CFH -related genes 3 and 1 ( CFHR3-CFHR1 ) have been detected in pediatric cancer patients post-hematopoietic stem cell transplant (HSCT) [ 49 ]. Heterozygous deletions in CFHR3-CFHR1 genes have also been linked to atypical hemolytic uremic syndrome in pediatric ALL patients and transplant-associated thrombotic microangiopathy in neuroblastoma patients [ 50 , 51 ]. As such, the role of CNVs in PID-related genes and their significance in the development, maintenance, and outcomes of pediatric cancers should be thoroughly considered.…”

Section: Discussionmentioning

confidence: 99%

Identification of Altered Primary Immunodeficiency-Associated Genes and Their Implications in Pediatric Cancers

Standing

Tran

Murguía-Favela

et al. 2022

Cancers

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Background: Cancer is the leading cause of disease-related mortality in children and malignancies are more frequently observed in individuals with primary immunodeficiencies (PIDs). This study aimed to identify and highlight the molecular mechanisms, such as oncogenesis and immune evasion, by which PID-related genes may lead to the development of pediatric cancers. Method: We implemented a novel bioinformatics framework using patient data from the TARGET database and performed a comparative transcriptome analysis of PID-related genes in pediatric cancers between normal and cancer tissues, gene ontology enrichment, and protein–protein interaction analyses, and determined the prognostic impacts of commonly mutated and differentially expressed PID-related genes. Results: From the Fulgent Genetics Comprehensive Primary Immunodeficiency panel of 472 PID-related genes, 89 genes were significantly differentially expressed between normal and cancer tissues, and 20 genes were mutated in two or more patients. Enrichment analysis highlighted many immune system processes as well as additional pathways in the mutated PID-related genes related to oncogenesis. Survival outcomes for patients with altered PID-related genes were significantly different for 75 of the 89 DEGs, often resulting in a poorer prognosis. Conclusions: Overall, multiple PID-related genes demonstrated the connection between PIDs and cancer development and should be studied further, with hopes of identifying new therapeutic targets.

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“…The second patient was affected by aHUS with a heterozygous deletion in CFHR3-CFHR1 deletion, considered a common benign variant that has been reported to be found in 3.3 – 6.7% of the Japanese population [ 26 ] and a novel heterozygous variant c.1067G>A in CFHR5 gene, of unknown significance. However, these genetic variants may represent a predisposition for the development of aHUS in the setting of KT from uDCD donors characterized by potential additional triggers, in particular if associated with other potential causative factors [ 27 , 28 ]. The patient was in treatment with eculizumab at the time of the KT and experienced neither post-transplant aHUS recurrence nor evidence of progressing subclinical hematological TMA, in line with previously published literature.…”

Section: Discussionmentioning

confidence: 99%

Hemolytic uremic syndrome and kidney transplantation in uncontrolled donation after circulatory death (DCD): A two-case report

Caroti

Cestone

Maria

et al. 2021

CNCS

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Background: Hemolytic uremic syndrome (HUS) is a rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal involvement. Complement-mediated atypical HUS (aHUS) is a result of genetic defects in the alternative complement pathway components or regulators. The introduction of eculizumab has improved renal and overall survival of aHUS patients. Nowadays, given organ shortage, it is necessary to consider kidney transplantation (KT) even in protocols with a high risk of HUS recurrence, such as from donation after circulatory death (DCD) donors. Here, we describe two patients with HUS who underwent a KT from an uncontrolled DCD (uDCD). Case summary: The first patient, affected by aHUS due to a heterozygous deletion in CFHR3-CFHR1 and a novel heterozygous variant in CFHR5 gene, underwent a KT with eculizumab prophylaxis. The patient did not experience a post-transplant aHUS recurrence. The second patient, who experienced an HUS episode characterized by a hypertensive crisis and with no underlying mutations in complement system genes, underwent a KT without eculizumab prophylaxis. At day 5, anti-complement treatment commenced due to hematological signs of thrombotic microangiopathy (TMA). After the introduction of eculizumab, we observed a stabilization of kidney function and hematological remission. Conclusion: We present herein two different patients with HUS who both underwent successful KT from uDCD donation under the umbrella of eculizumab therapy. Taking into account the importance of increasing the number of organs available for transplantation, uDCD could represent an additional resource in this subset of HUS patients.

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A Heterozygous CFHR3-CFHR1 Gene Deletion in a Pediatric Patient With Transplant-associated Thrombotic Microangiopathy Who was Treated With Eculizumab

Cited by 11 publications

References 16 publications

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy

Identification of Altered Primary Immunodeficiency-Associated Genes and Their Implications in Pediatric Cancers

Hemolytic uremic syndrome and kidney transplantation in uncontrolled donation after circulatory death (DCD): A two-case report

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