Biallelic pathogenic variants in EXOSC3 mediate thrombotic microangiopathy of the kidney

Introduction Thrombotic microangiopathy (TMA) is characterized by the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Complement inhibition with eculizumab is highly efficacious in TMA secondary to complement dysregulation. However, a growing number of eculizumab-nonresponsive TMAs are reported. Recently, a syndromic form of TMA due to recessive variants in RNA exosome components ( EXOSC3 and EXOSC5 ) has been identified. The underlying pathogenesis remains unclear. Methods We identified 34 children across Europe with pontocerebellar hypoplasia 1b (PCH1b) due to EXOSC3 rare variants and reviewed their clinical history for signs of TMA. To further examine the pathogenesis, a tamoxifen-inducible whole-body Exosc3 conditional knockout mouse model ( Exosc3 KO ) was used. Results Thirteen (eight male, five female) cases of EXOSC3-TMA were identified. In the United Kingdom, the incidence of EXOSC3-TMA was 0.004/million/year. Three children received long-term eculizumab therapy: one child failed to respond and two relapsed on treatment. Exosc3 KO demonstrated cell-cycle arrest and apoptosis resulting in death in a median of eight days, with sequelae noted in actively dividing cells in the bone marrow and large intestine. In this timeframe, no kidney pathology was identified. Conclusions EXOSC3-TMA is a severe, early-onset, C5 inhibitor–resistant TMA. EXOSC3-TMA should be considered in eculizumab-resistant pediatric TMA, particularly in the context of neurodevelopmental disease.