Biallelic pathogenic variants in EXOSC3 mediate renal 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: ) was used. RESULTS: 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.