Thrombotic microangiopathy (TMA) is a rare disease in which abnormalities of arteriolar vascular wall cause a triad of non-immune hemolytic anemia, thrombocytopenia, and organ dysfunction including kidney, brain, and intestine. Neonatal TMA can be secondary to complement system abnormalities as well as metabolic or inherited coagulation disorders. Here we describe a term infant who presented with concomitant neonatal TMA and Hirschsprung disease. The patient had a partial colectomy at age four days due to suspected necrotizing enterocolitis (NEC-like pathology). The surgery was followed by serial-pattern phases of ileus/pseudo-obstruction-like symptoms. Each episode was accompanied by non-immune hemolytic anemia, severe thrombocytopenia, acute kidney injury (KDIGO stage III) and uncontrolled high blood pressure. Considering dysregulations in the alternative complement pathway, a complement-mediated neonatal TMA was suggested. Exome sequencing revealed a paternally inherited heterozygous variant (c.782G>A; p.Gly261Asp) in complement factor I (CFI) gene, previously associated with TMA. Functional assays demonstrated dysregulated alternative complement pathways due to abnormal functioning of CFI. Notably, the absolute level of CFI was normal. The clinical and molecular diagnosis prompted treatment with an anti-C5 monoclonal antibody, Eculizumab, which has resulted in marked improvement of TMA symptoms. Interestingly, the gastrointestinal symptoms (initially attributed to TMA) persisted and a rectal biopsy demonstrated complete aganglionosis compatible with Hirschsprung disease. The patient underwent total colectomy, with complete resolution of the GI symptoms. This report is the first known case of a complement-mediated TMA associated with, and possibly triggered by primary Hirschsprung disease.
