INTERPLAY BETWEEN AUTOINFLAMMATION, COMPLEMENT DYSREGULATION AND STEC (OR INFECTIOUS) TRIGGER: A PEDIATRIC CASE OF ATYPICAL HEMOLYTIC UREMIC SYNDROME

Hemolytic Uremic Syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. While Shiga toxin-producing Escherichia Coli (STEC)-associated HUS is most prevalent in pediatric patients, atypical HUS (aHUS) is a rare, complement-mediated disorder often linked to genetic mutations (e.g., CFH) and/or autoantibodies. Autoinflammatory syndromes, arising from innate immune system dysregulation, have been associated with endothelial dysfunction, but their relationship with HUS remains poorly understood.

We describe the case of a 9-year-old female with a medical history of epilepsy, congenital cataracts, adrenal insufficiency, and an undiagnosed autoinflammatory disease. The patient presented with recurrent fever, maculopapular rash, and polyarthritis, each responsive to Anakinra. Laboratory and genetic investigations revealed C3 hypocomplementemia and a 1p13.3 chromosomal duplication. The patient developed a severe renal TMA triggered by an STEC infection. A multiplex ligation-dependent probe amplification (MLPA) genetic test identified a heterozygous variant of uncertain significance (VUS) in the CFH intronic region (c.3133+4C>G). 

The patient was treated with a single infusion of the C5 inhibitor (iC5) eculizumab due to neurological concerns, resulting in clinical improvement. However, during hospitalization, she suffered cranial trauma leading to subdural and subarachnoid hemorrhages, requiring orotracheal intubation and multiple surgical evacuations of the hematoma. Three weeks later, she experienced a relapse of TMA, raising suspicion for aHUS. The patient underwent another cycle of continuous kidney replacement therapy and subsequently developed posterior reversible encephalopathy syndrome initially refractory to treatment. In light of the marked neurological involvement, the slow clinical response, and new persistent consumption of haptoglobin and platelets, a kidney biopsy was performed. Histopathology demonstrated active kidney TMA, and thus iC5 treatment was resumed with weekly infusions for two months along with four doses of rituximab. Genetic findings were re-evaluated, and testing for factor H autoantibodies was negative. A blood sample of the family trio was sent to the NIH for research genome sequencing, which also identified variants in the PAX6 and PTPRC genes and three heterozygous pathogenic variants in the HBB, MPO, and PEPD genes. A C5b-9 deposition assay on cultured HMECs revealed over 160% complement deposition on activated endothelial cells. Long-term treatment was switched from eculizumab to ravulizumab to allow less-frequent dosing.

This case highlights the complex interplay between autoinflammatory disorders and complement dysregulation in TMAs. It also underscores the overlap between different types of TMAs and the efficacy of complement inhibition in managing refractory cases, especially when combined with immunomodulators. This observation supports growing evidence that, in individuals with genetic or immunological predisposition, infectious triggers such as STEC may precipitate aHUS driven by dysregulated complement activation. This is a complex framework in which external endothelial triggers interact with complement and immune dysregulation, suggesting that TMAs may be viewed as overlapping syndromes on a continuum and not as mutually exclusive entities.

This abstract was also submitted for the ESPN Annual Meeting 2025.