Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a cytosolic protein, plays an essential role in signaling pathways responsible for inflammation and programmed cell death. In humans, two main clinical syndromes associated with RIPK1 have been described. The first syndrome results from a loss-of-function in RIPK1, leading to immunodeficiency and auto-inflammatory conditions. The second syndrome involves a non-cleavable variant of RIPK1 and is characterized predominantly by auto-inflammation, manifesting as recurrent fevers and lymphadenopathy.
The patient, a 3-month-old infant, was admitted for further evaluation following initial presentation of bloody diarrhea and abdominal pain, first suspected to be milk protein allergy. Over time, clinical symptoms worsened, including poor weight gain, persistent fever, and elevated inflammatory markers. Endoscopic evaluation with esophagogastroduodenoscopy (EGD) and colonoscopy raised concerns for very early onset-inflammatory bowel disease (VEO-IBD). Genetic testing revealed a homozygous variant of unknown clinical significance in RIPK1 (c.460-5C>A). This mutation is predicted to create a splice acceptor site upstream of exon 5, within the first domain of the protein, as indicated by Splice AI. Multiple in silico prediction tools suggest that this variant is likely deleterious. Further analysis with western blot showed no detectable RIPK1 protein, confirming a deficiency. To date, the patient has experienced CMV viremia; however, because he remains asymptomatic and continues to show clinical improvement, treatment for viremia has been deferred. Immunological evaluations have been normal and do not indicate combined immune deficiency. Initial treatment was anakinra, but has since been transitioned to infliximab.
The variant identified in this patient has not previously been reported and was classified as a variant of uncertain significance (VUS). However, given the clinical diagnosis of VEO-IBD and the established association of RIPK1 deficiency with inflammatory bowel disease, there was strong suspicion that the mutation may be causative. However, as this specific variant is novel, functional validation was necessary. The absence of RIPK1 protein on western blot provided definitive confirmation of the deficiency.
Kathleen Sullivan: Relevant financial relationships with proprietary interests: Elsevier (royalties); Immune Deficiency Foundation (board member, consultant); UpToDate (royalties). The other authors have no financial relationships or conflicts of interest to report.
