RIPK1 plays a role in mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors and pattern recognition receptors. Loss-of-function mutations of RIPK1 have been shown to lead to immune deficiencies and/or autoinflammation. Cleavage resistant RIPK1-induced autoinflammatory (CRIA) syndrome has shown to be caused by heterozygous mutations in different areas of RIPK1. Normally, cleavage of RIPK1 by caspase 8 prevents abnormal cell death; however, mutations may lead to overactivation and increased RIPK1-dependent apoptosis and necroptosis, leading to autoinflammation.
16-year-old female with recurrent fevers, rashes, arthralgias, and oral ulcers. Healthy until age 12, when she developed abnormal gait, joint hypermobility, headaches, musculoskeletal pain, at the time diagnosed with Lyme disease, long COVID syndrome, and myalgic encephalomyelitis/chronic fatigue syndrome. Three years later she started to develop further symptoms consisting of periodic daily fevers that would last for weeks at a time without an infectious source, as well as oral ulcers and joint pain during these episodes with new-onset rectal bleeding. She saw rheumatology and was subsequently started on colchicine, with some symptomatic improvement. She then saw Immunology, with workup showing normal serum immunoglobulins and lymphocyte subsets, as well as normal and switched memory B cells. A targeted gene panel was sent and identified a heterozygous RIPK1 variant, c.1934C>T (p.Thr645Met), previously described in a CRIA cohort. Family history is notable for her mother having a similar autoinflammatory phenotype without fulminant symptoms and with the same RIPK1 variant.
Cleavage-resistant RIPK1 variants have been shown in a small subset of individuals to be associated with autoinflammation. This case reinforces the importance of genetic testing to identify potential molecular diagnoses in autoimmune/autoinflammatory presentations, as it may shape management. Despite partial response to colchicine, this patient is undergoing discussion to potentially start an IL6-R antagonist or IL-1 inhibitor, given their previous success in some patients with CRIA.
