RIPK1 is a key regulator for mediating inflammatory signaling and cell death. This includes apoptosis, necroptosis, and innate immune signaling. Given these important functions of RIPK1, abnormalities in its pathway can lead to immune deficiency and/or autoinflammatory disease, with autosomal dominant cleavage-resistant RIPK1-induced autoinflammatory (CRIA) disease associated with RIPK1 gene mutations.
A 15-year-old female with a history of recurrent lymphadenitis and infections since early childhood was referred to immunology during an admission for recurrent fevers of unknown origin, night sweats, and lymphadenopathy. Previous infections included bacterial sinusitis and pneumonia, bronchitis, otitis media, and skin and soft tissue infections. Additionally, she had nonspecific gastrointestinal symptoms, including abdominal pain and intermittent diarrhea, that were attributed to irritable bowel syndrome. For seven years, she was seen by multiple subspecialties without a unifying diagnosis. She had an extensive workup, which ruled out rheumatologic disorders, ongoing chronic infection, and malignancy. Workup showed CBC with mild thrombocytosis, normal immunoglobulin levels, elevated inflammatory markers (both ESR and CRP), and elevated B cells on flow cytometry (later normalized). She had a normal bone marrow biopsy. CT chest/abdomen/pelvis showed prominence of abdominal lymph nodes and several cervical and occipital lymph nodes. Her left neck lymph node was biopsied, with pathology showing reactive follicular and parafollicular hyperplasia and no evidence of lymphoproliferative disorder or changes on flow cytometry. After her extensive workup, genetic testing was pursued and the patient was found to have a heterozygous RIPK1 variant (c.82T>C (p.Phe28Leu)), classified as of unknown significance, but in silico analysis suggesting the variant to likely be disruptive.
The patient’s clinical and immunological phenotype, with increased inflammatory markers, regular prolonged fevers, lymphadenopathy, ulcers, and GI symptoms, has features that overlap with CRIA. The patient was trialed on colchicine; however, she had limited response. This particular RIPK1 variant has not been described as pathogenic, but her presentation warrants further functional evaluation and a possible treatment trial with an IL-6R or IL-1 blocker.
