Very early-onset inflammatory bowel disease (VEO-IBD), diagnosed before the age of 6, is a severe IBD subtype often associated with monogenic causes. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of inflammation and cell death. Biallelic pathogenic variants in the RIPK1 gene lead to RIPK1 deficiency, which disrupts these processes, causing immunodeficiency and autoinflammation, such as recurrent infections, early-onset IBD, and polyarthritis. Here, we report a VEO-IBD case associated with a novel variant in the RIPK1 gene.
A 3-month-old male with suspected milk protein allergy presented with a 3-week history of hematochezia, intermittent fevers, vomiting, poor feeding, irritability, and large oral ulcers. Initial evaluation revealed anemia, elevated fecal calprotectin (>3000 µg/g), and gastritis with erosions, lymphocytic infiltrates in the duodenum, crypt abscesses in the sigmoid colon, focal active colitis, and colon ulcers. Imaging demonstrated splenomegaly, and an infectious workup was negative. Initial management included nasogastric tube feeds, total parenteral nutrition, RBC transfusions, iron supplementation, metronidazole, and anti-inflammatory therapy with an IL-1 receptor antagonist. Despite treatment, the patient was readmitted 1 week later with worsening symptoms. Repeat endoscopy revealed severe ulcerations and a cobblestone appearance in the stomach, along with ulcers and cobblestoning in the duodenum and the colon. In response, therapy was transitioned to infliximab, to which the patient thus far has shown a good response.
The patient underwent genome sequencing, which identified a homozygous c.460-5C>A variant in the RIPK1 gene, inherited from consanguineous unaffected parents. Reported as a variant of uncertain significance (VUS), it was predicted to disrupt the splice acceptor site of exon 5, likely resulting in aberrant splicing and loss of function. The pathogenicity of this previously unreported variant was validated through western blot analysis, which served as a crucial diagnostic tool in confirming the deficiency of RIPK1 in the patient.
RIPK1 deficiency causes severe VEO-IBD. Western blot analysis confirmed a novel pathogenic variant. Anti-TNF therapy stabilized symptoms. Early diagnosis and personalized treatment are critical for management.
A novel RIPK1 variant highlights the importance of genetic testing and functional studies in VEO-IBD. Early recognition and targeted therapies improve outcomes in severe cases.
