P2A286: A Novel Case of Germline RANBP2 Mutation Associated with Refractory Very Early Onset Inflammatory Bowel Disease and Aggressive Acute Necrotizing Encephalopathy

Introduction: Acute Necrotizing Encephalopathy (ANE) is a rare disease that induces rapidly progressive encephalopathy triggered by a viral illness. ANE is associated with missense mutations in the RANBP2 that have incomplete penetrance. Common symptoms include altered mental status, headache, and seizure. Very early onset inflammatory bowel disease (VEO-IBD) is a severe form of inflammatory bowel disease that presents before the age of 6 years and is linked to several genes but has not previously reported with RAN Binding Protein 2 (RANBP2). Here, we report the case of a 3-year-old female with germline RANBP2 mutation who developed both refractory VEO-IBD and aggressive ANE.

Case Description: A three-year-old female with a VEO-IBD minimally controlled with infliximab was admitted to the hospital due to severe anemia and perianal cellulitis. Over the course of hospitalization, she developed shoulder pain and purpuric rash but was otherwise clinically improving. On day 6 of admission, she complained of headache and shortly afterwards she developed status epilepticus and became unresponsive and hypoxic, necessitating intubation. An MRI of the brain revealed significant swelling and T2 hyperintense signal abnormality in the bilateral thalami. The upper cervical spinal cord showed extension of the abnormality, with possible involvement of the basal ganglia bilaterally. With the radiologic impression concerning for venous infarct versus infectious encephalitis, the patient was started on Amphotericin, Meropenem, and Vancomycin. Extensive infectious workup was unremarkable. Repeat MRI showed progressing encephalitis. Considering the severe injury to the brain she sustained and her poor prognosis, her parents chose to withdraw life sustaining therapies and she died. Genome sequencing revealed a germline mutation in the RANBP2 gene, which can be associated with Genetic Acute Necrotizing Encephalopathy (ANE). No other mutations were found.

Discussion: Genetic ANE is often overlooked and results in delayed treatment, despite a high mortality rate and most surviving patients having persistent neurologic deficits. The RANBP2 mutation associated with ANE causes an incompletely penetrant predisposition to encephalopathy. However, the exact mechanism of which other factors contribute to disease penetrance remains poorly understood. VEO-IBD is a severe form of chronic inflammation of the colon and rectum linked to several genes, including IL-10, IL-10RA, IL-10RB, and MSH6. Our case is the first report of RANBP2 linked to both ANE and VEO-IBD. Additionally, our patient had an aggressive clinical course of both diseases; a treatment-resistant form of VEO-IBD and a rapidly progressive ANE.

Conclusion: Our case highlights a potential novel association between RANBP2 and both ANE and VEO-IBD. Further studies are necessary to elucidate the exact genetic mechanisms underlying VEO-IBD and the possible link between these two diseases. Clinicians should be aware of this rare association to facilitate earlier diagnosis and treatment.