S4874 Double Trouble: Managing Therapy-Refractory Crohn’s Disease in a Patient With Smith-Magenis Syndrome

Introduction: Pediatric-onset inflammatory bowel disease (IBD) is increasingly recognized to have an underlying genetic component, particularly in cases that are non-responsive to conventional therapies. We report a case of a 19-year-old woman with early-onset, treatment-refractory Crohn’s disease with intellectual disability and growth failure. Genetic analysis revealed a heterozygous chromosomal deletion, raising the possibility of monogenic or genetically influenced IBD phenotype. Case Description/Methods: A 19-year-old woman, born to non-consanguineous parents, at term, had facial dysmorphism, intellectual disability and short stature, which was not evaluated during childhood. She presented with chronic bloody diarrhea, tenesmus and fatigue since the age of 10. Colonoscopy revealed linear, deep ulcers and a stricture in the rectosigmoid region. Biopsies revealed features of chronic active colitis. Computed tomography enterography showed pancolitis with loss of haustrations, ileocecal junction thickening, and mesenteric fat stranding. A diagnosis of Crohn’s colitis was made, and patient initiated on oral corticosteroids followed by advanced therapy (infliximab). Simultaneously, genetic testing with whole exome sequencing was done, which revealed a heterozygous missense variant in SLC39A4, and heterozygous deletion on chromosome 17 encompassing multiple genes. The patient subsequently had secondary loss of response to Infliximab and in August 2024, she was re-admitted with similar complaints and repeat sigmoidoscopy showed persistent ulcerations and narrowing in the rectosigmoid region. She was started on adalimumab, however, she has had only partial resolution in symptoms with persistent anemia and hypoalbuminemia. She is now being planned for combined advanced therapy with addition of ustekinumab. Discussion: This case illustrates diagnostic and therapeutic complexities in managing pediatric-onset Crohn’s disease, especially when associated with systemic clinical findings. The deletion on chromosome 17 leads to loss of genes including RAI1, SREBF1, TNFRSF13B. RAI1 deletion, which is causative of Smith-Magenis syndrome, is associated with intellectual disability, including speech and motor delay, craniofacial and skeletal anomalies and sleep disturbance. However, we could not find any case report linking IBD with Smith-Magenis syndrome. This case underscores the need for an evolving understanding of monogenic and genetically influenced IBD, which may pave the way for more targeted interventions in these patients.