Abstract Alagille syndrome (ALGS) is a rare multisystem disorder caused by pathogenic variants in the JAG1/NOTCH2 pathway, usually manifesting in childhood with cholestasis, cardiac defects, and vascular dysplasia. Although structural vascular anomalies such as intracranial aneurysms, renal artery stenosis, and moyamoya are well recognized, immune-mediated vasculitis has not been previously reported in ALGS. We describe what appears to be the first confirmed case of microscopic polyangiitis (MPA) in an adult with ALGS. A 34-year-old man with genetically confirmed ALGS diagnosed at age three presented with recurrent pneumonias, anemia, and acute dyspnea with hemoptysis following bronchoscopy. On admission, he was febrile, tachycardic, and hypoxemic. Laboratory findings revealed progressive anemia (Hb 11.3→8.2 g/dL), thrombocytopenia (155 × 109/L), transient creatinine elevation (1.7 mg/dL), increased cholestatic enzymes, and CRP 98 mg/L. Extensive infectious testing (nasopharyngeal and BAL viral/bacterial panels, CMV PCR) was negative. Autoimmune screening demonstrated ANA 1:640 (dense fine speckled), anti-DNA 1:40, and p-ANCA 1:640 with MPO positivity and PR3 negativity, confirming MPA. Imaging (image 1) and clinical presentation were consistent with diffuse alveolar hemorrhage (DAH), and structural or iatrogenic causes were excluded. Treatment consisted of intravenous methylprednisolone pulses, followed by oral prednisone 60 mg/day and two 1-g doses of rituximab. The patient showed rapid resolution of hemoptysis, normalization of inflammatory markers, and stabilization of renal function. This case expands the phenotypic spectrum of ALGS and suggests that endothelial fragility related to JAG1/NOTCH2 dysfunction may, in rare instances, predispose to autoimmune small-vessel vasculitis. The coexistence of congenital vasculopathy and ANCA-associated inflammation represents a previously unrecognized overlap mechanism. Clinicians should consider immune-mediated vasculitis in ALGS patients presenting with alveolar hemorrhage or renal involvement once structural and infectious etiologies are excluded. These findings raise the hypothesis that congenital endothelial signalling defects may provide a substrate for secondary autoimmune activation, linking Notch signalling to ANCA-associated vasculitis. Funding None. Disclosure The authors declare no conflicts of interest and no tobacco/cannabis industry support. References 1. Singh SP, Pati GK. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol. 2018;8(2):140-147. PMCID: PMC6395485 2. Kamath BM et al. The Epidemiology, Natural History, and Burden of Alagille Syndrome. J Pediatr Gastroenterol Nutr. 2018;67:148-156. 3. Lauque D et al. Microscopic polyangiitis with alveolar hemorrhage: a study of 29 cases. Medicine (Baltimore). 2000;79(4):222-233. 4. Kim MJ, Shin K. Interstitial Lung Disease and Diffuse Alveolar Hemorrhage in Microscopic Polyangiitis. E-TRD. 2021. This abstract is funded by: None
Rabahi et al. (Fri,) studied this question.