Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling

Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys–Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys–Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non-eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms that chronic ulcerative colitis may be associated with Loeys–Dietz syndrome. This finding suggests that an alteration of transforming growth factor beta signaling may by itself predispose to inflammatory colitis in humans, and represent an invaluable model to understand inflammatory bowel diseases.