Granulomatous inflammation in cartilage-hair hypoplasia: Risks and benefits of anti-TNF-α mAbs

Background: Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH. Objective: We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options. Methods: In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation. Results: Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-alpha mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas. Conclusion: To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-alpha antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients. (J Allergy Clin Immunol 2011;128:847-53.)