COPA Syndrome and Its Many Flavors

Introduction Pathogenic variants in the COPA gene are associated with autosomal-dominant autoimmune interstitial lung, joint, and kidney disease, a condition known as COPA syndrome. It is associated with a type I interferon signature and with good response to JAK inhibitors in the literature. Not all variants present all the features. Case Description 6-year-old male with a history of recurrent pneumonia referred to immunology for bilateral leg and joint pain. For over a year, he experienced pain 3–4x per week upon awakening, which worsened with exertion. MRI showed no structural changes or evidence of arthropathy or myopathy. Orthopedics referred him to the immunology clinic for further evaluation due to the persistence of symptoms. History is also notable for 5–6 episodes of pneumonia successfully treated with outpatient antibiotics, presumed asthma, and allergic rhinoconjunctivitis. Family history is notable for a pathogenic RIPK1 variant in his sister (treated with tocilizumab) and Hashimoto’s and celiac disease in his mother. His presentation and pertinent history raised concern for an inborn error of immunity, warranting further workup. Initial labs showed several signs of immunodysregulation, including a moderate type I IFN signature on a majority of Cd14bright monocytes, suggestive of a type I interferonopathy, and increased gamma delta double-negative T cells. Next-generation sequencing was obtained for further evaluation, revealing the presence of a heterozygous COPA variant, c.766G>T (p.Val256Phe). Additional autoantibody testing was negative, which would be atypical in the setting of COPA syndrome. However, given the different signs of immunodysregulation, the variant is undergoing further characterization on a research level. Discussion This case illustrates the importance of maintaining a broad differential to include in the presence of signs of autoimmunity and immunodysregulation. While he does not have overt kidney involvement, his arthralgias and pulmonary involvement further support the decision to explore the COPA variant with functional studies, given the potential therapeutic implications.