Heterogeneous phenotype of autoinflammatory disease in a patient with mutations in <i>NOD2</i> and <i>MEFV</i> genes

Background: Autoinflammatory diseases are a genetically heterogeneous group of conditions characterized by excessive activation of the innate immune system. They frequently present with overlapping features, particularly in cases of digenic or polygenic inheritance. The most common cause of autoinflammation arises from causative variants in the MEFV gene, responsible for familial Mediterranean fever. Clinical features include recurrent episodes of fever with serositis and amyloidosis. Individuals with variants in MEFV that present atypically with heterogeneous autoinflammatory features have also been described. Notably, gene modifiers of MEFV, such as NOD2 encoding an intracellular bacterial sensor, can result in more severe disease. NOD2 underlies a number of autoinflammatory and immunodeficiency conditions, including Blau syndrome. To date, Blau syndrome has not been described in the context of MEFV. Aim: To expand the presentation and phenotype of autoinflammatory disease associated with defects in the NOD2 and MEFV genes. Methods: A retrospective review of the patient’s chart was performed, including family history, medical history, immune laboratory evaluation, and genetics. Results: We describe here a 68-year-old male with a remarkable medical history since childhood of skin rash, erythroderma, recurrent infections, autoinflammation, arthritis, uveitis, and malignancy. A significant family history of cancer and autoinflammation was noted. Genetic work-up involving a 17-gene autoinflammatory panel revealed 3 heterozygous variants of uncertain significance, 2 of which were present in the MEFV gene and one in the NOD2 gene. His features were consistent with an overlapping phenotype of Blau syndrome and atypical FMF. Conclusion: Heterozygous variants in NOD2 and MEFV can result in a spectrum of autoinflammatory disorders with a heterogeneous phenotype. The NOD2 variant identified in our patient has not previously been associated with Blau syndrome. Statement of Novelty: We describe a patient harbouring heterozygous mutations in the MEFV and NOD2 genes marked by recurrent childhood infections.

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