Phenotypic Spectrum of Adult Autoinflammatory Patients Carrying the MEFV E148Q Variant - A Case Series

Objectives To describe the phenotypic spectrum of adult autoinflammatory patients carrying the MEFV E148Q variant. Methods Patients were enrolled from an autoinflammatory clinic in Toronto. Inclusion criteria were age >18 years, unexplained inflammatory features with genetic testing positive for the MEFV E148Q variant. Gene panel was performed at the Division of Genome Diagnostics, Hospital for Sick Children. All patients provided written consent to be included in a case series. Results Epidemiology: 17 patients were included (82% female). The most common ethnicities were Southeast Asian (35%), followed by South Asian (33%). The mean age was 39 years, and the mean age of disease onset was 22.6 years. Eight patients had a family history of similar symptoms. Clinical Features: Patients carried clinical labels such as Unclassified Systemic Autoinflammatory Disease or atypical FMF (both 5/17), FMF (3/17), PFAPA (2/17), and Behcet’s or Still’s disease (both 1/17). 10 patients experienced flares with intermittent wellness, and 7 had flares with chronic lingering symptoms. 9/17 identified triggers with stress and physical exertion being the most common. Recurrent fevers >38°C were present in 11 patients. The most common organ system affected was dermatologic (12/17 patients). Oral ulcers and urticaria-like lesions were the predominant manifestations. Neutrophilic infiltration was demonstrated in 2 out of 3 skin biopsies. Other manifestations included arthritis (11/17), gastrointestinal symptoms (10/17) and aseptic pharyngitis (7/17). CRP was elevated during inflammatory flares in 13/15, and even at baseline in 4/15 patients. Colchicine was effective in 13 out of 15 patients. Two were started on interleukin-1 inhibitor; both showed clinical and biochemical improvement. Genetic Architecture: 13/17 patients carried additional variants. The most common were MEFV, NLRP3, and NOD2. Exome sequencing was performed in 3 patients with no diagnostic results. Conclusion To our knowledge, this is the largest cohort of patients gathered with the MEFV E148Q variant. While a minority of patients did not show signs of inflammasomopathy (eg, distinct flares/elevated CRP/response to colchicine), some exhibited these classic features of FMF. Some patients exhibited features unusual for FMF but appeared autoinflammatory in nature (eg, mucocutaneous ulcerations, hive-like lesions with neutrophilic dermatoses on biopsy) (Figure). These observations may suggest that E148Q is a low penetrance variant with variable expressivity,[1] and possibly associated with unique clinical features that fall outside the spectrum of classic FMF. Larger multicenter cohorts with exome sequencing and functional studies will be helpful in further elucidating the role of MEFV E148Q in patients presenting with autoinflammation. [1.] Gattorno M. Int J Mol Sci 2023:1-24.