Novel presentations of periodic fever syndromes: Discrepancies between genetic and clinical diagnoses

Abstract

Objective: The Periodic fever syndromes (PFS) are a group of disorders of the innate immune system.We investigated patients diagnosed with PFS at the Dartmouth Hitchcock Pediatric RheumatologyClinic.Methods: Case acquisition was performed by reviewing ICD 9/10 coded records for familial Medi-terranean fever (ICD 9 277.31), laboratory test records for PFS genetic screening, and clinic recordsbetween 1/1/2011 and 12/31/2017.Results: Twenty-seven cases had clinical evaluations including PFS genetic screening. Clinical diag-noses included familial Mediterranean fever (FMF) (10 cases), Muckle-Wells (2 cases), tumor necrosisfactor receptor associated periodic syndrome (TRAPS) (4 cases), hyper IgD syndrome (HIDS) (1 case),Crohn's Disease (1 case), systemic onset juvenile idiopathic arthritis (SoJIA) (1 case), fever of unknownorigin (FUO) (1 case), periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) (6 cases), and cold-in-duced urticaria (1 case). Fifteen cases were associated with a genetic cause. Seven of the 10 FMF caseswere confirmed genetically and were either heterozygous or compound heterozygotes. Both cases ofMuckle-Wells had either a compound heterozygote for CIAS 1 or a NOD gene mutation. Both TRAPScases presented atypically with patients developing systemic lupus erythematosus (SLE) or beingasymptomatic. Two patients had novel syndromes. One FMF patient had a TRNT1 gene mutation whoresponded to intravenous immunoglobulin (IVIg) and colchicine after failing multiple treatments. Theother had SoJIA with a LPIN 2 gene mutation but responded to colchicine. Only one of the 15 genet-ically proven cases had classical presentation and genetics (HIDS secondary to a mevalonate kinase(MVK) gene mutation).Conclusion: PFS screening was helpful in over half of the cases to develop therapeutic treatment plans.Given the atypical clinical presentations seen with genetically determined PFS, extensive genetic test-ing is indicated for all patients presenting with a PFS, excluding classical PFAPA syndrome.