Features of clinical and laboratory manifestations of periodic syndrome associated with variants of the Tumor Necrosis Factor receptor gene TNFRSF1A
Authors:   National Medical Research Center of Children's Health, Moscow, Russian Federation, Shingarova M.Sh. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Isaeva K.B. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Chomakhidze A.M. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Lomakina O.L. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Fetisova A.N. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Chibisova K.V. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Krekhova E.A. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Kriulin I.A. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Kriulina T.Yu. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Association of Pediatric Rheumatologists, Moscow, Russian Federation, Tsulukiya I.T. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Botova M.S. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Kondrateva N.M. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Kokina M.Yu. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Savostyanov K.V. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Pushkov A.A. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Zhanin I.S. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Demianov D.S. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Alexeeva E.I. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Association of Pediatric Rheumatologists, Moscow, Russian Federation
Published: August 2024

Periodic syndrome associated with variants in the Tumor Necrosis Factor receptor gene (hereinafter referred to as TNFRSF1A gene) – Associated periodic syndrome (hereinafter referred to as TRAPS) – is an autoinflammatory genetic disease that often occurs under the "mask" of juvenile arthritis (JA), as well as other rheumatic diseases. Knowledge of phenotypic and genetic features of the periodic syndrome associated with variants in the Tumor Necrosis Factor receptor gene will allow timely verification of the diagnosis and initiation of pathogenetic therapy, thereby reducing the risk of patient disability, complications and improving prognosis. Objective. To identify the peculiarities of clinical and laboratory manifestations of periodic febrile syndrome associated with variants in the Tumor Necrosis Factor receptor (TNFRSF1A) gene. Patients and Methods. A comparative retrospective analysis of clinical and laboratory manifestations of the disease was performed in 66 patients hospitalized in the rheumatology department of the National Medical Research Center for Children's Health (FSAI NMRC for Children's Health", Ministry of Health of Russia Moscow) in the period from March 1, 2013 to August 31, 2022, with the diagnosis of juvenile idiopathic arthritis and febrile syndrome: 33/66 (50%) with variants in the TNFRSF1A gene detected by molecular genetic study, 33/66 (50%) without variants in the TNFRSF1A gene. Results. Due to the presence of febrile syndrome, all patients underwent molecular genetic study to identify variants in genes associated with the development of autoinflammatory disease. In 33/66 patients a large variety of variants in TNFRSF1A gene was detected, of which: in 4/33 (12%) – variants were classified as probably pathogenic (c.337_339del, p.Glu113del, c.792del, p.Lys265Serfs*87, c.374G>A, p.Cys125Tyr, c.184 T>A, p.Cys62Ser in heterozygous state), in 1/33 (3%) – as pathogenic (c.242G>T, p.Cys81Phe in heterozygous state), in 3/33 (9.1%) – as variants of uncertain significance (c.596T>C, p.Ile199Thr, c.472+6C>T, p.?, c.194-14G>A p.? in heterozygous state). The most frequent variant of uncertain significance with incomplete penetrance was c.362G>A, p.Arg121Gln in heterozygous state in 27/33 (82%) patients. Patients with variants in the TNFRSF1A gene (n = 33) were diagnosed with autoinflammatory disease, patients without variants in genes associated with AID- with systemic SA. At disease debut, 65/66 (98.5%) patients presented with fever, 55/66 (83.3%) with rash, and 43/66 (65.1%) with joint involvement. Patients with variants in the TNFRSF1A gene showed clinical manifestations that were absent in patients diagnosed with sJIA: attack-like fever (48.5%), abdominal pain (33.3%), gastrointestinal lesions (27.2%): Diarrhea with pathological impurities (6.1%), diarrhea without impurities (12.1%), vomiting (6.1%); eye lesions (uveitis and retinal angiopathy) (24.2%), chest pain (12.1%), hearing loss (9.1%), periorbital edema (9.1%), delay in psychoverbal development (6.1%), aseptic meningitis (3%) and hydrocephalus (3%). Similar symptoms that developed in patients with TNFRSF1A gene variants and sJIA were characterized by features for each disease: In sJIA, fever persisted for more than 7 days, the rash was patchy-papular in nature, and arthralgia was prevalent; in patients with TNFRSF1A gene variants, fever lasted less than 7 days, the rash had a smallspotted, large-spotted, vesicular character, the joint syndrome developed significantly more often than in sJIA (in 78.8% and 51.5%, respectively, p = 0.03) and was manifested by oligo- and polyarthritis. Conclusion. The presence of variants in the TNFRSF1A gene may be associated with a wide variety of clinical manifestations, therefore, all patients with febrile syndrome with suspected juvenile idiopathic arthritis, joint involvement in combination with rash and/or other manifestations should undergo a molecular genetic study to identify variants in the TNFRSF1A gene to verify the diagnosis of autoinflammatory disease at an early stage in order to initiate pathogenetic therapy and prevent the development of complications. Key words: autoinflammatory syndrome, recurrent syndrome associated with tumor necrosis factor receptor gene mutation, TRAPS, molecular genetic diagnosis, rheumatology, pediatrics, children