Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant in TNFRSF1A Gene

Abstract

BackgroundTumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date.ObjectiveTo analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset.MethodsA retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series.ResultsOur series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups.ConclusionThis study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset.

Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative

“…This treatto-target approach successfully controls disease activity and can prevent organ damage in patients with AIDs [59]. In contrast, there is a very mild AID phenotype with limited disease activity: some CAPS patients experience significantly fewer symptoms during warm seasons, TRAPS patients may have very infrequent episodes of clinically active disease [60]. In addition, the risk of organ damage may differ dramatically between AID patients as demonstrated for the risk of hearing loss in CAPS [40].…”

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor—Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network

“…On this basis, the R92Q mutation is currently classified as a variant of uncertain significance, and its pathogenic role in causing TRAPS phenotypes is already controversial [29]. When considered pathogenic, it has been associated to a protean clinical phenotype consisting in fever, abdominal pain, arthralgia/arthritis, fatigue, myalgia, and less frequently headache, odynophagia, skin rash, and chest pain with a broad range of age at disease onset [3]. In line with previous evidences, in our cohort of patients carrying R92Q variant, disease onset was quite varied (ranging 1 to 54 years), with frequent flares lasting 12 days on average characterized by musculoskeletal symptoms, lymphadenopathy, skin rash, and chest pain as most frequently complained symptoms.…”

“…According to criteria used in previous studies, patients aged <16 and ≥16 years at disease onset were considered to have pediatric and adult disease onset, respectively [2,3,14,15]. In order to distinguish patients according to genotype, we divided the cohort into two main groups: patients carrying TNFRSF1A HP mutations (HP group) and patients carrying TNFRSF1A LP mutations (LP group).…”

“…In particular, the autoinflammatory disease activity index (AIDAI) is used in clinical practice for measuring disease activity during a 1-month period according to the presence or absence of selected inflammatory manifestations reported day by day [10]; the autoinflammatory disease damage index (ADDI) is used to establish chronic organ damage owing to disease activity over time [11]. Few studies in the literature compared clinical features according to the age of disease onset [1,3,12], and no data at all are available about the performance of the new TRAPS classification score in different age groups and compared to the preexisting Eurofever score [13]. This multicenter study was designed to define demographic, clinical, and therapeutic features of a large cohort of TRAPS patients in Italy, distinguished according to different age at onset and genetic variants, on the basis of the nation-wide collaborative experience of the Autoinflammatory Disease Alliance (AIDA) Network and the Working Group for Autoinflammatory Disease of the Italian Society of Rheumatology.…”

TNFRSF1A gene variant identified in a boy with recurrent episodes of fever

“…Furthermore, the low-penetrance variants appear to produce their effects through a different pathophysiological mechanism compared with clearly pathogenic gene alterations, and are, at least in part, connected to the functional status of regulatory T cells [19]. An analysis of a series of patients who carry a well characterized low-penetrance variant has shown that severity of symptoms and risk of complications are highly variable and at least partially correlated with the age of onset [20]. In the light of all this, it appears quite justified to speak of a "TRAPS spectrum" as a diagnostic category (as opposed to the diagnosis of TRAPS per se).…”