Abstract
Tumor 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. To 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. A 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. Our 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. This study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset.
Highlights
The term autoinflammatory diseases was first coined in 1999 by Kastner et al to encompass a group of clinical syndromes characterized by an increased systemic inflammatory reaction, mediated predominantly by cells and molecules of the innate immune system, and caused by mutations in genes involved in the control of inflammatory pathways (1)
From January 2006 to June 2016, we retrospectively reviewed medical charts of pediatric and adult patients diagnosed with an autoinflammatory disease attributed to R92Q variant in TNFRSF1A gene, in four reference centers for autoinflammatory diseases
Patients were included if an autoinflammatory disease was suspected after ruling out autoimmune, infectious, or malignant causes, and R92Q low-penetrance variant in TNFRSF1A gene was found
Summary
The term autoinflammatory diseases was first coined in 1999 by Kastner et al to encompass a group of clinical syndromes characterized by an increased systemic inflammatory reaction, mediated predominantly by cells and molecules of the innate immune system, and caused by mutations in genes involved in the control of inflammatory pathways (1). Tumor necrosis factor receptor-associated periodic syndrome (TRAPS; OMIM 142680), described as familial Hibernian fever in 1982 (2), was defined as an autosomal-dominant disease caused by mutations in the TNFRSF1A gene (located on chromosome 12p13) in 1999 (1). Classically TRAPS affects mostly children below 10 years of age, it can occur in adult patients (3–9). Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date
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