The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: Clinical manifestations and long-term follow-up

Abstract

Objective

To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up.

Methods

We performed a retrospective chart review of 36 patients carrying low-penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed.

Results

Individuals with low-penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-penetrance variants ultimately require these therapies.

Conclusions

Our study confirms that low-penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment.

Introduction

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene, encoding the 55-kD receptor for tumor necrosis factor (TNF)-α (TNFRSF1A) [1]. Its most common clinical features include recurrent long-lasting fever episodes usually persisting 1–3 weeks, periorbital edema, conjunctivitis, a migratory erythematous skin rash with underlying fasciitis and myalgia, and arthralgia or arthritis [2], [3]; polyserositis is another common clinical manifestation; however, sometimes only one serous membrane can be involved [4], [5], [6], [7], [8], [9]. TRAPS treatment is tailored according to the severity of the clinical features and is aimed at controlling symptoms, improving patients' quality of life, and preventing long-term complications [10], [11].

Disease onset occurs early in life, usually around 3 years of age. However, significant variability both in terms of age at disease onset and in clinical phenotype is observed in TRAPS [3], [4], [5], [8], [10], [12], [13]. This heterogeneity is largely related to the wide spectrum of known TNFRSF1A mutations [14]. TRAPS mutations are distinguished into clearly pathogenetic high-penetrance variants and low-penetrance variants, also described as variants of uncertain significance [15], due to the fact that they have been found to occur also in 1–3% of healthy individuals of different ethnicity. The former are mostly missense substitutions, mainly affecting the highly conserved cysteine residues of the extracellular cysteine-rich domains, involved in disulfide bond formation and in the folding of the extracellular portion of TNFRSF1A [2], [3]. These mutations are associated with an earlier disease onset and a more severe phenotype, including a higher number of fever episodes, a greater severity of attacks, and an increased risk of developing amyloidosis, the most troublesome complication of TRAPS [2], [3], [16]. On the contrary, low-penetrance mutations seem to be associated with a milder phenotype, a later disease onset, even in adulthood, and a lower risk of amyloidosis [3], [17]. In addition, patients carrying low-penetrance TNFRSF1A variants may show atypical inflammatory signs and symptoms that mimic other autoinflammatory disorders and/or autoimmune diseases, such as idiopathic recurrent acute pericarditis (IRAP), thus hindering an appropriate differential diagnosis [5], [6], [8], [17], [18]. The most common low-penetrance TNFRSF1A variants are R92Q and P46L, for which epidemiologic and clinical data are available [4], [17], [19], but long-term follow-up data in adults are still lacking. Moreover, some rare variants have been recently reported (e.g., D12E, V95M, and R104Q) that behave similarly to R92Q and P46L: these have been described in patients with recurrent inflammatory attacks lacking the most typical TRAPS manifestations, and have even been also identified in healthy controls [14]. Their actual pathogenetic role and genotype–phenotype correlation are still a matter of scientific debate [9], [20], [21].

The aim of our study was to analyze the clinical manifestations and the response to treatment in a cohort of adult patients carrying the low-penetrance R92Q, P46L, D12E, V95M, and R104Q variants of the TNFRSF1A gene, to compare them with both patients carrying structural TNFRSF1A mutations and a cohort of genetically negative individuals presenting with recurrent inflammatory attacks, and to provide data on their long-term follow-up.