Phenotypic variability in two patients with tumor necrosis factor receptor associated periodic fever syndrome emphasizes a rare manifestation: Immunoglobulin A nephropathy
Introduction
Periodic fever syndromes are a heterogeneous group of disorders characterized by repeated attacks of fever and localized inflammation, predominantly affecting the skin, serosal surfaces and the musculoskeletal system. Tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) caused by dominantly inherited mutations in the TNFRSF1A caused different clinical symptoms in different ages. TRAPS was originally described as familial Hibernian fever in a large Irish/Scottish family in 1982 (Williamson LM et al., 1982). After the discovery of autosomal dominant mutations in the gene for tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), it was renamed as TRAPS in 1999 (McDermott MF et al., 1999). The majority of TNFRSF1A mutations related to TRAPS exists within the exons 2 to 4. Over-representation of missense substitutions disrupt structurally important cysteine–cysteine disulfide bonds in the extracellular domain; however, the underlying mechanism by which heterozygote mutation culminating in TRAPS phenotype is still unclear and probably differ between variants (Bachetti and Ceccherini, 2014; Simon A et al., 2010). Clinical manifestations of TRAPS mainly arise in childhood and adolescence; however, about 20% of the patients may present in adulthood (de Jesus AA et al., 2015). Recurrent fever attacks, abdominal pain, pleuritis, migratory rash and underlying myalgia, periorbital edema together with conjunctivitis are the presenting features of disease (de Jesus AA et al., 2015). One of the distinctive features of the disease is prolonged attacks, with a mean length of 14 days, sometimes continuing up to 4 weeks. Periorbital edema and conjunctivitis are the other definitive characteristics of TRAPS, which distinguish it from other periodic fever syndromes (de Jesus AA et al., 2015). In 2019, the Paediatric Rheumatology International Trials Organisation (PRINTO) proposed a novel set of validated classification criteria for autoinflammatory recurrent fevers (Gattorno M et al., 2019). According to the classification criteria; a-presence of confirmatory TNFRSF1A genotype and at least one among the following criteria or presence of a not confirmatory TNFRSF1A genotype and at least two among the following criteria; duration of episodes ≥7 days, myalgia, migratory rash, periorbital edema, relatives affected are considered as TRAPS (Gattorno M et al., 2019).
The present study reports two cases of TRAPS with different clinical findings according to the genetic variant in TNFRSF1A.
Section snippets
Patient 1
A 15-year-old male was admitted to our pediatric rheumatology department due to recurrent fever attacks. His parents were 4th degree relatives. Fever attacks recurring monthly and lasting 4–5 days accompanied by macular rashes on different parts of his body, abdominal pain, and diarrhea had begun at 6 months of age. Over time, the frequency of fever attacks decreased to one or 2 times per year. In the course of the disease, periorbital edema with hyperemic conjunctivitis and generalized myalgia
Discussion
TRAPS (OMIM 142680) is the most common autosomal dominant AID in Europe with an about one per million prevalence in Germany (Lainka E et al., 2009). TRAPS patients have been more frequently reported in Caucasians; however, the reason of which is uncertain, whether it is due to the true increased incidence among Caucasians or ascertainment bias (Lachmann HJ et al., 2014; Lachmann, 2017). The attack frequency of TRAPS can be variable, very discrete or near continuous and attacks are often lasting
Conclusions
TRAPS is among rare diseases, presenting with variable clinical manifestations; therefore, diagnosis mainly relies on suspicion followed by genetic testing of TNFRSF1A. A possible association between TRAPS and IgA nephropathy needs to be clarified in further comprehensive studies including large number of TRAPS patients.
Funding
No funding was received.
Contributors’ statement page
Dr. Balci and Dr. Yilmaz conceptualized and designed the study, designed the data collection instruments, drafted the initial manuscript, and reviewed and revised the manuscript. Dr. Kisla Ekinci, Dr.Atmis, and Dr. Melek collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr. Bisgin carried out the genetic analyzes, interpretation of the results and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and
Declaration of competing interest
Authors; Sibel Balci, Rabia Miray Kisla Ekinci, Engin Melek, Bahriye Atmis, and Mustafa Yilmaz declare that they have no conflicts of interest.
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