Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) with a New Pathogenic Variant in TNFRSF1A Gene in a Family of the Adult Male with Renal AA Amyloidosis-Diagnostic and Therapeutic Challenge for Clinicians.

Jolanta Zegarska,Magdalena Kacprzak,Ewa Wiesik-Szewczyk,Beata Wolska-Kusnierz,Ewa Hryniewiecka,Ewa Bernatowska,Pawel Siedlecki,Leszek Paczek,Agnieszka Sobczynska-Tomaszewska,Karina Jahnz-Rozyk,Dariusz Soldacki,Radoslaw Zagozdzon,Kamila Czerska

doi:10.3390/jcm10030465

Abstract

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of TNFRSF1A gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient’s daughters inherited the same variant of the TNFRSF1A gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications.

Highlights

Monogenic autoinflammatory diseases (AIDs) cover a spectrum of syndromes, which lead to chronic or recurrent inflammation caused by activation of the innate immune system, typically in the absence of high autoantibody titers [1]
33-year-old Caucasian male was referred for nephrology consultation because of proteinuria 3.2–5.7 g/day; chronic renal failure with estimated glomerular filtration rate 69 mL/min./1.73 m2 and biopsy-proven kidney AA amyloidosis
Because the NM_001065.5:p.(Arg121_Asp122insAlaArgHisArg) insert has been identified in the tumor necrosis factor receptor 1 (TNFR1) protein for the first time, we decided to assess the potential effects of this insertion on the protein structure by 3D modeling (Figure 2)

Summary

Introduction

Monogenic autoinflammatory diseases (AIDs) cover a spectrum of syndromes, which lead to chronic or recurrent inflammation caused by activation of the innate immune system, typically in the absence of high autoantibody titers [1]. The four most common monogenic AIDs are: NLRP3-associated autoinflammatory disease (NLRP3-AID), familial. Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS). TRAPS is an autosomal dominant disease, caused by mutations in TNFRSF1A gene which encodes the protein named tumor necrosis factor receptor 1 (TNFR1), which plays a crucial role in the inflammation and apoptosis [1]. Symptoms include recurrent episodes of fever, lasting about 3 weeks, abdominal, chest, and muscle pains, skin rash, typically found on the limbs, periorbital edema, and joint pain [2].

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