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

doi:10.3390/jcm10030465

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

J Clin Med. 2021 Jan 26;10(3):465. doi: 10.3390/jcm10030465.

Authors

Jolanta Zegarska¹, Ewa Wiesik-Szewczyk², Ewa Hryniewiecka¹, Beata Wolska-Kusnierz³, Dariusz Soldacki^{2

4}, Magdalena Kacprzak⁵, Agnieszka Sobczynska-Tomaszewska⁵, Kamila Czerska⁵, Pawel Siedlecki^{6

7}, Karina Jahnz-Rozyk², Ewa Bernatowska³, Radoslaw Zagozdzon^{1

4

6}, Leszek Paczek^{1

6}

Affiliations

¹ Department of Immunology, Transplant Medicine and Internal Diseases, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland.
² Department of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine in Warsaw, 128 Szaserów St., 04-141 Warsaw, Poland.
³ Department of Immunology, Children's Memorial Health Institute, 20 Dzieci Polskich Ave., 04-730 Warsaw, Poland.
⁴ Department of Clinical Immunology, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland.
⁵ MEDGEN Medical Centre, 9a Wiktorii Wiedenskiej St., 02-954 Warsaw, Poland.
⁶ Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5a Adolfa Pawinskiego St., 02-106 Warsaw, Poland.
⁷ Department of Systems Biology, University of Warsaw, 1 Miecznikowa 1., 02-096 Warsaw, Poland.

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.

Keywords: anakinra; damage index; diagnostic delay; genetic inheritance; monogenic autoinflammatory syndrome; new genetic variant; personalized therapy.