Tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS)-related AA amyloidosis: a national case series and systematic review

International audienceAbstract Objectives TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review. Methods This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, familial hibernian fever and hibernian familial fever. Results A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept). Conclusion TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function

Somatic mosaic mutation in TNFRSF1A as a cause of Tumor necrosis factor receptor-associated periodic syndrome- Impact on genetic counselling

Introduction: Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare monogenic systemic autoinflammatory disease caused mainly by germline heterozygous missense mutations in exons 2-4 of the TNF receptor super family member 1A (TNFRSF1A) gene. TRAPS is known as a familial disorder of autosomal dominant inheritance. Objective: To identify the genetic defect underlying the disease in a patient with a phenotype evocative of TRAPS. Methods: (i) The patient’s DNA was analyzed by Sanger sequencing of TNFRSF1A exons 2-4 followed by a NGS approach based on the targeted sequencing of the main genes involved in systemic autoinflammatory disorders; and (ii) Subpopulations of peripheral blood cells were subsequently analyzed in order to study the cellular distribution of the identified molecular defect.Results: (i) Clinical phenotype: A 36-year-old man presented since the age of 24 with recurrent episodes of fever (38-40C°) lasting for 1-2 weeks. The febrile attacks were accompanied with severe abdominal, thoracic and lower back pain, myalgia, and transitory erythematous eruptions localized at elbows and left lower limb. He also had an acute episode of pericarditis. No lymphadenopathy, ophthalmological or neurological symptoms were observed. Laboratory tests showed elevated inflammatory biological markers: increased serum levels of CRP (171 mg/l) with hyperleukocytosis (15000/l). Serum ferritin levels and kidney function tests were normal. (ii) Molecular bases: No heterozygous mutation was identified after Sanger sequencing of exons 2-4 of TNFRSF1A. The patient’s phenotype, highly evocative of TRAPS, prompted us to deepen the molecular investigations through the use of our autoinflammatory disorders NGS panel. We identified the c.176G>A p.(Cys59Tyr) TNFRSF1A mutation in a mosaic state with 14% of mutated allele in whole blood. This mutation (also known as C30Y) has already been reported, but in the heterozygous state, in three TRAPS families. We further studied the distribution of the mutated alleles in blood cells and observed a higher percentage of the mutated allele in myeloid cells (i.e. 15.8% in monocytes and 14.1% in neutrophils) than in lymphoid cells (i.e., 9.6% in T cells and 8.9% in B cells). Discussion: So far, only 3 other patients have been reported with a somatic mutation in TNFRSF1A. Among them, one displayed a germinal mosaicism. In our patient, the mosaicism predominantly involved the myeloid lineage (involved in the pathophysiology of TRAPS). In the 4 patients now identified with a TNFRSF1A somatic mosaic mutation, the phenotypic severity of TRAPS appears not to be related to the germinal/mosaic status of TNFRSF1A mutations.Conclusion: Somatic mosaic TNFRSF1A mutations should be sought in sporadic cases of TRAPS with no mutation identified by Sanger sequencing. Genetic counseling should take into account the fact that somatic mosaic mutations are not restricted to myeloid cells and may be present in other cell lineages

Mosaic variants in TNFRSF1A : an emerging cause of tumour necrosis factor receptor-associated periodic syndrome

International audienceObjective To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS). Methods (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously. Results In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected. Conclusion This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells