Clinical Guidance

Most pathogenic variants in TNFRSF1A are missense variants affecting the cysteine residues, which are important for protein folding and intracellular trafficking. Generally, people with these pathogenic variants have more severe symptoms and are more likely to have AA amyloidosis if left untreated. Missense variants at residues that do not affect protein folding (see Molecular Genetics, ) may play a role in inflammation but do not lead to the severe symptoms seen with pathogenic variants affecting cysteine residues.

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"

Penetrance

Most individuals with severe pathogenetic variants in TNFRSF1A (such as or those at cysteine residues) have at least some manifestations of the disease. There are a few notable low-penetrance variants in TNFRSF1A. Individuals with these low-penetrance variants typically either have mild symptoms or may not experience symptoms at all, in which case they are generally not considered to have TRAPS (see Molecular Genetics, ).

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"

Diagnostic Criteria

Many clinical diagnostic criteria for TNF receptor-associated periodic fever syndrome (TRAPS) have been proposed. A classification system that incorporates molecular genetic testing and clinical features has been found to have a sensitivity of 95%, a specificity of 99%, and an accuracy of 99% .

Suggestive Findings

TRAPS should be considered in individuals with the following clinical, supportive laboratory, and family history findings.

Clinical findings

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"

Differential Diagnosis

Table 3.

Hereditary Disorders of Interest in the Differential Diagnosis of TNF Receptor-Associated Periodic Fever Syndrome (TRAPS)

Gene | Disorder | MOI | Key Features

MEFV | Familial Mediterranean fever (FMF) | AR(AD1) | Recurrent short episodes of inflammation serositis incl fever, peritonitis, synovitis, pleuritis, (rarely) pericarditis

NLRP3

| Familial cold autoinflammatory syndrome 1 (FCAS1) (OMIM 120100) | AD | Cold-induced attacks of fever, rash, arthralgia but no deafness or amyloidosis

Muckle-Wells syndrome (MWS) (OMIM 191900) | AD | Urticaria, deafness, renal amyloidosis

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"

Management Guidelines

Clinical practice guidelines for the management of monogenic autoinflammatory conditions, including TNF receptor-associated periodic fever syndrome (TRAPS), have been published; see (full text; log in or purchase required) and (full text). Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with TRAPS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with TNF Receptor-Associated Periodic Fever Syndrome

Clinical Guidance

For affected individuals managed with continuous biologic agents, consideration should be given to whether live-attenuated versus non-live vaccines should be administered. Data on the effect of live-attenuated vaccines are limited, and risks/benefits should be considered. Before undertaking any live vaccinations, individuals should discuss the risk/benefit of receiving such vaccines. It should be noted that affected individuals may have severe, paradoxical reactions that have been associated with anti-TNF monoclonal antibodies.

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"

Surveillance Guidelines

In addition to a complete physical examination (performed annually or sooner if clinically indicated) with blood pressure and other vital signs, full skin examination, assessment for the presence of lymphadenopathy and hepatosplenomegaly, and musculoskeletal evaluation, the evaluations outlined in are recommended.

Table 6.

Recommended Surveillance for Individuals with TNF Receptor-Associated Periodic Fever Syndrome

System/Concern | Evaluation | Frequency

Rheumatologic

| • Measure acute-phase reactants incl CRP, ESR, serum level of AA amyloid, fibrinogen, haptoglobin, CBC w/differential.1

• Assess w/Autoinflammatory Diseases Activity Index (AIDAI).2

| Annually or more frequently if indicated

Gastrointestinal

| • Liver function tests3

• Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.

Renal

| Measurement of renal function4 urinalysis5

Eyes | Ophthalmologic exam for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage

Infectious/

Immunologic

| Measure quantitative serum immunoglobulins.

Screen for tuberculosis, typically by QuantiFERON® measurement. | For any affected person on biologic treatment, as risk of infection may be

CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; TRAPS = TNF receptor-associated periodic fever syndrome

Source: GeneReviews — "TNF Receptor-Associated Periodic Fever Syndrome"