TNF receptor 1-associated periodic fever syndrome

Summary

TNF receptor 1-associated periodic fever syndrome (MONDO:0007727) is a disease caused by TNFRSF1A (GenCC Definitive), with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include canakinumab, empagliflozin, and givinostat.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: TNFRSF1A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 523
• Phenotypes (HPO): 40
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000988	Skin rash	Very frequent (80-99%)
HP:0001055	Erysipelas	Very frequent (80-99%)
HP:0001701	Pericarditis	Very frequent (80-99%)
HP:0001954	Recurrent fever	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0003565	Elevated erythrocyte sedimentation rate	Very frequent (80-99%)
HP:0011227	Elevated circulating C-reactive protein concentration	Very frequent (80-99%)
HP:0012733	Macule	Very frequent (80-99%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002102	Pleuritis	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0005214	Intestinal obstruction	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0100796	Orchitis	Frequent (30-79%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001034	Hypermelanotic macule	Occasional (5-29%)
HP:0001637	Abnormal myocardium morphology	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002586	Peritonitis	Occasional (5-29%)
HP:0002633	Vasculitis	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)
HP:0100537	Fasciitis	Occasional (5-29%)
HP:0100539	Periorbital edema	Occasional (5-29%)
HP:0100614	Myositis	Occasional (5-29%)
HP:0100658	Cellulitis	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)
HP:0100776	Recurrent pharyngitis	Occasional (5-29%)
HP:0100781	Abnormality of the sacroiliac joint	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	TNF receptor 1-associated periodic fever syndrome
Mondo ID	MONDO:0007727
MeSH	C536657
OMIM	142680
Orphanet	32960
DOID	DOID:0090018
ICD-11	1869883509
NCIT	C119051
SNOMED CT	403833009
UMLS	C1275126
MedGen	226899
GARD	0008457
NORD	1804
Is cancer (heuristic)	no

Also known as: autosomal dominant familial periodic fever · familial Hibernian fever · FHF · FPF · Hibernian fever, familial · TNF receptor 1-associated periodic fever syndrome · TNF receptor 1-associated periodic syndrome · TNF receptor-associated periodic syndrome · TRAPS · TRAPS syndrome · tumor necrosis factor receptor 1 associated periodic syndrome · tumor necrosis factor receptor 1-associated periodic syndrome · Tumor Necrosis Factor Receptor-Associated Periodic Syndrome · tumor necrosis factor receptor-associated periodic syndrome · tumour necrosis factor receptor 1 associated periodic syndrome · tumour necrosis factor receptor 1-associated periodic syndrome · tumour necrosis factor receptor-associated periodic syndrome

Data availability: 523 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › TNF receptor 1-associated periodic fever syndrome

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

523 retrieved; paginated sample, class counts are floors:

201 uncertain significance, 189 likely benign, 44 conflicting classifications of pathogenicity, 37 not provided, 13 benign/likely benign, 13 pathogenic, 12 likely pathogenic, 8 benign, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12335	NM_001065.4(TNFRSF1A):c.185G>A (p.Cys62Tyr)	TNFRSF1A	Pathogenic	no assertion criteria provided
12336	NM_001065.4(TNFRSF1A):c.236C>T (p.Thr79Met)	TNFRSF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
12337	NM_001065.4(TNFRSF1A):c.175T>C (p.Cys59Arg)	TNFRSF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
12338	NM_001065.4(TNFRSF1A):c.242G>T (p.Cys81Phe)	TNFRSF1A	Pathogenic	criteria provided, single submitter
12339	NM_001065.4(TNFRSF1A):c.349T>C (p.Cys117Arg)	TNFRSF1A	Pathogenic	no assertion criteria provided
12340	NM_001065.4(TNFRSF1A):c.350G>A (p.Cys117Tyr)	TNFRSF1A	Pathogenic	no assertion criteria provided
12342	NM_001065.4(TNFRSF1A):c.176G>C (p.Cys59Ser)	TNFRSF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12344	TNFRSF1A, 3-BP DEL, NT211	TNFRSF1A	Pathogenic	no assertion criteria provided
12345	NM_001065.4(TNFRSF1A):c.295T>A (p.Cys99Ser)	TNFRSF1A	Pathogenic	no assertion criteria provided
12346	C55A	TNFRSF1A	Pathogenic	no assertion criteria provided
572070	NM_001065.4(TNFRSF1A):c.305G>A (p.Cys102Tyr)	TNFRSF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97643	NM_001065.4(TNFRSF1A):c.123T>G (p.Asp41Glu)	TNFRSF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97646	NM_001065.4(TNFRSF1A):c.151C>T (p.His51Tyr)	TNFRSF1A	Pathogenic	no assertion criteria provided
97651	NM_001065.4(TNFRSF1A):c.173G>T (p.Cys58Phe)	TNFRSF1A	Pathogenic	criteria provided, single submitter
97652	NM_001065.4(TNFRSF1A):c.176G>A (p.Cys59Tyr)	TNFRSF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97673	NM_001065.4(TNFRSF1A):c.251G>A (p.Cys84Tyr)	TNFRSF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
97686	NM_001065.4(TNFRSF1A):c.295T>C (p.Cys99Arg)	TNFRSF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97690	NM_001065.4(TNFRSF1A):c.306C>G (p.Cys102Trp)	TNFRSF1A	Pathogenic	criteria provided, single submitter
97710	NM_001065.4(TNFRSF1A):c.596T>A (p.Ile199Asn)	TNFRSF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12343	NM_001065.4(TNFRSF1A):c.184T>G (p.Cys62Gly)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
1469585	NM_001065.4(TNFRSF1A):c.305G>T (p.Cys102Phe)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
1509170	NM_001065.4(TNFRSF1A):c.172T>G (p.Cys58Gly)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
1917928	NM_001065.4(TNFRSF1A):c.349T>G (p.Cys117Gly)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
2682154	NM_001065.4(TNFRSF1A):c.950_951insTG (p.Tyr318fs)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
97663	NM_001065.4(TNFRSF1A):c.214T>C (p.Cys72Arg)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
97664	NM_001065.4(TNFRSF1A):c.215G>A (p.Cys72Tyr)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
97668	NM_001065.4(TNFRSF1A):c.241T>C (p.Cys81Arg)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
97672	NM_001065.4(TNFRSF1A):c.250T>C (p.Cys84Arg)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter
97694	NM_001065.4(TNFRSF1A):c.361C>T (p.Arg121Trp)	TNFRSF1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
97698	NM_001065.4(TNFRSF1A):c.380G>A (p.Cys127Tyr)	TNFRSF1A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TNFRSF1A	Definitive	Autosomal dominant	TNF receptor 1-associated periodic fever syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF1A	Orphanet:32960	Tumor necrosis factor receptor 1 associated periodic syndrome
TNFRSF1A	Orphanet:329967	Intermittent hydrarthrosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNFRSF1A	HGNC:11916	ENSG00000067182	P19438	Tumor necrosis factor receptor superfamily member 1A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF1A	Tumor necrosis factor receptor superfamily member 1A	Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF1A	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gall bladder	1
left uterine tube	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF1A	292	ubiquitous	marker	tendon of biceps brachii, gall bladder, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFRSF1A	4,523

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF1A	P19438	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR1-mediated ceramide production	1	1903.3×	0.004	TNFRSF1A
TNFR1-induced proapoptotic signaling	1	439.2×	0.004	TNFRSF1A
TNF signaling	1	423.0×	0.004	TNFRSF1A
TNFs bind their physiological receptors	1	393.8×	0.004	TNFRSF1A
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.004	TNFRSF1A
Interleukin-10 signaling	1	233.1×	0.004	TNFRSF1A
Regulation of TNFR1 signaling	1	223.9×	0.004	TNFRSF1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete positive regulation of amide metabolic process	1	8426.0×	0.001	TNFRSF1A
positive regulation of apoptotic process involved in morphogenesis	1	5617.3×	0.001	TNFRSF1A
obsolete regulation of membrane lipid metabolic process	1	5617.3×	0.001	TNFRSF1A
pulmonary valve development	1	4213.0×	0.001	TNFRSF1A
negative regulation of extracellular matrix constituent secretion	1	4213.0×	0.001	TNFRSF1A
aortic valve development	1	3370.4×	0.001	TNFRSF1A
positive regulation of lipid metabolic process	1	3370.4×	0.001	TNFRSF1A
regulation of establishment of endothelial barrier	1	1872.4×	0.002	TNFRSF1A
negative regulation of cardiac muscle hypertrophy	1	1123.5×	0.003	TNFRSF1A
prostaglandin metabolic process	1	842.6×	0.003	TNFRSF1A
positive regulation of execution phase of apoptosis	1	842.6×	0.003	TNFRSF1A
regulation of tumor necrosis factor-mediated signaling pathway	1	702.2×	0.003	TNFRSF1A
extrinsic apoptotic signaling pathway via death domain receptors	1	401.2×	0.006	TNFRSF1A
canonical NF-kappaB signal transduction	1	366.4×	0.006	TNFRSF1A
tumor necrosis factor-mediated signaling pathway	1	330.4×	0.006	TNFRSF1A
intrinsic apoptotic signaling pathway in response to DNA damage	1	324.1×	0.006	TNFRSF1A
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.006	TNFRSF1A
cellular response to mechanical stimulus	1	216.1×	0.007	TNFRSF1A
negative regulation of canonical NF-kappaB signal transduction	1	172.0×	0.009	TNFRSF1A
positive regulation of inflammatory response	1	145.3×	0.010	TNFRSF1A
negative regulation of inflammatory response	1	137.0×	0.010	TNFRSF1A
cytokine-mediated signaling pathway	1	130.6×	0.010	TNFRSF1A
protein polyubiquitination	1	115.4×	0.011	TNFRSF1A
protein localization to plasma membrane	1	108.7×	0.011	TNFRSF1A
defense response to bacterium	1	108.0×	0.011	TNFRSF1A
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.015	TNFRSF1A
transcription by RNA polymerase II	1	70.5×	0.015	TNFRSF1A
inflammatory response	1	37.7×	0.027	TNFRSF1A
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	TNFRSF1A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNFRSF1A	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
METOCHALCONE	2	TNFRSF1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TNFRSF1A	24	Binding:23, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
METOCHALCONE	2	TNFRSF1A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	TNFRSF1A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05857085	PHASE4	COMPLETED	Novel Therapeutics and Endothelial Dysfunction in T1DM Patients
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT05292768	Not specified	NOT_YET_RECRUITING	Are Mast Cells Involved in Autoinflammatory Diseases
NCT06838143	Not specified	RECRUITING	Ilaris NIS in Korea

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	1
EMPAGLIFLOZIN	4	1
GIVINOSTAT	4	1
CHEMBL5177502	0	1