Tumor necrosis factor receptor-associated periodic syndrome

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Disease Profile

Unknown

US Estimated

Europe Estimated

Age of onset

Childhood

ICD-10

E85.0

Inheritance

TRAPS is inherited in an autosomal dominant manner. This means that having a mutation in only one of the 2 copies of the responsible gene is enough to cause signs and symptoms of the condition. When a person with an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit the mutated copy of the gene. In many cases, a person with TRAPS inherits the condition from an affected parent. In other cases, the mutation occurs for the first time in the affected person and is not inherited from a parent. For unknown reasons, some people who inherit the mutated gene never develop features of TRAPS. When this occurs, a condition is said to have reduced penetrance.^[1]

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

FPF; Familial Hibernian fever; FHF;

Summary

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an inherited condition characterized by recurrent episodes of fever. Episodes can begin at any age but most often begin in early childhood. Fevers typically last about 3 weeks but can last from a few days to a few months. The amount of time between episodes may vary from weeks to years. Episodes usually occur spontaneously, but are sometimes brought on by a variety of triggers (such as injury, infection, or stress). Symptoms during fever episodes may include abdominal, muscle or joint pains; skin rashes (usually on the limbs); puffiness around the eyes; and inflammation in various areas of the body. Some people develop amyloidosis.^[1] TRAPS is caused by mutations in the TNFRSF1A gene and is inherited in an autosomal dominant manner.^[1]^[2] Treatment may include systemic corticosteroids at the beginning of an episode to reduce its severity and duration.^[2]

Symptoms

The characteristic feature of TRAPS is recurrent episodes of fever. Episodes may begin at any age, but most often begin in early childhood. Fevers usually last around 3 weeks but can last from days to months. The time between episodes can vary considerably from weeks to years. Fevers are often associated with other symptoms, which may include muscle, joint, and/or abdominal pain; a spreading rash; puffiness and/or swelling around the eyes; and/or inflammation in various other areas of the body including the heart muscle, joints, throat, or mucous membranes.^[3]^[1] About 25% of people with TRAPS develop amyloidosis, which can lead to kidney or liver failure.^[1]^[2]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Abdominal pain	Pain in stomach Stomach pain [ more ]	0002027
Diarrhea	Watery stool	0002014
Elevated C-reactive protein level		0011227
Elevated erythrocyte sedimentation rate	High ESR	0003565
Erysipelas		0001055
Myalgia	Muscle ache Muscle pain [ more ]	0003326
Pericarditis	Swelling or irritation of membrane around heart	0001701
Recurrent fever	Episodic fever Intermittent fever Increased body temperature, episodic [ more ]	0001954
Skin rash		0000988
30%-79% of people have these symptoms
Arthritis	Joint inflammation	0001369
Constipation		0002019
Erythema		0010783
Intestinal obstruction	Bowel obstruction Intestinal blockage [ more ]	0005214
Leukocytosis	Elevated white blood count High white blood count Increased blood leukocyte number [ more ]	0001974
Lymphadenopathy	Swollen lymph nodes	0002716
Orchitis	Inflammation of testicles	0100796
Pleuritis	Inflammation of tissues lining lungs and chest	0002102
Splenomegaly	Increased spleen size	0001744
Vomiting	Throwing up	0002013
5%-29% of people have these symptoms
Abnormal myocardium morphology		0001637
Abnormality of the sacroiliac joint		0100781
Arthralgia	Joint pain	0002829
Behavioral abnormality	Behavioral changes Behavioral disorders Behavioral disturbances Behavioral problems Behavioral/psychiatric abnormalities Behavioural/Psychiatric abnormality Psychiatric disorders Psychiatric disturbances [ more ]	0000708
Bruising susceptibility	Bruise easily Easy bruisability Easy bruising [ more ]	0000978
Cellulitis	Bacterial infection of skin Skin infection [ more ]	0100658
Chest pain		0100749
Conjunctivitis	Pink eye	0000509
Cranial nerve paralysis		0006824
Fasciitis	Inflammation of the fascia	0100537
Hypermelanotic macule	Hyperpigmented spots	0001034
Migraine	Intermittent migraine headaches Migraine headache Migraine headaches [ more ]	0002076
Myositis	Muscle inflammation	0100614
Paresthesia	Pins and needles feeling Tingling [ more ]	0003401
Periorbital edema		0100539
Peritonitis		0002586
Recurrent pharyngitis	Recurrent sore throat	0100776
Uveitis		0000554
Vasculitis	Inflammation of blood vessel	0002633
Vertigo	Dizzy spell	0002321
1%-4% of people have these symptoms
Bone pain		0002653
Cervical lymphadenopathy	Swollen lymph nodes in the neck	0025289
Chronic constipation	Infrequent bowel movements	0012450
Chronic diarrhea		0002028
Conjunctival hyperemia		0030953
Gastrointestinal hemorrhage	Gastrointestinal bleeding	0002239
Headache	Headaches	0002315
Hepatomegaly	Enlarged liver	0002240
Maculopapular exanthema		0040186
Oligoarthritis		0040313
Polyarticular arthritis		0005764
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance		0000006
Hepatic amyloidosis		0012280
Muscle stiffness		0003552

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Cause

TRAPS is a genetic condition caused by mutations in a gene called TNFRSF1A. This gene gives the body instructions to make a protein called tumor necrosis factor receptor 1 (TNFR1). This protein exists in cell membranes where it binds to another protein called tumor necrosis factor (TNF). The binding sends signals that tell the cells to trigger inflammation (producing immune system proteins) or self-destruct.

Most TNFRSF1A gene mutations that cause TRAPS result in incorrectly-shaped TNFR1 proteins, which become trapped in cells and cannot reach the surface to bind with TNF. The trapped proteins then clump together and are thought to trigger other pathways involved in causing inflammation. Affected people typically have a mutation in only one of their 2 copies of the TNFRSF1A gene, so some normal TNFR1 proteins are still produced, leading to even more inflammation. This is what leads to excess inflammation in people with TRAPS. It is unclear if abnormalities in the cells' ability to self-destruct also plays a role in causing the features of TRAPS.^[1]

Treatment

While there is no proven treatment for TRAPS, non steroidal anti-inflammatory drugs (NSAIDS) may be used to relieve symptoms of fever, and corticosteroids may be used to reduce severity of symptoms in most people. However, these medications typically don't decrease the frequency of attacks. Etanercept, a TNF inhibitor, has been shown to be effective but its efficacy tends to wane over time. Standard doses of etanercept twice a week have been shown to decrease the frequency, duration, and severity of attacks in some people and it may also reverse or slow the progression of amyloidosis. More studies are needed to evaluate this medication for TRAPS.^[4]^[5]

Additional information about the treatment of TRAPS can be viewed on Medscape's Web site.

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Canakinumab(Brand name: Ilaris) Manufactured by Novartis Pharmaceuticals Corporation
FDA-approved indication: Treatment for Familial Mediterranean Fever (FMF) in adult and pediatric patients; for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients; and for Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.
National Library of Medicine Drug Information Portal

Related diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes other diseases characterized by periodic fever such as familial cold urticaria, juvenile idiopathic arthritis, Behçet disease, PFAPA syndrome, and Muckle-Wells syndrome (see these terms). Visit the Orphanet disease page for more information.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

FMF & AID Global Association
Schüracherstrasse 25a
8306 Brüttisellen
Switzerland
Telephone: +41 76 415 4010
E-mail: info@fmfandaid.org
Website: https://www.fmfandaid.org/

Social Networking Websites

RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The Cleveland Clinic provides an overview of the different types of periodic fever syndromes.
DermNet NZ is an online resource about skin diseases developed by the New Zealand Dermatological Society Incorporated. DermNet NZ provides information about this condition.
Genetics Home Reference (GHR) contains information on Tumor necrosis factor receptor-associated periodic syndrome. This website is maintained by the National Library of Medicine.
The Merck Manuals Online Medical Library provides information on this condition for patients and caregivers.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Tumor necrosis factor receptor-associated periodic syndrome. Click on the link to view a sample search on this topic.

References

Tumor necrosis factor receptor-associated periodic syndrome. Genetics Home Reference. August, 2011; https://ghr.nlm.nih.gov/condition/tumor-necrosis-factor-receptor-associated-periodic-syndrome.
Delwyn Dyall-Smith. Tumour necrosis factor receptor-associated periodic syndrome. DermNet NZ. December 15, 2014; https://dermnetnz.org/systemic/traps.html.
Periodic Fever Syndromes. Cleveland Clinic Department of Rheumatic and Immunologic Diseases. 2009; https://my.clevelandclinic.org/disorders/periodic_fever_syndrome/rheumatology_overview.aspx. Accessed 1/9/2009.
Marco Gattorno. Tumor necrosis factor receptor 1 associated periodic syndrome. Orphanet. September, 2014; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=32960.
Shinawi M. Hereditary Periodic Fever Syndromes. Medscape. January 11, 2013; https://emedicine.medscape.com/article/952254-overview#a4.

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