Periodic Fever Syndrome

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(Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) , Hyperimmunoglobulin D syndrome (HIDS), also called Mevalonate Kinase Associated Periodic Fever Syndrome, Neonatal Onset Multisystem Inflammatory Disease (NOMID), in Europe called Chronic Inflammatory Neurological Cutaneous Articular (CINCA) syndrome and related diseases, Muckle-Wells syndrome and Familial Cold auto inflammatory syndrome and Periodic fever, Aphthous-stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome)

These syndromes refer to diseases that cause periodic (episodic) fever that do not have an infectious (virus, bacteria) cause. In general children with these syndromes are well between episodes. Many of these syndromes are hereditary (passed down from parents) and result from a mutation (defect or mistake) in a gene (this is the code that determines the structure of our proteins). The syndromes are defined by the gene defect as well as by the clinical features of the syndrome, the parts of the body affected in addition to fever, the age of the child when the syndrome starts, and the ethnicity (the area of the world where the child or parents come from) of the child and parents. Many of these syndromes have a specific treatment, often based on understanding the problem caused by the genetic defect.

Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is the most common periodic fever syndrome. Patients suffer from recurrent episodes of fever, accompanied by abdominal, chest and joint pain and swelling. The disease generally affects people of Mediterranean and Middle Eastern descent, typically Sephardic Jews, Turks, Arabs and Armenians. Since the discovery of the gene defect, it is being diagnosed more frequently, even among populations where it was thought to be very rare, such as Italians, Greeks and Ashkenazi Jews. FMF episodes start before the age of 20 years in approximately 90% of the patients. In more than half of them the disease appears before the age of 10 years.

What causes the disease?

FMF is a genetic disease. The responsible gene is called the MEFV gene , named after the Mediterranean Sea, and it affects a protein called pyrin, which plays a role in the natural control of inflammation. When this gene has a defect, the regulation of inflammation cannot be done properly and patients experience episodes of fever and other symptoms. Infection, trauma, menses (“periods”) or psychological stress may trigger episodes.

How is it inherited?

FMF is inherited as an autosomal recessive disease (which means that while the child may have the disease neither parent needs to show symptoms of the disease). In this case, the child receives two mutated genes, one from the mother and the other from the father. The parents are then called carriers. Often somebody in the extended family has the disease. If one child has the disease and the parents are carriers there is a 25% chance another child will get FMF. If one of the children has FMF and also one of the parents has FMF there is a 50% chance of another child getting FMF.

Is FMF contagious?

The fever of FMF is not contagious.

What are the main symptoms?

The main symptoms of the disease are recurrent fever, accompanied by abdominal, chest, or joint pains. Not all children will have all symptoms and symptoms may change over time. Episodes resolve without treatment and usually last between one and four days. Most children are totally normal between episodes, but some children have such frequent episodes they do not fully recover or do not grow properly. Some of the attacks may be so painful that the patient or family seeks medical help in the emergency department. For example, severe abdominal attacks may mimic acute appendicitis and therefore some patients may undergo abdominal surgery, such as an appendectomy. The chest pain may be so severe that it may be difficult to breathe deeply.

Usually, only one joint is affected at a time, most commonly an ankle or a knee. The joint may be so swollen and painful that the child cannot walk. In about a third of these patients there is a red rash over the involved joint. In some children, the sole finding of the disease may be episodes of joint pain and swelling, which is misdiagnosed as acute rheumatic fever, or juvenile idiopathic arthritis. Usually the joint swelling resolves over 5-14 days. In about 5-10% of cases the joint involvement may become chronic. Some children report muscle pain in the legs.

Rarely, children have recurrent pericarditis (inflammation of the outer layer of the heart), myositis (muscle inflammation), meningitis (inflammation of the membrane surrounding the brain and spinal cord) and orchitis (testicular inflammation). Frequent attacks can affect the child's and family’s life, including school attendance.

The most severe complication of FMF if untreated is the development of amyloidosis. Amyloid is a protein that deposits in certain organs in children with chronic inflammatory diseases that are not well controlled. The most common organ involved is the kidney, but amyloid can deposit in the gut, skin and heart. Eventually amyloid causes a loss of function, especially of the kidneys. Children who are properly treated (see below under medications) are safe from the risk of developing this life-threatening complication.

Can FMF appear or be active in adults?

Yes, but often the disease is milder and less obvious (thus harder to diagnose) than in children. The risk of amyloidosis is lower in adult onset disease.

How is it diagnosed?

Despite the knowledge that FMF is a genetic disease, a genetic mutation is not found in all children with FMF. Therefore the diagnosis of FMF is still based on clinical signs. FMF is suspected in children with episodic fever with an ethnic origin typical for FMF and/or with a family history of FMF or unexplained kidney failure. Often children initially have episodes of fever without the other symptoms so it takes careful observation (families should write a diary documenting the episodes and describing what happens) until a diagnosis is made. Because not all children have typical episodes it may take a long time to suspect FMF and to make the diagnosis. Examining the child during an episode and obtaining laboratory tests showing signs of inflammation are helpful (like tests for a sedimentation rate or a complete blood cell count). Generally, these tests become positive during an episode and return to normal, or near normal, after the episode ends. A sample of urine is also tested for the presence of protein. Patients with amyloidosis will have high levels of protein in urine tests. This warns the physician to do more tests to see if the protein in the urine is from amyloidosis.

In children suspected of having FMF, a genetic test to look for the gene mutation will be obtained. If these tests are positive (homozygote, which means that the gene defect is found in both gene copies, one from each parent), the diagnosis of FMF is definite. However, it is possible to have FMF with a defect in only one gene copy (called heterozygote) or even without any gene defect, since the genetic test looks at only part of the entire FMF gene. In the United States more than 30% of the patients with FMF do not have mutations in both gene copies. In that case the response to the specific FMF treatment, colchicine, will determine the diagnosis. It is highly probable that children have FMF if they do not have episodes or have a lot fewer episodes when they are being treated with colchicine. Usually a trial of 6 months of treatment is given.

How is it treated?

FMF cannot be cured, but it can be well controlled with life-long use of colchicine. In this way, episodes can usually be prevented (in 60% of patients completely prevented, in 33% partially prevented, and in about 5% colchicine is not effective) and amyloidosis can be prevented in 100% of patients. If the patient stops taking the drug, episodes (often after missing only one dose!) and the risk of amyloidosis may return. Compliance (taking the medicine as recommended) is very important. If colchicine is taken regularly the child can live a normal life with a normal life expectancy. The patient or the parents should not change the medication dose without discussing this first with the doctor. Some children initially need psychological support for a disease that means taking medications for their entire life. Colchicine prevents episodes from starting but does not treat an episode that has already started. Therefore, the dose of colchicine should not be increased during an already active episode.

What are the side effects?

Colchicine is a safe drug with minor side effects that usually respond to dose reduction or other methods of treatment. The most frequent side effect is diarrhea. Some children cannot tolerate the given dose because of frequent watery stools. In these cases, the dose should be reduced until it is tolerated and then slowly increased back to the appropriate dose. Other methods include reducing the intake of milk or dairy products and sometimes it is necessary to give a medicine to treat diarrhea (like Imodium). Other side effects are nausea, vomiting, and abdominal cramps. In rare cases, it may cause muscle weakness. The blood count (white and red blood cells and platelets) may decrease occasionally, but recovers with dose reduction. Children taking colchicine grow normally. A decrease in the sperm count later in life is very rare. Female patients do not have to stop taking colchicine during pregnancy or breast-feeding, but amniocentesis (obtaining fluid from the fluid surrounding the fetus) is recommended. Children treated with colchicine should have blood count and urine tests at least twice a year.

What is the long-term outcome and course of the disease?

If treated properly with life-long colchicine, children with FMF live a normal life. If there is a delay in diagnosis, or lack of compliance with treatment, the risk of developing amyloidosis increases. Children who develop amyloidosis may eventually need dialysis or a kidney transplant. There are no restrictions on the child’s everyday life.

Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)

TRAPS is a genetic disease with an autosomal dominant (one gene defect is enough to result in having the disease) inheritance. That means that either one of the parents is ill with a variant of the disease or that the gene defect was newly formed in the child with the disease (de novo mutation). Besides episodes of fever, other symptoms include abdominal pain, diarrhea, migratory (moves from one place to another) painful red skin rashes, muscle pain and swelling around the eye. The gene defect was only recently discovered. The former name of this syndrome was Familial Hibernian fever.

How common is it?

TRAPS is a rare disease but since the gene defect was discovered more patients with different clinical features have been discovered. Thus, the actual frequency is still unknown. It affects males and females equally and the onset seems to be during late childhood, or adulthood.
The first cases were reported in patients from Irish-Scottish ancestry; however the disease has also been identified in almost all ethnic groups.

What causes TRAPS?

TRAPS is due to a gene defect in a protein called Tumor Necrosis Factor Receptor (TNFR), which leads to an increase of the patient’s normal inflammatory response. The protein that causes inflammation, called tumor necrosis factor (TNF), overacts, since the receptor (TNFR) that usually binds to TNF is not present to control its activity. Infection, trauma or psychological stress may trigger episodes. However, not every person that has a gene defect will have the clinical signs of TRAPS.

Is it contagious?

No. It is a genetic disease.

What are the main symptoms?

The main symptoms are recurrent episodes of fever typically lasting two or three weeks, associated with chills and intense muscle pain involving the trunk and the upper limbs. The typical rash is red and painful, representing underlying inflammation of the skin and muscle. The rash moves from one place to another on the body, usually from the arms and legs to the trunk. Most patients feel cramping muscle pain at the onset of attacks that gradually increases in strength and also moves from one part of the body to another. Abdominal pain with nausea and vomiting are common. Inflammation of the membrane covering the front of the eye (conjunctiva), and/or swelling around the eye is common. Other less common features include chest pain, due to inflammation of the pleura (the membrane surrounding the lungs), or the pericardium (the membrane surrounding the heart). Like FMF (see above) amyloidosis is the most severe late complication of TRAPS and often results in large amounts of proteins in the urine and kidney failure. The disease symptoms vary from person to person, as well as the length of episodes and the time between episodes. The reasons for these differences are based in part on differences in the specific gene defect.

How is it diagnosed?

An expert physician will suspect TRAPS based on the clinical symptoms identified, the physical examination and from taking a family medical history. Blood tests will show signs of inflammation during an episode. The diagnosis is confirmed only by genetic tests showing a genetic defect in the TNFR gene. The physician will probably test for other types of periodic fever syndromes.

What are the treatments?

There is still no proven definitive treatment to prevent or cure the disease. Non-specific anti-inflammatory agents, including steroid use, help to relieve symptoms, but long-term steroid use leads to serious side effects. Giving a medicine that is similar to the TNF receptor called Enbrel (a medicine used to treat juvenile idiopathic arthritis) has been shown to be an effective treatment in some patients when given at the beginning of an attack or even as preventive medicine.

How long will the disease last?

Patients with TRAPS will have episodes of symptoms throughout their life.

What is the long-term outcome and course of TRAPS?

It is hard to predict the outcome in any one patient since amyloidosis appears in only a minority of patients. This risk is dependent in part on the genetic defect and on other unclear environmental factors.

Hyperimmunoglobulin D syndrome (HIDS), also called Mevalonate Kinase Associated Periodic Fever Syndrome

HIDS is a autosomal recessive (which means that while the child is sick neither parent needs to show symptoms of the disease) genetic syndrome that results in episodic high fever with skin rash, swelling of lymph nodes (glands that are part of the immune system) in the neck, abdominal pain, vomiting and diarrhea. The disease starts early in infancy. The name of this disease comes from the fact that most patients have very high amounts of immunoglobulin (proteins that are part of the immune system) of type D. The most severe form of this disease starts at birth and is called mevalonic aciduria. These patients also have neurologic (nervous system) disease and suffer from poor growth. We will describe here the more mild form of this disease since it is only this form that starts with episodes of fever.

How common is it?

HIDS is a very rare disease. The disease is mostly found in Western Europe, especially in the Netherlands and in France but has been described in all ethnic groups. Boys and girls are equally affected. Symptoms usually start in early childhood, most commonly in the first year of life.

What are the causes HIDS?

HIDS is a genetic disease. The gene defect is in a protein called mevalonic kinase (MVK). MVK is a protein that facilitates a chemical reaction in the body (enzyme) involved in the process of making cholesterol. In HIDS the MVK enzyme is active in only 1-10% of the normal enzyme activity. We still do not know why the gene defect causes fever. Episodes can be triggered by infection, stress, and vaccination or without any obvious trigger. HIDS is inherited in an autosomal recessive way (which means that while the child is sick neither parent needs to show symptoms of the disease). In that case, the child receives two mutated genes, one from the mother and the other from the father. The parents are then called carriers. Often somebody in the extended family has the disease. If one child has the disease and the parents are carriers there is a 25% chance another child will get HIDS.

Is it contagious?

No, the fever of HIDS is not contagious.

What are the main symptoms?

Fever episodes are the major symptom, lasting three to seven days and recurring every 2-12 weeks. The attacks begin suddenly, often with shaking chills. Headache, abdominal pain, loss of appetite and flu-like symptoms are common. Most patients experience nausea, vomiting or diarrhea. Skin rashes, painful ulcers in the mouth and joint pain all occur, but the most striking feature is swelling of the lymph nodes in the neck, or other parts of the body. The disease symptoms and severity can differ from patient to patient.

How is it diagnosed?

It usually takes a physician expert in this disease to diagnose HIDS. The disease is suspected in patients with the symptoms listed above. Blood tests showing signs of inflammation during an episode are usually seen. Most (but not all, especially very young patients) have elevated levels of immunoglobulin D. During episodes, a urine test for organic acid (these are acids in the body that have the carbon atom in them) will show high levels of mevalonic acid. The diagnosis will be confirmed by a genetic test finding the genetic defect in the MVK protein or by showing low levels of MVK activity in blood cells.

Can it be treated or cured?

HIDS cannot be cured. An effective treatment to prevent attacks is not available. Research is being done to search for effective treatments. During an episode non-steroidal anti-inflammatory drugs (like ibuprofen, naproxen) or steroids may be partially helpful.

How long will the disease last and what is the outcome?

HIDS is a lifelong disorder but episodes usually get milder and less frequent over time, often resolving later in life. Some patients develop arthritis. Except for amyloidosis in very rare cases, HIDS does not lead to severe organ damage.

Neonatal Onset Multisystem Inflammatory Disease (NOMID), in Europe called Chronic Inflammatory Neurological Cutaneous Articular (CINCA) syndrome and related diseases

NOMID is a rare genetic disease causing episodes of fever. The symptoms start at birth, or are observed within the first weeks of life. The first symptoms are usually a skin rash and fever. Infants also have neurologic symptoms, such as chronic meningitis (inflammation of the membranes surrounding the brain), hearing and vision loss. About 50% of the children later develop severe joint involvement and have significant growth abnormalities. Two other less severe diseases that are caused by defects on the same gene of NOMID are called Muckle-Wells syndrome (MWS) and familial cold auto inflammatory – also called familial cold urticaria - syndrome (FCAS). These diseases start later in life. The entire group of these diseases are now called the cryopyrin- associated auto inflammatory diseases.

How common is it?

NOMID is a very rare condition. MWS and FCAS are probably seen more frequently but are still rare.

What are the causes of the disease?

NOMID is a genetic disease. The disease is inherited as an autosomal dominant disease. That means that either one of the parents is ill with a variant of the disease or that the gene defect was newly formed in the sick child (de novo mutation). A genetic defect is found in only 50% of patients. The gene defect is in a protein called cryopyrin, which has the important task of controlling inflammation in the body. NOMID occurs equally in males and females. It has been observed in all populations, Caucasian, black or Asiatic. There is no seasonal influence.

Is it contagious?

No, the fever of NOMID is not contagious.

What are the main symptoms?

Some of the infants with NOMID are born prematurely. The babies often have signs of infection (fever, rash) at birth but no infection is found. The rash resembles urticaria (hives), but is not itchy. The rash increases in intensity with fever. Patients have neurologic problems from chronic meningitis (inflammation of the membranes surrounding the brain). This can result in vision difficulties, hearing loss and other neurologic problems. The eyes often appear as bulging and children often have episodes of vomiting. The skull is often slightly increased in size. In some children, there is delayed closure of the anterior fontanel (the soft part in the skull of infants where the skull bones attach to each other). Later they complain of headaches. Later (usually after 1 year of age) patients develop joint pain and swelling. In severe cases an overgrowth of cartilage and of the bone epiphysis (the ends of the bone), especially at the knee, may occur, resulting in joint deformity. These bone changes are seen in X-rays. There is a delay in growth and the children with NOMID are often very short. In older children, the hands appear short and wide and there may be clubbing (widening) of the finger and toe tips. Not all children have all these symptoms.

How is it diagnosed?

NOMID is suspected by the clinical features. The diagnosis is confirmed by the genetic test. However, 50% of the children do not have a genetic mutation.

How is it treated?

Until recently there was no effective treatment. Patients were treated with medications to reduce symptoms like nonsteroidal anti-inflammatory drugs, steroids or methotrexate. Exciting recent research has shown that medications that target specific molecules involved in the inflammatory process that may be increased in NOMID due to the genetic defect may be very effective for treating NOMID. Initial studies have shown that most NOMID patients respond dramatically to treatment with Kineret. However this treatment must continue indefinitely as there is no known cure to NOMID.

Physical therapy, splints and other aids are necessary to treat joint deformities if they occur. Splints and walking aids might be necessary. Surgery is occasionally needed to correct these deformities. Hearing aids are needed for children with deafness.

What is the long-term outcome of the disease?

The outcome of NOMID used to be poor, with severe growth disturbances. Many patients developed severe joint deformities and neurologic damage, mainly to the ears and eyes. There were also cases of death from brain damage. New treatment may have changed this poor outcome. Future studies are planned to answer this question.

Muckle-Wells syndrome and Familial Cold auto inflammatory syndrome

These syndromes are related to gene defects on the same cryopyrin protein gene causing NOMID. As in NOMID, no gene defect is found in about 50% of the patients. These syndromes occur later in life than NOMID and are milder. In familial cold auto inflammatory syndrome, cold, and perhaps other environmental triggers, causes a hive (urticaria) like rash to occur.

In Muckle-Wells syndrome patients also develop episodic fever and deafness. In both syndromes untreated patients often develop amyloidosis. Amyloid is a protein that deposits in certain organs in children with chronic inflammatory diseases that are not well controlled. The most common organ involved is the kidney, but amyloid can deposit in the gut, skin and heart. Eventually amyloid causes a loss of function, especially of the kidneys. As in NOMID, recent studies have shown that the use of Kineret for these syndromes is very effective.

Periodic fever, Aphthous-stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome

This syndrome includes recurrent episodes of fever with aphthous-stomatitis (mouth sores), pharyngitis (sore throat with redness and sometimes a throat that has a white covering – exudate - like that seen in a throat with streptococcal infection. PFAPA affects children in early childhood, usually starting at age two to four years. Episodes usually decrease in frequency and resolve after the age of 10 years. This disease was recognized for the first time in 1987 and was called Marshall’s.

How common is it?

The frequency of PFAPA is not known, but the disease appears to be more common than generally appreciated.

What causes PFAPA?

The answer to this question is not yet known. No gene defect has yet to be found in PFAPA, although in some cases more than one family member has the disease. No infectious cause has been found in PFAPA, thus it is not a contagious disease. It is clear that the inflammatory process is activated during episodes but it is not clear why it is triggered.

What are the main symptoms?

The main symptoms are episodic fevers, accompanied by a sore throat, mouth ulcers, or enlarged cervical lymph nodes (glands in the neck, an important part of the immune system). The episodes of fever start abruptly and last for three to seven days. During episodes, the child looks very ill and complains about at least one of the three symptoms mentioned above. The episodes of fever recur every few weeks and often families know the exact day when an attack will start. On the day the fever starts the child will feel a little ill before the attack and the family knows an attack is about to start. Not all children have all symptoms, especially mouth sores. Some children have other symptoms like joint pain, abdominal pain, headache, vomiting or diarrhea.

How is PFAPA diagnosed?

There are no laboratory tests, or imaging procedures, specific for diagnosing PFAPA. The disease will be diagnosed based on the results of a physical examination and other symptoms. Inflammatory blood tests like the white blood cell count, erythrocyte sedimentation rate and the C-reactive protein are increased during attacks. Before the diagnosis is confirmed, it is important to exclude all other diseases that may present with similar symptoms (especially a streptococcal throat). The dramatic response to treatment (see below) also helps diagnose PFAPA.

How is PFAPA treated?

There is no specific treatment to cure PFAPA. The aim of treatment is to control symptoms during the episodes of fever, to shorten the duration of episodes, and in some children to prevent attacks from occurring. In most children, the disease will resolve by itself without treatment, usually after the age of 10 years. The fever does not usually respond well to Tylenol or nonsteroidal anti-inflammatory drugs. A single dose of steroids (usually prednisone), given when symptoms first appear, has been shown to shorten an episode and sometimes even end the episode. However, the interval between episodes may also be shortened with this treatment, and the next episode may occur earlier than expected. In some patients using cimetidine (a medicine that is used to treat stomach ulcers) may prevents attacks from occurring. In patients with very frequent attacks, a tonsillectomy (removing the tonsils by surgery) may be considered.

What is the outcome and course of PFAPA?

The disease may last for several years. Over time, the intervals between the episodes will increase and usually after the age of 10 years resolve by itself. Children with PFAPA continue to grow and develop normally.

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