Periodic fever syndromes

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, 2011.

What are periodic fever syndromes?

Periodic fever syndromes are conditions in which the patient experiences recurrent episodes of fever with associated inflammatory symptoms, in the absence of infection, allergy, malignancy, immunodeficiency or autoimmune conditions. They are one category of autoinflammatory syndromes.

Familial Mediterranean fever (FMF) is the most common and best known of the hereditary periodic fever syndromes. Inherited (genetic) forms of periodic fever syndromes are also known as hereditary recurrent fever syndromes. Nonfamilial syndromes have also been described.

What are the hereditary periodic fever syndromes, who gets them and why?

Periodic fever syndromes can be genetic conditions. Therefore some periodic fever syndromes are seen predominantly in specific racial groups. Familial Mediterranean fever, for example, affects races originating from around the eastern Mediterranean area.

The hereditary periodic fever syndromes can be classified by the type of inheritance:

Autosomal recessive periodic fever syndromes

Genetic conditions with this type of inheritance require two copies of the abnormal gene; one copy inherited from each parent. Although the defective gene is usually the same in each parent, the actual mutation may be different, i.e., heterogeneous homozygotes or compound heterozygotes. The parents are asymptomatic carriers of the defect.

Autosomal recessive periodic fever syndromes with skin involvement include:

Autosomal dominant periodic fever syndromes

Only a single copy of the defective gene is required to develop symptoms and signs of an autosomal dominant periodic fever syndrome. Therefore the condition is usually inherited from an affected parent or, less commonly, is due to a spontaneous mutation in the affected child.

Autosomal dominant periodic fever syndromes with skin involvement include:

Molecular biology of periodic fever syndromes

The defective gene has been identified for these hereditary periodic fever syndromes. The defective gene is different for each of the syndromes with the exception being the three clinically distinct syndromes that are now clustered as the cryopyrin-associated periodic syndromes (CAPS).

All periodic fever syndromes result in overstimulation of the innate immune system, usually due to over-activity of interleukin 1.

What are the nonhereditary periodic fever syndromes, who gets them and why?

Nonhereditary periodic fever syndromes with skin involvement include:

The cause of these syndromes is not yet known.

How do periodic fever syndromes present clinically?

The one clinical feature in common between all the periodic fever syndromes is the recurrent episodes of fever in the absence of infection, autoimmune disease or malignancy.

The frequency of febrile attacks can vary between individuals and syndromes from daily to once every ten years. The duration of the fever during an attak may be hours or be virtually continuous, but is usually typical for a particular syndrome. The height of the fever may range from a slight elevation of temperature to over 40 degrees Celsius.

The age at which the febrile attacks begin is also highly variable between the different syndromes with some beginning at or shortly after birth but others being delayed even as late as middle age.

In some periodic fever syndromes there are well-recognised triggers for a febrile attack, such as generalised exposure to cold triggering a fever in familial cold autoinflammatory syndrome (FCAS). But in others no trigger is identified.

Most periodic fever syndromes have associated symptoms and signs of inflammation at the same time as the fever. Commonly these affect the serosal surfaces, joints, eyes and skin. In some forms the predominant associated symptom is severe abdominal pain often leading to unnecessary exploratory surgery. In others, joint or neurological involvement can result in major disability.

Quality of life can be severely impacted, particularly if febrile attacks are frequent or in those forms of periodic fever syndrome that develop joint or neurological complications.

Secondary systemic amyloidosis develops in some periodic fever syndromes and this can result in life-threatening complications.

How are hereditary periodic fever syndromes diagnosed?

Periodic fever syndromes should be suspected clinically when the patient presents with recurrent episodes of fever associated with other inflammatory symptoms. However this can be difficult if the attacks are very infrequent, such once every few years, or continuous. A family history of such episodes is not always present, but is helpful if known.

Periodic fever syndromes can only be considered after infections, allergies, malignancy, immunodeficiencies and autoimmune diseases are excluded.

In children, it can be difficult to distinguish hereditary periodic fevers from the much commoner PFAPA syndrome as there are overlapping clinical features. The Gaslini score may help identify those most likely to benefit from genetic testing, and then to determine the order in which genes should be sequenced.

Some specific periodic fever syndromes can be diagnosed on biochemical testing or challenge with the known trigger. An example of the former is HIDS, which typically is associated with a very high level of IgD in the blood. Triggering of an attack within hours of generalised exposure to cold in FCAS is an example of the latter category.

Genetic testing is often definitive if positive, but not all mutations are known or easily tested for. A negative test does not exclude the diagnosis. In these cases, the diagnosis must be reached on clinical criteria. Genetic testing of the MEFV, TNFRSF1A and MVK genes detects a mutation in 20% of patients with clinical symptoms suggestive of a periodic fever syndrome.

A rapid and complete response to a trial of therapy may support the clinical diagnosis. Familial Mediterranean fever (FMF) responds to colchicine in over 90% of cases. Interleukin-1 blockade with biologic agents results in dramatic resolution of symptoms within hours of the first injection in some specific syndromes.

Treatment of hereditary periodic fever syndromes

Acute attacks of hereditary periodic fever syndromes are usually treated with bed rest, anti-inflammatory agents, analgesics and sometimes systemic corticosteroids. The fever does not respond to aspirin or paracetamol.

Avoidance of triggers, where known, can reduce the frequency of attacks. Sufferers of familial cold-associated syndrome (FCAS) often move to temperate climates to avoid cold winters and hot summers, for example.

To prevent febrile episodes, improve quality of life and minimise longterm complications, continuous treatment may be required for some forms. Apart from colchicine for familial Mediterranean fever, treatment of the hereditary periodic fever syndromes is with biologic agents such as anakinra, given by subcutaneous injection. Treatment should be started as early as possible to prevent the development of life-threatening complications in such periodic fever syndromes.

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