Cryopyrin-Associated Autoinflammatory Syndromes

Cryopyrin-associated autoinflammatory syndromes, also called cryopyrin-associated periodic syndromes, are a group of three diseases in which the protein called cryopyrin, or NLRP3, is defective. It is a relatively rare condition, occurring in less than one in 300,000 people. It covers a spectrum of severity, with the least severe being familial cold autoinflammatory syndrome (FCAS). The most severe is neonatal onset multisystem inflammatory disease (NOMID), occurring in the neonatal period. The third disorder is called Muckle-Wells syndrome (MWS).

There is no significant difference in the incidence between males and females, or between different ethnic groups.

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Neonatal onset multisystem inflammatory disease

NOMID is fortunately the least common of all the CAPS, and presents as fever associated with inflammation in several organs. Its features comprise fever, joint disease and urticaria. They are seen to begin soon after the affected baby’s birth, when the temperature goes up, often with an associated urticaria-like rash, but no sign of infection.

Other clinical features include chronic meningitis resulting in blindness, hearing loss, bulging eyes, and vomiting. If the condition is not treated, half these children experience arthralgia and the bones of the large joints become swollen. The most commonly affected is the knee joint. Patients experience joint deformities and neurologic damage. Growth delay may occur causing markedly short stature. Of course, the symptoms may occur in various combinations.

Muckle-Wells syndrome

In this condition the patient has regular bouts of fever with chills, rashes, red eyes, joint pain and intense headache. The stimulus for these symptoms is often exposure to cold. The symptoms resolve within three days at most. However, the inflammation producing the fever often leads to partial or total hearing loss by the time the patient enters adolescence. In the long term, if left untreated, this condition could lead to amyloidosis.

Cryopyrin Associated Periodic Syndrome (CAPS)

Familial cold autoinflammatory syndrome

With FCAS, the patient cannot tolerate air-conditioning or other cold environments, which trigger urticaria-like rashes, fever with chills, nausea, headache and arthralgia, lasting for a day or so. However, the patient remains healthy between episodes.

What is the etiology of CAPS?

CAPS is caused by a mutation in the gene encoding the protein cryopyrin, which regulates the inflammatory cascade by forming bodies called inflammasomes. Defective production of these causes oversecretion of an inflammatory chemical called interleukin-1, resulting in systemic manifestations of inflammation.

It is transmitted as an autosomal dominant trait, which means that only one parent needs to pass on a defective copy of the gene to have it expressed in the offspring.

Sometimes the mutation is absent in both parents, which means the mutation occurred in the affected child and was not genetically transmitted.

The presence of the mutation is found in almost 100% of patients with FCAS, up to 75% of patients with MWS, and about 60% of patients with NOMID.

Diagnosis and management of CAPS

A careful history, followed by the examination of the patient during a bout of fever, will usually indicate the diagnosis of CAPS.

Blood tests confirm the presence of severe inflammation during these acute episodes. Genetic testing is usually confirmatory, but sometimes false-negatives are reported.

Other investigations that may be ordered as required include skin biopsy, ocular and auditory examination, lumbar puncture, and magnetic resonance imaging (MRI) of the inner ear and brain.

Treatment of CAPS

The best treatment for CAPS consists of biologics which interrupt the pathway of inflammation caused by exaggerated interleukin-1 production. These must be given throughout life since the condition is not curable. Early diagnosis and treatment are essential to prevent or minimize damage to multiple organs, including the brain, ears, eyes and joints.

If brain involvement such as meningitis is present, more intensive protocols are followed.

In all cases, physical therapy is important in preventing and treating joint deformities. Surgery is required in some cases to correct the problem, while deafness may be countered by hearing aids.

Self-care could include moving to a location with a mild climate to avoid cold air triggers. Support is essential for both caregivers and patients to live as fully as possible, a task made easier by today’s effective medications.

Treatments for patients with cryopyrin-associated periodic syndromes (CAPS)

Further Reading

Last Updated: May 14, 2019

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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