Cryopyrin-associated periodic syndrome overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]
Overview
Cryopyrin-associated periodic syndrome (CAPS) is a rare disease entity encompassing three different clinical phenotypes including Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disorder (NOMID), and familial cold autoinflammatory syndrome (FCAS). The three aforementioned phenotypes occur due to a common gene mutation.
Historical Perspective
In 1940, Dr. Kile first described Familial cold autoinflammatory syndrome (FCAS) in a family presenting with recurrent urticaria, arthralgia, and fever after general exposure to cold. In 1962, Muckle-Wells syndrome (MWS), the intermediate phenotype of cryopyrin-associated periodic syndrome (CAPS), in terms of severity, was first described by Muckle and Wells. The association between NLRP3 gene and MWS was made in 1999 by Dr. Cuisset. Neonatal-onset multi-system inflammatory disease (NOMID), the most severe phenotype of CAPS, first discovered by Dr. Lorber in 1973. CAPS was first described by Dr. Hoffman, in 2001, following the identification of the NLRP3 gene as the causative mutant gene in families with Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).
Classification
The cryopyrin-associated periodic syndrome may be classified according to clinical phenotype into three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID)
Pathophysiology
The exact pathogenesis of cryopyrin-associated periodic syndrome is not fully understood. However, it occurs due to the dysregulation of innate immune system. NLRP3 gene encoding a protein called cryopyrin involved in the pathogenesis of this disorder.
Causes
Cryopyrin-associated periodic syndrome is caused by a mutation in the NLRP3, also known as CIAS1, gene.
Differentiating cryopyrin-associated periodic syndrome from Other Diseases
Cryopyrin-associated periodic syndrome must be differentiated from other diseases that cause fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling.
Epidemiology and Demographics
The incidence cryopyrin-associated periodic syndrome is approximately 0.0343 per 100,000 individuals aged 16 years old or younger worldwide. The prevalence of cryopyrin-associated periodic syndrome is approximately 0.1 per 100,000 individuals worldwide. CAPS is usually first presented in the infancy. There is no racial predilection to cryopyrin-associated periodic syndrome. Cryopyrin-associated periodic syndrome affects men and women equally. The majority of CAPS cases are reported in Europe.
Risk Factors
There are no established risk factors for the cryopyrin-associated periodic syndrome.
Screening
There is insufficient evidence to recommend routine screening for the cryopyrin-associated periodic syndrome.
Natural History, Complications, and Prognosis
The symptoms of neonatal-onset multisystem inflammatory disease (NOMID) usually develops during infancy, and start with symptoms such as continuous often low-grade fever, skin rash, neurological involvement, and arthropathy. Some of the possible complications include, renal failure, amyloidosis, and destructive arthropathy. Prognosis of cryopyrin-associated periodic syndrome varies according to the clinical phenotype and other factors.
Diagnosis
Diagnostic Study of Choice
Cryopyrin-associated periodic syndrome is primarily diagnosed based on the clinical presentation. Genetic analysis of NLRP3 gene is the gold standard test for the diagnosis.
History and Symptoms
The cryopyrin-associated periodic syndrome is a spectrum of three different clinical phenotypes with the mildest form being familial cold autoinflammatory syndrome (FCAS), formerly called familial cold urticaria and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic cutaneous and articular (CINCA) as the most severe form. Muckle-Wells syndrome (MWS) is the intermediate form of the disease in terms of severity. Symptoms of the cryopyrin-associated periodic syndrome include episodes of cold-induced fever, skin rash, and joint pain.
Physical Examination
Physical examination of patients with the cryopyrin-associated periodic syndrome (CAPS) is usually remarkable for recurrent episodes of cold-induced fever, urticaria-like painful rash, and arthritis. Hearing loss, ophthalmologic involvement, and focal neurologic signs are more suggestive of NOMID.
Laboratory Findings
An elevated concentration of serum acute-phase reactant is diagnostic of cryopyrin-associated periodic syndrome.
Electrocardiogram
There are no ECG findings associated with cryopyrin-associated periodic syndrome.
X-ray
There are no x-ray findings associated with the cryopyrin-associated periodic syndrome. However, an x-ray may be helpful in the diagnosis of arthropathy associated with neonatal-onset multisystem inflammatory disease (NOMID) which may indicate enlargement of the unossified physis leading to a mass-like lesion and later appearance of stippled calcifications.
Echocardiography and Ultrasound
There are no echocardiography/ultrasound findings associated with Cryopyrin-associated periodic syndrome.
CT scan
There are no CT scan findings associated with the cryopyrin-associated periodic syndrome.
MRI
There are no MRI findings associated with the cryopyrin-associated periodic syndrome. However, an MRI may be helpful in the diagnosis of arthropathy associated with neonatal-onset multi-system inflammatory disease (NOMID) which includes enlarged, heterogenous physis with hypointense calcifications and presence of popliteal lymph node.
Other Imaging Findings
There are no other imaging findings associated with the cryopyrin-associated periodic syndrome.
Other Diagnostic Studies
There are no other diagnostic studies associated with cryopyrin-associated periodic syndrome.
Treatment
Medical Therapy
There is no definitive treatment for cryopyrin-associated periodic syndrome; the mainstay of therapy is supportive care. Supportive therapy for cryopyrin-associated periodic syndrome includes anakinra, rilonacept, and canakinumab. Patients with NOMID are treated with anakinra, whereas patients with FCAS and MWS are treated with canakinumab. Symptomatic treatment options include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and glucocorticoids.
Surgery
Surgical intervention is not recommended for the management of the cryopyrin-associated periodic syndrome.
Primary Prevention
There are no established measures for the primary prevention of cryopyrin-associated periodic syndrome.
Secondary Prevention
There are no established measures for the secondary prevention of cryopyrin-associated periodic syndrome.