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Cryopyrin-Associated Autoinflammatory Syndromes

Andrew Zeft, MD, MPH



The cryopyrin-associated autoinflammatory syndromes (CAPS) are autoinflammatory disorders that characteristically have an autosomal dominant Mendelian inheritance. Gene defects are present in the CIAS1/NLRP3 gene (NOD-like receptor family, pyrin domain) which encodes the protein cryopyrin. The prevalence of mutation positive CAPS is relatively rare, with a rate of approximately 1 per 400,000.1

Three CAPS have been identified:

  • Familial cold urticaria syndrome or familial cold autoinflammatory syndrome (FCAS),
  • Muckle-Wells syndrome (MWS),
  • Neonatal-onset multisystemic inflammatory disease (NOMID)/chronic infantile neurological cutaneous articular syndrome (CINCA).


The cryopyrin-associated autoinflammatory syndromes are separate entities; patients differ in symptoms, organ manifestations, severity, and triggers (Table 1). Although the three CAPS syndromes are phenotypically heterogeneous, they have overlapping signs and symptoms. It is not unusual that a patient has overlapping clinical symptomatology of both FCAS and MWS or MWS and NOMID.

On the milder side of the CAPS spectrum is FCAS. Patients with FCAS have a less severe disease and patient’s manifestations primarily affect quality of life. Alternatively, patients with NOMID have inflammatory signs and symptoms within days of life leading to morbidity and skeletal dysmorphism if left untreated. All CAPS conditions have urticarial rash, which is not characteristically responsive to antihistamines. Skin biopsy typically shows a neutrophilic infiltrate.

Table 1. Clinical spectrum of CAPS.

Cold triggered Rare cold triggered No cold triggered
Recurrent episodes of fever Recurrent episodes of fever Fever
Urticaria Urticaria Urticaria
Arthralgia/myalgia Arthralgia/arthritis Arthralgia/arthritis/severe arthropathies
Conjunctivitis Conjunctivitis, uveitis, episcleritis Conjunctivitis, uveitis, episcleritis, optic neuritis, optic atrophy, papilledema
  Amyloidosis Amyloidosis
  Sensorineural hearing loss Sensorineural hearing loss
  Headache (meningitis) Chronic meningitis
Abbreviations: FCAS = Familial cold urticaria syndrome or familial cold autoinflammatory syndrome (FCAS); MWS = Muckle-Wells syndrome; NOMID/CINCA = Neonatal-onset multisystemic inflammatory disease and chronic infantile neurological cutaneous articular syndrome.

With FCAS, inflammatory episodes are characteristically triggered by cold exposure, such as going into a cold swimming pool, exposure to cold outside temperatures, or opening a freezer. Episodes tend to be brief, usually lasting less than 24 hours.

In contrast, inflammatory episodes in MWS can be frequent but are only variably triggered by cold depending on the degree of FCAS phenotypic overlap. Episodes can occur randomly. Most attacks last fewer than 36 hours but can last up to 5 days. The clinical symptoms of fever and urticarial rash are more characteristic of patients with MWS than FCAS.

Patients with MWS commonly have arthritis and can experience episodes of headache (aseptic meningitis). Hearing loss is bilateral, progressive, and often appears clinically during the second decade of life, although it could present later. It is a sensory neural hearing loss. Eye inflammation, such as uveitis, may be present in addition to conjunctivitis. Patients may have lymphadenopathy and/or hepatosplenomegaly.

The CINCA/NOMID syndrome typically presents shortly after birth. Urticarial rash is present, but initially infants have diffuse erythema. Patients with NOMID tend to have persistent inflammation. Chronic aseptic meningitis is common, and if it is not recognized and treated with aggressive IL-1 therapy, patients typically develop progressive mental retardation and neurologic injury. Also, patients develop osteopathy and long-bone epiphyseal overgrowth, growth delay, and progressive sensory neural hearing loss, lymphadenopathy, with/or without hepatosplenomegaly. Interestingly, it is understood that cryopyrin is expressed in peripheral leukocytes and chondrocytes, which makes sense given the clinical characteristics of a NOMID patient.

Features of otolaryngolic and audiologic manifestations of cryopyrin-associated periodic syndromes were defined in an NIH study reported in 2011.2 Patients were classified as NOMID (n=31), NOMID/MWS overlap (n=11), MWS (n=9), or FACS (n=6). Investigators collected comprehensive data on clinical manifestations, audiologic phenotype, and MRI of the brain and inner ear with flare sequencing. Patients with more severe phenotypes — NOMID and NOMID/MWS — had significantly more pronounced and higher frequency hearing loss. More advanced age also was associated with a greater degree of progressive hearing loss.


CAPS symptoms stem from mutations within the NLRP3 gene (NOD-like receptor family, pyrin domain) which encodes the protein cryopyrin. Inheritance patterns in CAPS are autosomal dominant, but spontaneous mutations are also common. In fact, approximately two-thirds of patients with mutation-negative NOMID have somatic NLRP3 mutations, indicating that somatic NLRP3 mosaicism contributes. To date, more than 150 NLRP3 mutations have been identified.3

Cryopyrin is part of a multiprotein inflammasome complex that mediates activation of caspase-1. Caspase-1 regulates the production of IL-1 beta. NLRP3 mutations result in an abnormal cryopyrin structure, leading to abnormally heightened inflammasome activity. An activated caspase-1 complex results in increased signaling from pro-IL-1 beta to active IL-1 beta. Cellular danger signals such as stress, inflammation, infection, or metabolic dysregulation affect inflammasome function.

There is poor genotype-phenotype association in CAPS; the same NLRP3 mutation can result in variable features, typically of either FCAS and MWS or MWS and NOMID phenotypes overlap, supporting the hypothesis that modifier genes play a role in phenotypic expression. Thus, the phenotype cannot be predicted based on the mutation. The CAPS are considered autosomal dominant with a Mendelian inheritance. Using conventional sequencing, the disease is associated with mutations in 60% of patients, which suggests genetic heterogeneity. In the other one-third, nongermline NLRP3 mutations or non-Mendelian inheritance can identify mutations. In 2010, Arostegui4 described a clinical case of NOMID in which novel heterogeneous variants were detected in about one-third of circulating leukocytes, absent in healthy controls and parents, a de novo-true disease causing mutation.

A 2012 paper5 described in vitro translational research findings on an 8-year-old boy with overlapping clinical phenotype features of FCAS and MWS who did not have an NLRP3 mutation. In the lab, his monocytes were exposed to mild hypothermia. The enhanced IL-1 beta expression by the monocytes was reversed by anakinra. Lipopolysaccharide (LPS) stimulation of monocytes produced high IL-1 beta, IL-6, and TNF compared with controls.


Treatments vary depending on disease severity. For patients with FCAS, treatment also depends on the climate where they live. Those in warmer climates typically require fewer treatments.

Table 2. Treatments of cryopyrin-associated autoinflammatory syndromes.

Disease Medication Comment
FCAS +/-   IL-1 inhibition Fewer treatments needed in warmer climates
MWS IL-1 inhibition: anakinra, rilonacept, canakinumab Good prognosis; lowers risk for sensorineural hearing loss, amyloidosis
NOMID/CINCA IL-1 inhibition: rilonacept, canakinumab Provides symptomatic relief and long-term disease control optimistically with high doses
Abbreviations: CINCA = chronic infantile neurological cutaneous articular syndrome; FCAS = Familial cold urticaria syndrome; MWS = Muckle-Wells syndrome; NOMID = Neonatal-onset multisystemic inflammatory disease.

Inhibition of IL-1 is the standard treatment for CAPS. The earlier the onset and more pronounced the phenotype, the more crucial it is to control the IL-1 mediated pro-inflammatory disease manifestations.6 Dosing patients with CAPS is driven by their individual degree of phenotypic severity. Recent research described canakinumab dose responses in 13 patients with CAPS; seven were patients with NOMID, four with MWS, and two with an MWS-NOMID overlap.7 To achieve inactive disease, doses were titrated with the objective of achieving inactive disease. Patients with a pure NOMID phenotype required canakinumab doses as high as 4 mg/kg; patients with MWS required doses ranging from 2.0 to 2.4 mg/kg.

With targeted treatment, there is the potential of progressive improvement in FCAS patients with minimal amyloid risk. Patients with MWS have better prognosis with IL-1 antagonists and are at lower risk for developing sensory neural hearing loss. Left untreated, MWS patients have close to a 25% risk of amyloidosis.6 With NOMID, there is a high risk for sensorineural hearing loss, amyloidosis, growth delay, and CNS sequelae if patients are not treated early and aggressively with IL-1 inhibition.

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