SUMMARY

 

1. Mutations in the cold induced autoinflammatory syndrome 1 (C1AS1) gene cause three clinically overlapping autosomal dominant periodic fever syndromes.

 

2. The following three diseases were previously believed to be separate and distinct entities. However, following the discovery of C1AS1 gene, it has become clear that these conditions represent a spectrum of the same disease ranging from mild (FCAS) to moderate (Muckle-Wells) to severe (CINCA).

 

Familial Cold Autoinflammatory Syndrome (FCAS)

This syndrome is characterized by:

- Cold-induced attacks of fever

- Urticaria-like rash (after cold exposure)

- Arthralgia

- Conjunctivitis

- Fevers typically last less than 24 hours.  Onset of symptoms usually occurs before 6 months of age. There is a small risk of developing amyloidosis. Patients do not develop neurologic symptoms.

 

Muckle-Wells Syndrome (MWS)

This syndrome is characterized by episodic attacks with:

- Fever and urticaria-like rash

- Arthralgia

- Progressive sensorineural hearing loss

- Approximately 25% of patients will develop amyloidosis with nephropathy.

 

Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA)

This syndrome is also referred to by the term NOMID and is characterized by the following:

- Fever with urticaria-like rash

- Arthritis (with bony overgrowth)

- Severe neurological symptoms (mental retardation, seizures, cerebral atrophy, and sensorineural hearing loss)

- High rate of mortality (20% of untreated patients dying before adulthood)

 

3. The C1AS1 gene encodes for the protein Cryopyrin. Cryopyrin is a component of the Cryopyrin inflammasome (NALP3 inflammasome) along with ASC and cardinal. This inflammasome is responsible for cleaving pro-caspase-1 to active caspase-1 which goes on to activate IL-1 and IL-18, two key pro-inflammatory cytokines. The cryopyrinopathies are caused by gain of function mutations in the cryopyrin inflammasome that result in excessive IL-1 production and inflammation.

 

4. The diagnosis of cryopyrinopathies should be suspected for patients with classic clinical features (recurrent fevers, urticaria-like rash, arthritis) and a family history consistent with an autosomal dominant inheritance pattern. The diagnosis is confirmed by sequencing of the C1AS1 gene. Approximately one-half of patients with CINCA do not have mutations in C1AS1.

 

5. The treatment of choice is Anakinra, a recombinant IL-1 receptor antagonist. Anakinra can reduce inflammation and has been used successfully to treat renal amyloidosis.

 

                                                                                                                                       

 

OVERVIEW

 

          Mutations in the cold induced autoinflammatory syndrome 1 (C1AS1) gene cause three clinically overlapping autosomal dominant periodic fever syndromes.

 

          The following three diseases were previously believed to be separate and distinct entities. However, following the discovery of C1AS1 gene, it has become clear that these conditions represent a spectrum of the same disease ranging from mild (FCAS) to moderate (Muckle-Wells) to severe (CINCA).

 

Familial Cold Autoinflammatory Syndrome (FCAS) This syndrome is characterized by cold-induced attacks of fever, urticaria-like rash (2-3 hours after cold exposure), arthralgia, and conjunctivitis. Fevers typically last less than 24 hours. Onset of symptoms usually occurs before 6 months of age. There is a small risk of developing amyloidosis. Patients do not develop neurologic symptoms.

 

Muckle-Wells Syndrome (MWS) This syndrome is characterized by episodic attacks with fever and urticaria-like rash, arthralgia, and progressive sensorineural hearing loss. This hearing loss may be the result of cochlear inflammation. Approximately 25% of patients will develop amyloidosis with nephropathy.

 

Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA) This syndrome is also referred to by the term NOMID. As with the other syndromes, patients develop episodic attacks of fever, urticaria-like rash, and arthritis (with bony overgrowth). Patients also develop severe neurological symptoms including mental retardation, seizures, cerebral atrophy, and sensorineural hearing loss. There is a high rate of mortality with 20% of untreated patients dying before adulthood.

 

 

 

PATHOGENESIS

 

         The C1AS1 gene (also known as NALP3) encodes for the protein Cryopyrin. Cryopyrin is a member of the Nod-like Receptor protein family that responds to intracellular pathogen and danger associated molecular patterns. The structure of Nod-like receptors is quite similar to toll-like receptors. Cryopyrin forms a complex with ASC and cardinal called the Cryopyrin inflammasome (NALP3 inflammasome). This inflammasome is responsible for cleaving pro-caspase-1 to active caspase-1 which goes on to activate IL-1 and IL-18 (two key pro-inflammatory cytokines).

 

 

 

 

DIFFERENTIAL DIAGNOSIS

 

1. FMF

2. TRAPS

3. Hyper IgD Syndrome

4. PFAPA

5. Blau Syndrome

6. DIRA

 

 

 

                                           

EVALUATION

 

The diagnosis of cryopyrinopathies should be suspected for patients with a classic clinical history (recurrent fevers, urticaria-like rash, arthritis, and neurologic abnormalities) and a family history consistent with an autosomal dominant inheritance pattern. The diagnosis is confirmed by sequencing of the C1AS1 gene. Approximately one-half of patients with CINCA do not have mutations in C1AS1.

 

 

Step 1: Screening Studies

         

                      - C reactive protein / Erythrocyte sedimentation rate

                      - BUN/Creatinine and Urine Protein

 

-CRP and ESR are often elevated during and between attacks.

 

- Renal function and urine protein should be checked to screen for potential renal disease from amyloid deposition.

 

 

 

Step 2:  Genetic confirmation

The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations but not necessarily required. 

 

- C1AS1 gene sequencing

 

- This is the definitive test for establishing a diagnosis of a Cryopyrin Associated Periodic Syndrome.

 

 

                                                                              

MANAGEMENT

 

          The central role of IL-1 beta in the pathogenesis of these disorders has been confirmed by the successful use of IL-1 receptor antagonist (Anakinra) to treat patients with cryopyrin associated periodic syndromes.

 

- Anakinra has been shown to prevent disease flares in patients with FCAS, Muckle-Wells, and CINCA.

- Anakinra has also been effective in treating patients with renal amyloidosis improvement in proteinuria and serum creatining has been reported.

- One downside of Anakinra is that it does require daily subcutaneous administration..

 

 

         Rilonacept (IL-1 trap) is a long-acting IL-1 receptor fusion protein which binds IL-1β. Rilonacept is administered subcutaneously once

weekly.

         Canakinumab is a human anti-IL- β monoclonal antibody which is administered subcutaneously once every 8 weeks..

 

 

                                                                           

 

RESOURCES

 

Diagnostic Resources    

 

Gene Dx: Offers sequencing for CIAS1.

A sample submission and informed consent form is required.

Testing typically takes 4-6 weeks.

www.genedx.com/services/dis_cg.php

Phone 301-519-2100 Fax 301-519-2892

 

 

Literature Resources

 

 

1.  Gattorno 2008

     Diagnosis and management of autoinflammatory diseases in childhood (review)

 

2.  Franchi 2009 

     Inflammasome (review)

 

3.  Goldbach-Mansky 2009

      IL-1 associated autoinflammatory diseases (review)

 

4.  Goldback-Mansky 2006 

      NOMID responsive to IL-1 beta inhibition (NEJM)

 

5.  Hawkins 2004 

     Spectrum of clinical features in Muckle-Wells and response to Anakinra

 

6.  Hoffman 2004

     Prevention of cold-associated infllammation in FCAS by Anakinra    

 

7.  Thornton 2007

     Successful treatment of renal amyloidosis due to FCAS using Anakinra