Diagnosis of cryopyrin-associated periodic syndrome: challenges, recommendations and emerging concepts

Abstract

Cryopyrin-associated periodic syndrome are rare autosomal dominantly inherited diseases. They include three overlapping phenotypes: familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem autoinflammatory syndrome (NOMID/CINCA). Recurrent fevers, joint pain, and urticarial skin rash are the main clinical features of these conditions. Renal amyloidosis and sensorineural complications may occur. Gain-of-function mutations in NLRP3 gene are responsible for the overactivation of the NLRP3 inflammasome, a multimolecular complex involved in the inflammatory process. Missense mutations are almost always encountered, particularly in exon 3, which encodes the nucleotide-binding domain. Mosaicism is not rare, especially in CINCA/NOMID. Next-generation sequencing will grant access to new insights about NLRP3 implication in oligogenic and multifactorial diseases.

Keywords:

• autoinflammatory syndrome
• CAPS
• CINCA
• cryopyrin
• FCAS
• inflammasome
• mosaicism
• MWS
• NLRP3

Financial & competing interest’s disclosure

The authors were supported by funding from the CHRU of Montpellier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• NOD-like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome is a multimolecular complex involved in pathogen-associated molecular patterns and danger-associated molecular patterns recognition and leading to IL-1β secretion and pyroptosis.

• The cryopyrin-associated periodic syndrome (CAPS) spectrum encompasses three overlapping phenotypes with common features, such as urticarial skin-rash, arthralgia: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem autoinflammatory syndrome (CINCA/NOMID).

• MWS major risk is renal amyloidosis, whereas CINCA/NOMID patients have a high mortality rate due to severe neurologic impairment.

• To date, IL-1 blockade is the most efficient treatment for CAPS patients.

• Mostly, all NLRP3 mutations are substitutions located in exon 3, encoding the nucleotide-binding domain (NBD).

• No NLRP3 mutation is found in 40% of the CINCA/NOMID patients. Up to 60% of the latter patients present with pathological somatic NLRP3 mosaicism.

• FCAS2 is a CAPS-like phenotype caused by NLRP12 mutations, but IL-1 blockade is ineffective.

• Schnitzler syndrome patients present with somatic NLRP3 mosaicism.

• Several studies show implication of NLRP3 in multifactorial diseases (crystalline arthropathies, Alzheimer disease and Type 2 diabetes mellitus).

Notes