De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.
Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome.
Dominant mutations in the CIAS1 gene cause a spectrum of autoinflammatory diseases such as familial cold autoinflammatory syndrome, FCAS, which is characterized by episodes of urticaria, arthralgia, fever and conjunctivitis after generalized exposure to cold.
To investigate the involvement of the CIAS1/PYPAF1/NALP3 gene in 7 unrelated Spanish families with recurrent autoinflammatory diseases characterized by early onset, recurrent fever, and a chronic urticarial rash, in whom a clinical diagnosis of cryopyrin-associated periodic syndromes (CAPS) is suspected.
In this report we describe a case of severe chronic infantile neurologic, cutaneous, articular (CINCA) syndrome with a novel G307Vcryopyrin mutation and all of the characteristic clinical and laboratory features of this autoinflammatory disease.
Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease.
Recent studies suggest that NALP3 and CARD-8 functional mutations contribute to the development of autoinflammatory diseases including hereditary periodic fever syndrome, arthritis as well as hypertension susceptibility.
Chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease and is caused by a heterozygous germline gain-of-function mutation in the NLRP3 gene.
Medical records of all male MWS patients with NLRP3 mutations followed in our tertiary center for inherited autoinflammatory diseases were reviewed retrospectively for data indicating fertility problems.
Activation of the inflammasome is a critical event triggering IL-1-driven inflammation and is central to the pathology of autoinflammatory diseases, such as gout and MWS.
: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS).
CAPS is a rare autoinflammatory disease associated with mutations in the NLRP3 gene that result in overactivation of the inflammasome, increased secretion of IL-1beta and IL-18, and systemic inflammation.
The NLRP3 inflammasome plays a critical role in host defense by facilitating caspase I activation and maturation of IL-1β and IL-18, whereas dysregulation of inflammasome activity results in autoinflammatory disease.
CARD8 encodes a protein component of the NLRP3 inflammasome, which plays an important role in inflammation and contributes to the pathology of various autoinflammatory diseases.
Moreover, the NLRC3 CARD alone could dampen IL-1β secretion and ASC speck formation induced by NALP3 mutants associated with autoinflammatory diseases.
Gain-of-function missense mutations in NLRP3 result in a group of autoinflammatory diseases collectively known as the cryopyrin-associated periodic syndromes (CAPS).