Familial cold auto-inflammatory syndrome, MWS and neonatal onset multisystem inflammatory disease are linked to heterozygous mutations in the NALP3 gene and are characterized under the umbrella of cryopyrin-associated periodic syndromes (CAPS). CAPS diseases result from an underlying innate deficiency in the function of the inflammasome.
Inflammasomes are critical mediators of the immune system, composed of multicellular protein bridges. Two different receptor types exist: NOD-like receptors, which include the NLRP3 protein, and AIM receptors.3 The NLRP3 inflammasome is activated once the pattern-recognition receptor and caspase-recruitment domain interact, leading to the biologic maturation of IL-1β and IL-18—both inflammatory cytokines.3
Particular mutations in the inflammasome have been associated with auto-inflammatory diseases. This association is clearly present in CAPS, with a gain of function mutation in the NLRP3 gene, resulting in the production of cryopyrin3 (see Figure 1). Cryopyrin is known as a danger sensor, activating caspase and eventually cleaving pro-1L-1β to active IL-1β to trigger an inflammatory response in the setting of immunologic threat and active infection. MWS is due to overproduction of IL-1β, resulting in debilitating, ongoing, end-organ damage.
The diagnosis of CAPS diseases, particularly MWS, is most commonly made in childhood. The Eurofever group has tracked 136 CAPS patients in Europe to better learn about risk stratification in this patient population. They found the median age of symptom onset to be 0.8 years (1–5 years); however, median age of diagnosis was 15 years.3 Our patient was not diagnosed until mid-adulthood.
A diagnosis of MWS is established via a genetic test showing a mutation in the NLRP3 genotype, along with clinical signs and symptoms, including urticaria-like rash, musculoskeletal symptoms, sensorineural hearing loss and cold-induced attacks.1-4 MWS is a moderately severe CAPS-disease type with a wide range of organ involvement. Chronic urticarial rashes manifest in infancy and continue throughout childhood, usually occurring two to four hours after cold exposure. Skin biopsy is significant for a neutrophilic predominant infiltrate.4 Recurrent fever episodes are also common, lasting one to two days, and can be triggered by exercise, stress or cold temperatures.
Severe joint pain and arthralgias affect a majority of patients; however, cartilage, bony destruction and joint space damage are usually not seen on radiographic imaging. Knee, wrist and ankle joints are commonly involved. Sensorineural hearing loss is usually present in infancy and can worsen over time, due to degeneration of sensory cells in the Organ of Corti.4 Active deterioration in hearing during the postpartum period is uncommon and should prompt further investigation. Disease flares can be brought on by stress; however, the relation to an immunocompromised state during pregnancy is uncharacteristic. Scarce literature addresses the reasons for an MWS flare during pregnancy. A change in uric acid, cholesterol or toxin metabolization by the NLRP3 inflammasome during pregnancy may play a role and is subject to future investigation.