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Familial cold urticaria in short

Familial cold urticaria (FCAS) is the mildest form of cryopyrin-associated periodic syndrome (CAPS) and is characterized by recurrent episodes of urticaria-like skin rash triggered by exposure to cold associated with low-grade fever, general malaise, eye redness and arthralgia/myalgia.

Epidemiology

The total number of FCAS cases remains undetermined.
The majority of reported instances come from the United States, with this CAPS variant potentially occurring less frequently in European populations compared to MWS and CINCA.

FCAS typically emerges during childhood (<10 years, often at birth), though occasional later onset occurs, featuring recurring episodes of non-itchy urticaria-like eruptions triggered by cold exposure (5 minutes to 3 hours, not necessarily through contact).
The eruptions persist for approximately 12 hours (ranging from 30 minutes to 72 hours) and typically produce a burning sensation. Patients experience mild fever lasting throughout the day, general discomfort, eye inflammation, and stomach distress.
Severe joint pain affects hands, knees, and ankles, causing significant disability. Additional joint involvement includes feet, wrists, and elbows.
Cold exposure also triggers excessive perspiration, lethargy, head pain, intense thirst, and stomach upset. While amyloidosis and joint inflammation rarely occur, hearing loss, swollen lymph nodes, and inflammation of serous membranes are not present.

FCAS results from gain-of-function point mutations in the NLRP3 gene (1q44), which produces cryopyrin. These NLRP3 mutations result in elevated production of the inflammatory protein interleukin (IL)-1 beta and uncontrolled inflammation.
This gene’s mutations also cause two other CAPS variants – Muckle-Wells syndrome (MWS) and CINCA syndrome, showing these three conditions are allelic.
Some individuals displaying typical FCAS, MWS, or CINCA symptoms lack NLRP3 mutations, suggesting other genes’ involvement. Furthermore, somatic NLRP3 mosaicism might explain 30-60% of cases showing negative standard genetic tests. Patients with identical amino acid changes can exhibit different clinical subtypes, indicating additional genetic and/or environmental factors influence the clinical presentation.

The condition follows autosomal dominant inheritance. Genetic counseling is available with a 50% inheritance risk.