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At a glance

A familial form of urticaria with systemic reactions that occurs as a result of cold exposure.

Synonyms

Familial Cold Urticaria; Familial Cold-Induced Autoinflammatory Syndrome; Familial Cold Autoinflammatory Syndrome; Familial Polymorphous Cold Eruption Syndrome.

Incidence

Approximately 1:1,000,000 of the general population is affected.

Genetic inheritance

Autosomal dominant inheritance, although sporadic cases (de novo mutations) have also been described. Gain-of-function mutations in the CIAS1 gene (also known as NLRP3 [NLR Family Pyrin Domain Containing 3] gene) have been mapped to chromosome 1q44 and encodes for cryopyrin, a protein that is expressed on peripheral leukocytes and chondrocytes and appears to be involved in apoptosis and caspase-1 activation. Cryopyrin can oligomerize and recruit other proteins such as caspase-1, and generate a multi-protein assembly called an inflammasome. These inflammasomes trigger the activation and secretion of interleukin (IL)-18 and IL-1β, which results in fever, vasodilation, and systemic inflammation through other inflammatory cytokines.

Diagnosis

The diagnosis is based on the clinical findings and the family history and is confirmed by genetic testing for CIAS1/NRLP3 mutations.

Clinical aspects

Usually the onset of symptoms occurs hours after birth or as soon as the baby is exposed to a cold environment (in >90% onset is in the neonatal period). Delayed presentation is possible, but the maximal age at onset is believed to be less than 6 months. Urticarial eruptions are triggered by exposure to cold, damp air, and/or wind (air conditioning), generally occur one-half to 48 hours after cold exposure, and initially present as macules and papules on exposed skin areas, which then spread to covered sites. However, it seems that other triggers are also possible, such as infection, trauma, food, and fatigue. The distinctive lesions have a purple cyanotic color and are surrounded by a white halo, causing a burning pain rather than itch. Intense cold exposure is not only associated with eruptions lasting for up to 48 hours, but potentially also with a systemic reaction of fever, sweating, arthralgia and myalgia (in >80% of patients), headache (in almost 30%), conjunctivitis, and leukocytosis, which usually follow 4 to 6 hours after exposure or sometimes even without being exposed to cold. Neurological involvement is detected in 12% of patients and can present as hydrocephalus, mental retardation, or seizures. Ocular involvement is present in most patients, with conjunctivitis being the most common manifestation (in 66%), while uveitis, cataract, glaucoma, optic nerve atrophy, and impaired vision are far less common. Impaired hearing is found in approximately 40% of patients. Systemic amyloidosis has been suspected in some cases, but the diagnosis in these cases was questioned and reevaluation found the diagnosis of Muckle-Wells Syndrome to be more likely. Nevertheless, a small percentage of patients (in 4%) with cold hypersensitivity syndrome suffers from renal amyloidosis. Despite being ...

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