Familial Cold Autoinflammatory Syndrome: Diagnosis & Treatment

Authoritative guide to FCAS (familial cold autoinflammatory syndrome), the mildest cryopyrin-associated periodic syndrome (CAPS).

What is familial cold autoinflammatory syndrome?

Familial cold autoinflammatory syndrome (**FCAS**) is a rare, inherited

autoinflammatory disease

characterised by acute, episodic attacks of

fever

with

rash

following

generalised exposure to cold

. These episodes typically onset in infancy and recur lifelong, triggered by even mild cooling temperatures.

FCAS belongs to the

cryopyrin-associated periodic syndromes (CAPS)

spectrum, representing the mildest phenotype compared to moderate Muckle-Wells syndrome (MWS) and severe neonatal-onset multisystem inflammatory disease (NOMID/CINCA). Unlike allergic cold urticaria, FCAS involves systemic inflammation driven by dysregulated innate immunity, not IgE-mediated hypersensitivity.

Demographics

FCAS has an estimated prevalence of

1:1,000,000

, making it extremely rare. It predominantly affects families of

North American and European descent

with no sex predilection—males and females are equally impacted. Large multigenerational pedigrees are common due to its autosomal dominant inheritance.

• Age of onset: Mean 47 days; 95% by 6 months. Rare adult presentations reported
• Lifelong persistence: Symptoms continue indefinitely without intervention
• Family history: Often positive in 50% of offspring from affected parents

Causes

FCAS results from

gain-of-function mutations

in the

NLRP3

gene (chromosome 1q44), encoding

cryopyrin

(also NALP3). Cryopyrin forms the core of the

inflammasome

, a multiprotein complex regulating IL-1β activation.

Mutant cryopyrin causes

constitutive inflammasome overactivation

, leading to excessive

interleukin-1β (IL-1β)

secretion. This pro-inflammatory cytokine drives the hallmark symptoms. Remarkably, FCAS monocytes exhibit

enhanced IL-1 release at subphysiologic temperatures

(<33°C), explaining cold sensitivity.

Clinical features

Attacks begin

2-3 hours post-cold exposure

(range 1-6 hours), last

<24 hours

(average 12 hours), and resolve spontaneously. Even brief generalised cooling (air conditioning, wind, cold drinks) suffices; local cold rarely triggers.

Symptoms during acute episodes

Symptom	Frequency	Description
Fever	100%	Mild-moderate (38-40°C), chills
Rash	95-100%	Urticarial, erythematous macules/papules on trunk/extremities. Non-pruritic, blanches
Arthralgia/Myalgia	90-95%	Symmetric joint pain (knees, ankles); transient synovitis rare
Fatigue/Malaise	96%	Profound drowsiness, weakness
Conjunctivitis	70-90%	Bilateral red, watery eyes; no vision loss
Other	Variable	Headache (50%), thirst, nausea, sweating, vertigo

Images: Characteristic FCAS rash shows confluent erythematous patches without angioedema or purpura

Complications

FCAS generally lacks the organ damage seen in severe CAPS:

• Amyloidosis: Rare (<5%); AA amyloid deposition causing proteinuria/renal failure
• Chronic inflammation: Absent in pure FCAS (vs MWS/NOMID)
• Dehydration: From fever/sweating during attacks

Diagnosis

Primarily

clinical

, supported by genetic confirmation. Key diagnostic clues:

Diagnostic criteria (requires ≥4/6)

• Recurrent fever + rash post-generalised cold exposure
• Age of onset <6 months
• Episode duration <24 hours
• Conjunctivitis during attacks
• Absence of periorbital edema, lymphadenopathy, serositis
• Family history of CAPS

Genetic testing: NGS/Sanger sequencing of NLRP3. Detects ~60-70% of cases; phenotypic FCAS exists without identifiable mutation.

Investigations during attacks

• ↑ Acute phase reactants: CRP, ESR (mild); normal between episodes
• Leukocytosis: Neutrophilia
• Anaemia: Mild chronic disease anaemia possible

Differential diagnoses

Condition	Distinguishing features
Acquired cold urticaria	Pruritic hives within minutes; local cold triggers; ice cube test +ve; no fever/systemic symptoms
Muckle-Wells syndrome	Longer attacks (24-48h); sensorineural deafness; urticarial vasculitis
NOMID/CINCA	Daily symptoms from birth; arthropathy, uveitis, CNS involvement
Common cold urticaria	Hives only; no inheritance/fever
Other periodic fevers	FMF/TNFRSF1A: abdominal pain, longer attacks

Treatment

IL-1 blockade is first-line and transformative:

• Anakinra (IL-1Ra): 1-2 mg/kg/day SC. Rapid symptom control; prevents attacks
• Canakinumab (anti-IL-1β): 150 mg SC every 8 weeks. Long-acting
• Rilonacept (IL-1 Trap): 160 mg weekly SC (US-approved for CAPS)

Non-responders: High-dose NSAIDs, colchicine (limited efficacy). Avoid steroids (rebound flares).

Outcome

Excellent with IL-1 inhibitors—near-complete symptom remission, normal quality of life. Untreated: recurrent debilitating flares, rare amyloidosis. Lifelong therapy typically required; some attain partial remission with age.

Frequently Asked Questions

What triggers FCAS attacks?

Generalised cold exposure (wind, AC, cold food/drink). Attacks begin 1-6 hours later, lasting <24h.

Is FCAS curable?

No cure, but IL-1 inhibitors (anakinra, canakinumab) provide excellent control. Genetic counselling recommended.

Does FCAS cause permanent damage?

Rare amyloidosis risk; no chronic arthropathy or deafness (unlike other CAPS).

Can FCAS be prevented?

Avoid cold triggers. Prophylactic anakinra prevents attacks effectively.

Is genetic testing necessary?

Confirms diagnosis (60-70% mutation detection rate); guides family screening.