Cryopyrin-associated periodic syndromes
The mildest form is familial cold autoinflammatory syndrome (FCAS), the intermediate form is Muckle-Wells syndrome (MWS), and the severe form is neonatal onset multisystemic inflammatory disease (NOMID, also known as chronic infantile neurologic cutaneous and articular syndrome [CINCA]).
These syndromes are all mediated by disruptions in innate immune signaling, most commonly through autosomal dominant gain-of-function mutations in the NLRP3 gene (encoding cryopyrin) leading to overactivation of the inflammasome. Subsequent overproduction of the pro-inflammatory cytokine interleukin (IL)-1β mediates much of the systemic and organ inflammation. Variable disease severity even within families suggests environmental influences as well.
FCAS typically presents within the first 6 months of life with recurrent outbreaks of fever, arthralgia, fatigue, and nonpruritic urticaria that occur after cold exposure. Systemic findings such as conjunctivitis, myalgia, and nausea may also be seen. Rarely, patients may experience headache, diaphoresis, drowsiness, and amyloidosis. Symptoms begin 10 minutes to 8 hours after cold exposure and generally subside within 24 hours. The time to resolution may be longer in cases of more prolonged cold exposure.
MWS presents with symptoms of FCAS, even in the absence of generalized cold exposure. Onset is usually in adolescence, but cases with earlier onset have been documented. Urticarial plaques may be painful and can last up to 24 hours. Flares last 2-3 days. Additionally, 70% of patients experience progressive sensorineural deafness, and 25% experience renal (amyloid A [AA]) amyloidosis that develops into renal dysfunction.
NOMID/CINCA often presents in neonates with more severe symptoms of FCAS and MWS along with central nervous system (CNS) manifestations that range from chronic headaches to hearing loss to intellectual disability secondary to aseptic chronic meningitis. The eruption consists of urticarial migratory plaques that may be generalized. Other manifestations include blindness secondary to optic disc changes, growth delay, distinctive osteoarthropathy seen in large joints, and overgrowth of proximal tibial epimetaphyseal cartilage to produce a "bread crumb" appearance on x-ray. One-third of children present with similar facial morphologies including a frontal prominence, saddleback nose, and facial hypoplasia.
M04.2 – Cryopyrin-associated periodic syndromes
430079001 – Cryopyrin associated periodic syndrome
Differential Diagnosis & Pitfalls
- – recurrent erysipelas-like erythema on inferior limbs; responds to colchicine
- – week-long febrile episodes
- Mevalonate kinase deficiency – recurring febrile episodes with elevated urinary excretion of mevalonic acid
- NLRP12-associated periodic fever syndrome (familial cold autoinflammatory syndrome 2)
- PLCG2-associated antibody deficiency and immune dysregulation (familial atypical cold urticaria)