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Familial cold autoinflammatory syndrome

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, 2011.

Table of contents

What is familial cold autoinflammatory syndrome?

Familial cold autoinflammatory syndrome (FCAS, MIM 120100) is a genetic periodic fever syndrome that presents with recurrent short episodes of fever, an urticaria-like skin rash and joint pain, typically following generalised exposure to cold. It was previously called familial cold urticaria.

Familial cold autoinflammatory syndrome (FCAS) is now grouped together with Muckle-Wells syndrome and NOMID/CINCA as a cryopyrin-associated periodic syndrome (CAPS). FCAS is the least severe of this clinical continuum.

Who gets familial cold autoinflammatory syndrome and why?

Familial cold autoinflammatory syndrome is an autosomal dominant condition, inherited from one affected parent.

Symptoms usually begin at birth (in 60% it occurs within days of birth) or within the first 6 months after birth (95%). However, a late presentation also occurs. There is commonly a delay in diagnosis of, on average, 10 years.

Molecular biology and genetics

Mutations occur in the NLRP3 gene which codes for cryopyrin, a component of protein complexes called inflammasomes found inside cells and involved in the innate immune system. Most mutations have been identified in exon 3 of this gene. Disease-linked mutations result in a ‘gain-of-function’ as the abnormal cryopyrin allows continuous stimulation of the inflammatory reaction. The mechanism of the temperature-dependence of this reaction is not yet understood.

What are the clinical features of familial cold autoinflammatory syndrome?

The distinctive clinical features of familial cold autoinflammatory syndrome are acute, short-duration attacks of fever with rash and joint pain following generalised exposure to cold.

Clinical features of the acute episodes of familial cold autoinflammatory syndrome can include:

  • Fever — in 93%, lasts less than 24 hours, preceding chills, associated with profuse sweating, often occur at night, settle within hours
  • Skin rash — in 100%, see below
  • Muscle pain (myalgia)
  • Joint pain (arthralgia)— in 96%, stiffness and swelling of the hands and feet
  • Headache
  • Nausea
  • Drowsiness
  • Extreme thirst
  • Eye — frequent conjunctivitis (in 84%), blurred vision, and pain.

What are the features of the skin rash of familial cold autoinflammatory syndrome?

The skin rash is often the first sign of this syndrome, appearing soon after birth or in early infancy. Although described as urticarial (hive-like), it usually presents as faint pink figurate patches or red flat macules and slightly raised papules (maculopapular rash) that disappear within 24 hours of onset.

The patient rarely describes the rash as itchy but uses words such as burning, stinging, warm or tight. The rash occurs on the trunk and limbs and moves around. It is often worse in the evening. The intensity of the rash varies between patients and disease activity. Petechiae have also been described.

What triggers attacks in familial cold autoinflammatory syndrome?

The characteristic trigger for an acute attack is general exposure to cold (but not localised cold), with symptoms developing 1–2 hours (range 30 minutes to 6 hours) after exposure. Symptoms peak at 2–6 hours and resolve by 24 hours. Attacks are more common in winter, on windy damp days, and can occur with a major drop in temperature or with air conditioning. The severity of an attack varies with the degree of cold, ie more severe if very cold.

Acute episodes usually last less than 24 hours (range 12–48 hours), then settle spontaneously.

How does familial cold autoinflammatory syndrome progress?

Attacks usually begin in early life and tend to get worse with increasing age.

Amyloidosis is a rare complication (< 5%) of familial cold autoinflammatory syndrome. Deafness is not usually observed. Overlap with Muckle-Wells syndrome has been described as the development of sensorineural deafness in otherwise typical FCAS or cold-triggered episodes in otherwise typical Muckle-Wells syndrome.

How is familial cold autoinflammatory syndrome diagnosed?

A diagnosis of familial cold autoinflammatory syndrome should be considered in patients presenting with recurrent acute febrile attacks occurring shortly after exposure to cold.

Note, the ice-cube provocation test is negative, a useful distinguishing feature from cold urticaria. A typical attack can be provoked by going into a 4°C cold room.

During an acute attack, tests reveal nonspecific features, including:

  • Acute phase reactants (blood tests) — elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA)
  • Leukocytosis (a high white cell count with a slight increase in peripheral neutrophils)

Skin biopsy from an urticaria-like lesion shows a perivascular, and sometimes peri-eccrine, neutrophil infiltrate in the upper dermis. As this is different from the histology of urticaria or urticarial vasculitis, it can be very useful in suggesting the diagnosis of FCAS.

A commercial genetic test is available to sequence exon 3 of the NLRP3 gene.

What is the treatment of familial cold autoinflammatory syndrome?

Until the biologic agents that blocked interleukin-1 were recognised to control the symptoms of familial cold autoinflammatory syndrome, many sufferers moved to temperate climates where they could avoid cold winters or hot summers requiring air conditioners.

Bed rest, warmth and corticosteroids can be used to treat an acute attack.

Anakinra, an interleukin-1 receptor antagonist, has successfully treated many patients with familial cold autoinflammatory syndrome in large clinical trials. Anakinra is administered as a daily subcutaneous injection with a usual dose range of 0.5–1.5 mg/kg/day. All patients respond if given a sufficient dose. Some sufferers use it intermittently such as alternate day, during winter, or when there will be exposure to a recognised trigger. Local injection site reactions are the commonest adverse effect. Clinical improvement was seen within 12 hours and blood tests returned to normal within one week in trials. Symptoms recurred within 26–48 hours of ceasing treatment.

Note: anakinra is not registered or subsidised in New Zealand (March 2011). In other countries such as the USA and Europe, its registered indication is rheumatoid arthritis.

Rilonacept is used as a weekly subcutaneous injection. In an open-label pilot study of five patients, after a single 300mg dose maximum clinical improvement was seen at day 6–10 with disease flares after 10–28 days. It is FDA-approved for the treatment of adults and children from the age of 12 years suffering from familial cold autoinflammatory syndrome.

Canakinumab is FDA-approved for the treatment of familial cold autoinflammatory syndrome affecting adults and children from the age of 4 years. It is administered as a subcutaneous injection every 8 weeks. Clinical trials report resolution of the urticaria-like rash within 1 day and complete resolution including joint pain and blood tests within 1 week.

Biologic agents that block the effect of interleukin-1β have a significant beneficial effect on the quality of life for sufferers of familial cold autoinflammatory syndrome.



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