Familial Cold Autoinflammatory Syndrome - Symptoms, Diagnosis, and Treatment

Introduction:

Familial cold autoinflammatory syndrome (FCAS) is one of the three types of syndromes classified under a condition called cryopyrin-associated autoinflammatory syndrome (CAPS). Cryopyrin or NLRP3 is a protein belonging to a group of proteins called intracellular NOD-like receptor (NLR) proteins.

They regulate and control the immune system’s response to any germs, chemicals, and foreign substances. They help activate certain molecules involved in the immune system. Cryopyrin identifies bacterial cells, silica, uric acid crystals, asbestos, and chemicals released by damaged cells. Cryopyrin forms a compound substance with other proteins and converts into inflammasomes. Normally, the inflammasomes activate the process of inflammation during any injury or invasion from foreign organsims and protect the body from any further damage and repair the affected cells.

This inflammation is cause by white blood cells and other signaling chemicals. When the need for defense against foreign body stops, inflammation also stops. Cryopyrin I found in white blood cells and cartilage-producing cells called chondrocytes.

What Is Familial Cold Autoinflammatory Syndrome?

Cropyrin protein is coded by the NLRP3 gene located on chromosome 1. Due to some genetic mutation to this gene, there is an alteration in cryopyrin structure which make it more active than required. The hyperactive cryopyrin will kickstart an inflammatory response even when there is no requirement. This way the autoinflammation starts self-destroying the body’s healthy tissues.

This leads to a group of symptoms like fever, rash, and joint pain called a familial cold autoinflammatory syndrome. It is a milder type of cryopyrin-associated autoinflammatory syndrome. Another type of gene mutation is reported which is the NLPR12 gene which codes for a protein called monarch-1. This protein controls the switch-off signal for inflammation.

How Is Familial Cold Autoinflammatory Syndrome Inherited?

This syndrome is passed on to an individual in an autosomal dominant manner. The affected person with one altered gene inherited from one affected parent will show signs of the disease.

A parent with an affected gene will have a fifty percent chance of having a child with the defective copy of the gene and hence will be showing traits of the disease.

And there will be a fifty percent chance of having a child with a normal copy of the gene without any abnormalities. Males and females have equal frequency percentages.

What Are the Signs and Symptoms of Familial Cold Autoinflammatory Syndrome?

In affected individuals, around 60 % start showing symptoms of the disease at birth,95 % of them present during the first six months of birth, and others in later years. The diagnosis is often made late at around 10 years of age. The symptoms develop when affected people are exposed to generalized cold temperatures like air-conditioned rooms, winter season, or cool dampened places and have a flare-up ( when symptoms become worse). They might remain asymptomatic until they are exposed to triggering situations. The clinical presentations are short-lived and sudden and can include:

• Fever: A low-grade fever develops with chills after four to six hours of exposure to cold. It occurs in 93 % of people and usually lasts for less than twenty-four hours.

• Itchy Rash: This is the first symptom to develop in almost all patients. It occurs at birth and presents hive-like light pink patches of random patterns or red flat areas or slightly elevated pimple-like rash. It disappears before 24 hours. The rashes might be itchy and burning and occur often on hands and legs which are exposed to cold

• Painful and Stiff Joints: There is a pain in the hands, legs, and ankles developing after four to six hours after cold exposure. Sometimes the joints get swollen.

• Eye Problems: The white portion of the eye is irritated and it becomes red called conjunctivitis. There is also blurring of vision, an increase in tear production

• Amyloidosis: This is the deposition of a protein called Amyloid A which causes amyloidosis. It is a rare complication.

• Muscle pain.

• Nausea.

• Abdominal pain.

• Diarrhoea.

• Fatigue.

• Headache.

• Excess sweating.

• Extreme thirst.

• Kidney failure.

The onset of symptoms occurs one to two hours after exposure to the cold and reaches a peak in two to six hours. The severity of symptoms increases with a decrease in temperature. They last up to 24 hours and then settle down on their own. Symptoms decrease in frequency and severity with age.

How Is Familial Cold Autoinflammatory Syndrome Diagnosed?

This syndrome is similar to acquired cold urticaria. But both are different conditions.

1. The diagnostic criteria to differentiate familial cold autoinflammatory syndrome from acquired cold urticaria and other similar disorders with episodic fevers are:

   1. A history of recurrent episodes of fever after exposure to cold.

   2. Any of the family members presenting with same syndrome.

   3. Manifestation of syndromes from the age of 6 months.

   4. The symptoms resolve within 24 hours.

   5. Presence of irritation in the eyes along with attacks of fever.

   6. Absence of hearing loss, swelling of eyes, serous membranes, and lymph nodes.

2. Blood Tests: The levels of erythrocyte sedimentation rate (ESR ), C-reactive protein (CRP), and amyloid A protein are increased.

3. Biopsy: A sample from the skin rash is taken to study its pathology under a microscope. Its microscopic examination reveals leukocyte infiltration in the upper skin layer.

4. Genetic Testing: The genome sequencing to test for defective NLRP3 gene is done.

What Is the Treatment for Familial Cold Autoinflammatory Syndrome?

1. Minimizing Cold Exposure: The triggering factor for this disease is cold, thus should be avoided. Patients can move from cold places to warm places, avoid using air-conditioners, and stay inside the house during the winter and rainy seasons.

2. Medications:

   1. Biologics: These drugs block the inflammatory protein interleukin-1 which controls inflammation and intensifies it. They are given as injections under the skin.

      • Anakinra: It is given daily as a subcutaneous injection. They help is resolving symptoms within 12 hours and blood tests show significant improvement in a week.

      • Rilonacept: This drug is given once a week.

      • Canakinumab: This FDA-approved biologic drug is given once in 8 weeks.

   2. Steroids: Corticosteroids suppress t the immune system and the process of inflammation will be slowed down to prevent symptoms. But they should be used only for a short duration.

   3. Non-Steroidal Anti-inflammatory Drugs: They help reduce episodes of pain and fever associated with cold exposure.

Conclusion

The syndrome is a persistent condition throughout life. Yet the affected individuals have a normal life expectancy. There is ongoing research work for discovering new treatment methods to treat this rare congenital autoimmune syndrome.