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NLRP12-associated autoinflammatory disorder

NLRP12-associated autoinflammatory disorder, also known as Guadeloupe-type fever syndrome, is a rare systemic autoinflammatory disorder characterized by episodic and recurrent rash, urticaria, arthralgia, myalgia, and headache. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report exposure to cold as a trigger for the episodes. Additional features may include abdominal pain, thoracic pain, and sensorineural deafness. The age at onset is variable.

Episodes usually begin in infancy and occur throughout life.

Symptoms may be delayed for up to a few hours after the cold exposure. Episodes last an average of 12 hours but may continue for up to 3 days.

In people with familial cold autoinflammatory syndrome, the most common symptom that occurs during an episode is an itchy or burning rash. The rash usually begins on the face or extremities and spreads to the rest of the body. Occasionally swelling in the extremities may occur.

In addition to the skin rash, episodes are characterized by fever, chills, and joint pain, most often affecting the hands, knees, and ankles. Redness in the whites of the eye (conjunctivitis), sweating, drowsiness, headache, thirst, and nausea may also occur during an episode of this disorder.

The clinical presentation of this condition overlaps with cryopyrin-associated periodic syndromes (CAPS); prior to the discovery of this novel mutation in 2008, patients were categorized as ‘mutation-negative’ CAPS. The most severely affected patients suffer from neurosensory signs such as headache or deafness. The inflammatory attacks last 5-10 days and are triggered by physical exertion or cold exposure.

Genetics

Mutations in this gene are associated with familial cold autoinflammatory syndrome type 2 (FCAS2), a rare autosomal dominant systemic inflammatory disease caused by mutations in the NLRP12 gene, also known as NALP12 and MONARCH-1. One copy of the altered gene in each cell is sufficient to cause the disorder. Monarch-1 is involved in the inhibition of the inflammatory response. Mutations in the NLRP12 gene appear to reduce the ability of the monarch-1 protein to inhibit inflammation.

FCAS2 presents with fever, joint pain, and urticarial rash after exposure to cold temperatures. Few patients with NLRP12 related autoinflammatory disease have been identified, therefore there is little data on the phenotypic presentation of this syndrome.

Other symptoms can also be arthralgias, myalgias, chills, swelling of the extremities, and conjunctivitis. The most severely affected patients suffer from neurosensory signs such as headache or deafness. The inflammatory attacks last 5-10 days and are triggered by physical exertion or cold exposure.

Clinical characteristics

  1. the disease started during the first year of life;

  2. the patients present more than one attack per month;

  3. episodes are triggered by generalized exposure to cold; and

  4. attacks that last several days associate high fever (>40°C), arthralgia, and headache 

 

Treatment

Studies have shown IL-1 blockade with anakinra and canakinumab to be successful.

 

 

Sources:

NLRP12 autoinflammatory disease: a Chinese case series and literature review. Shen, M., Tang, L., Shi, X. et al. Clin Rheumatol (2017) 36: 1661. https://doi.org/10.1007/s10067-016-3410-y

Mutations in NALP12 cause hereditary periodic fever syndromes. Jéru, P. Duquesnoy, et al.

Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. https://www.pnas.org/content/105/5/1614

The expanding spectrum of rare monogenic autoinflammatory diseases. Touitou, I., Galeotti, C., Rossi-Semerano, L. et al.  Orphanet J Rare Dis 8, 162 (2013) https://doi.org/10.1186/1750-1172-8-162

Mutations in NALP12 cause hereditary periodic fever syndromes. I. Jéru et al. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. doi: 10.1073/pnas.0708616105. Epub 2008 Jan 29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234193

Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Isabelle Jéru et al. ARTHRITIS & RHEUMATISM Vol. 63, No. 5, May 2011, pp 1459–1464. https://doi.org/10.1002/art.30241

Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases. Ter Haar NM, Eijkelboom C, Cantarini L, et al.  Ann Rheum Dis2019:pii: annrheumdis-2018-214472. doi:10.1136/annrheumdis-2018-214472

Missense mutation in nlrp12 associated with an atypical periodic fever syndrome. Annals of Allergy, Asthma & Immunology Volume 121, Issue 5, Supplement, November 2018, Page S108. https://doi.org/10.1016/j.anai.2018.09.356