CINCA Syndrome

Alternative Names

  • CINCA
  • Chronic Neurologic Cutaneous and Articular Syndrome
  • Multisystem Inflammatory Disease, Neonatal-Onset
  • NOMID
  • Cryopyrin-Associated Periodic Syndrome 3
  • CAPS3
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Certain disorders involving the immune mechanism

OMIM Number

607115

Gene Map Locus

1q44

Description

Chronic neurologic cutaneous and articular (CINCA) syndrome, also known as neonatal onset multisystem inflammatory disease (NOMID) is a rare monogenic autoinflammatory disorder, belonging to the spectrum of cryopyrin-associated periodic syndrome (CAPS). The condition is characterized by seemingly unprovoked inflammation, in the absence of autoimmune or infective causes. Three main manifestations of CINCA syndrome are cutaneous signs, including maculopapular urticarial eruptions, commonly observed in the infantile period, joint involvement of variable severity, and CNS involvement. All these signs may vary considerably over time. In addition, affected patients often show other features, including fever, lymphadenopathy, hepatosplenomegaly, progressive hearing loss, eye involvement (conjunctivitis, uveitis, papilledema, and optic nerve atrophy), abnormal crabiofacial features, and a failure to grow. The skin manifestations are caused by a neutophilic infiltrate in the dermis. The varied joint abnormalities range from merely mild articular attacks to cartilaginous abnormalities, suggestive of a pseudo-tumor. CNS involvement is the most damaging. Craniofacial abnormalities include macrocephaly with frontal bossing, saddle-back nose, and delayed closure of the anterior fontanel.

CINCA syndrome is extremely rare, with only close to 100 patients having been reported in medical literature. Non-steroidal anti-inflammatory drugs, steroids, slow acting anti-rheumatic drugs, and immune-suppressants have all have been used in the management of CINCA. However, they only appear to have some symptomatic relief. Treatment with IL-1 blocking drugs is being considered.

Molecular Genetics

CINCA syndrome is caused due to mutations in the NLRP3 gene (NLR Family, Pyrin Domain-Containing 3), located on the long arm of chromosome 1. The NLRP3 gene codes for a cytoplasmic protein, called cryopyrin, which is involved in the immune system, specifically in the inflammatory response. Activated cryosporin molecules assemble to form what are called inflammasomes as part of the body's defense mechanism. These inflammasomes help in recruiting and activating interleukins, specially IL-1 beta and IL-18. The protein contains a nucleotide binding domain and leucine rich repeats, and is found mostly in leukocytes and chondrocytes.

To date, more than 90 mutations in this gene have been identified in patients with CAPS. About 30 of these mutations have been found in patients with CINCA syndrome. Interestingly, almost all these mutations are localized to exon 3, which contains the nucleotide binding domain. Most of these mutations seem to hyperactivate the protein, thereby precipitating an excessive inflammatory response.

Epidemiology in the Arab World

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Other Reports

Kuwait

Ismail et al. (2001) reported the first Arab patient with CINCA syndrome. The patient was a male who was first seen at the age of 8-years for hepatosplenomegaly. He was the product of a first-cousin consanguineous marriage, and had six healthy siblings. Upon examination, he was found to be pale, with widely open anterior fontanel, hypotonic, and developmentally delayed. Hepatosplenomegaly was confirmed by abdominal ultrasound. A maculopapular skin rash was first observed at 11-months of age. Bone marrow biopsy was consistent with chronic infection or inflammation, although serological studies for several viruses and bacteria were negative. Mild cerebral atrophy was visualized on CT brain. Polyarthritis developed at the age of 4-years, which involved the left ankle, right elbow, and wrist. Subsequently, he had several such attacks involving the large joints; each attack resolving itself spontaneously over a period of a couple of days. These attacks were accompanied with a low grade fever and an almost persistent skin rash and generalized lymphadenopathy. Upon evaluation at 8-years of age, his height, weight and head circumference were below normal. He had frontal bossing, no wrinkling of palms and soles, a maculopapular skin rash, injected conjunctivae, hepatosplenomegaly, and clubbing. Tests ruled out the possibility of lipid storage diseases and oligosaccharidosis.

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