Cinca Syndrome

A number sign (#) is used with this entry because of evidence that CINCA syndrome (CINCA) is caused by heterozygous mutation in the gene encoding cryopyrin (NLRP3; 606416) on chromosome 1q44.

Description

Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central nervous system involvement, and arthropathy (Feldmann et al., 2002).

See also familial cold autoinflammatory syndrome-1 (FCAS1, CAPS1; 120100), an allelic disorder with a less severe phenotype.

Clinical Features

CINCA syndrome, also known as 'neonatal onset multisystem inflammatory disease,' or NOMID, is a rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation (Prieur and Griscelli, 1981; Hassink and Goldsmith, 1983; Torbiak et al., 1989; Prieur, 2001). Persistent and migratory skin rash associated with skin perivascular polymorphonuclear infiltrates is present in patients, starting at birth. A progressive neurologic impairment results from chronic meningitis caused by polymorphonuclear cell infiltration. A progressive visual defect and perceptive deafness frequently occur with increasing age. Joint symptoms manifest recurrent joint flares with or without severe radiologically evident modifications involving the growth cartilage or bone epiphysis. Distinctive facies with characteristic frontal bossing and protruding eyes have been described, as well as shortening of distal limbs and growth retardation, giving a sib-like resemblance between unrelated patients. Intrafamilial occurrence, although much rarer than sporadic cases, is suggestive of an autosomal dominant inheritance pattern (Feldmann et al., 2002).

Overgrowth of the patella and distal femur create a prominence of the knees that is characteristic of CINCA syndrome. This particular feature was noted in the report of Prieur and Griscelli (1981) and the review of Prieur et al. (1987) with clinical photographs and radiographs. Prieur et al. (1987) reported on the clinical presentation and course of 30 patients with CINCA syndrome observed in France, Germany, Finland, England, and the United States.

Leone et al. (2003) studied 3 patients with CINCA syndrome and found that all showed normal phagocytosis and oxidative burst functions of neutrophils. Because the patients had significantly increased expression of CD10 (120520), Leone et al. (2003) postulated that this finding may be a useful marker of the inflammatory disorder typical of some patients.

Molecular Genetics

Feldmann et al. (2002) identified heterozygous missense mutations in exon 3 of the CIAS1 gene (e.g., 606416.0007) in the affected members of each of 7 families with CINCA syndrome.

Of 3 patients with CINCA syndrome studied by Leone et al. (2003), only 1 had a mutation in exon 3 of the CIAS1 gene.

Aksentijevich et al. (2002) identified heterozygous missense mutations in exon 3 of the CIAS1 gene in 6 of 13 patients with CINCA syndrome. No mutation in the CIAS1 gene was found in the other 7 patients, suggesting genetic heterogeneity. Aksentijevich et al. (2002) found no discernible differences in the clinical features of patients with or without mutations in CIAS1.

Clinical Management

Boschan et al. (2006) reported a 5-year-old boy with a CIAS1 mutation and symptoms of severe systemic inflammation suggestive of NOMID. Although prior antiinflammatory therapy had only limited success, treatment with the IL1R antagonist (IL1RN; 147679) anakinra led to remarkable improvement of the clinical and laboratory findings. There was disappearance of rash, cessation of fever episodes with abdominal pain and vomiting, reduction in hepatosplenomegaly and lymph node size, progressive closure of the anterior fontanel, and reduction in papilledema. Serologically, white blood cell count, C-reactive protein (123260) and amyloid A (104750) levels, and erythrocyte sedimentation rate all normalized. The patient became more agile and outgoing and made large developmental advances within a short period of time.