Chronic Infantile Neurological Cutaneous Articular Syndrome Research Articles

Síndrome CINCA: presentación de un caso con exacerbación febril de sus lesiones cutáneas

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate.With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.

Exacerbation of Skin Lesions During Fever in a Patient With Chronic Infantile Neurologic Cutaneous Articular Syndrome

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate. With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.

Pattern of interleukin‐1β secretion in response to lipopolysaccharide and ATP before and after interleukin‐1 blockade in patients with CIAS1 mutations

To examine the synthesis, processing, and secretion of interleukin-1beta (IL-1beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra). Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1beta levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP. LPS-induced IL-1beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1beta secretion by the patients' cells in vitro. Our results showed that the requirements of ATP stimulation for IL-1beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1beta.

Clinical and genetic characterization of Italian patients affected by CINCA syndrome

We report the experience of the Italian Registry of patients affected by chronic infantile neurological, cutaneous, articular (CINCA) syndrome. The clinical and genetic features of 12 unrelated Italian patients with CINCA syndrome are described, focusing on the possible influence of the presence of CIAS1/cryopyrin mutations on the phenotype of the disease and on its prognosis. The clinical features of 12 Italian CINCA patients were evaluated. Genomic DNA of the patients was sequenced using specific primers for CIAS1 and ASC genes. Our patients shared typical CINCA characteristics and, sometimes, remarkable perinatal events, peculiar of CIAS1-mutated patients. Seven patients carried CIAS1 missense mutation, localized within the nucleotide binding domain of cryopyrin. Four previously described mutations and three new heterozygous CIAS1 missense mutations were identified. ASC gene, encoding for a direct interactor of cryopyrin, was not mutated in Italian CINCA patients. Finally, we reported the efficacy and safety of anti-IL1 therapy (Anakinra) in seven patients with a particularly severe CINCA phenotype. Despite some common signs-used as syndrome hallmarks-we observed a high variability in symptoms, genetic results and outcomes in Italian CINCA patients. In contrast with other authors, we cannot find out any correlation between mutations in CIAS1 and CINCA severity, but we underlined the concomitance of perinatal events and mental retardation only in CIAS1 mutated subjects. Finally, we confirmed the efficacy of Anakinra treatment, both in CIAS1-mutated and non-mutated patients.

A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents

In this report we describe a case of severe chronic infantile neurologic, cutaneous, articular (CINCA) syndrome with a novel G307V cryopyrin mutation and all of the characteristic clinical and laboratory features of this autoinflammatory disease. There was no clear response to standard therapies, including human interleukin-1 (IL-1) receptor antagonist (anakinra) and soluble tumor necrosis factor receptor (etanercept). The patient finally had a partial clinical response (reduction in fever and irritability) and complete laboratory response (improved C-reactive protein and serum amyloid A levels) to humanized anti-IL-6 receptor antibody (MRA), but died from congestive heart failure and interstitial pneumonia 2 months after initiation of therapy. We serially measured the serum cytokine levels and expression of NF-kappaB activation in the patient's peripheral blood mononuclear cells before and during consecutive therapies. Pathologic examination of autopsy specimens was also performed. This case illustrates the continued difficulty in management of patients with CINCA syndrome and the complexity of the inflammatory pathways in this disorder.

Hydrocephalus in CINCA syndrome treated with anakinra

Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome is a rare congenital autoinflammatory disease characterized by neonatal-onset chronic meningitis, hydrocephalus, sensorineural hearing loss, persistent urticarial rash, deforming arthritis, and recurrent fever. This clinical entity is believed to result from dysregulation of cytokine production. No recommended treatment protocol exists so far for CINCA syndrome. We report a 7-year-old child affected with CINCA syndrome in whom no therapy had resulted effective. Anakinra, an interleukin-1-receptor antagonist, was administered in a 1-year period with complete inflammatory symptom remission and dramatically ameliorated laboratory tests. This optimal response has been supported by the demonstration of a stabilized hydrocephalus upon magnetic resonance imaging and by an overall improvement of the neurodevelopmental issues. This paper emphasizes and discusses the medical approach with anakinra in CINCA syndrome presenting with hydrocephalus in which a consistent control of the neurological picture can be obtained.

Anakinra in mutation-negative CINCA syndrome

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare congenital inflammatory disorder with variable clinical manifestations but devastating in a great majority of the cases. The syndrome is characterized by a generalized, wandering palpable rash eruption of neonatal onset, chronic arthropathy characterized by abnormal proliferation of cartilage and an abnormal ossification, and a progressive neurological impairment as the result of a chronic meningitis caused by polymorphonuclear cell infiltration [1, 2]. Nevertheless, many other manifestations are described, including fever, generalized lymphadenopathy, hepatosplenomegaly, developmental retardation, hydrocephalus, cerebral atrophy, ocular involvement in the form of uveitis and papilitis, and perceptive deafness. Recently, the syndrome has been associated with mutations in the CIAS1 gene [3]. These mutations will imply a higher level of interleukin-1 (IL-1) and a good response with the recombinant human IL-1 receptor antagonist anakinra [4, 5]. Nevertheless, CINCA syndrome has not always been associated with CIAS1 mutations, but in these cases, patients can also respond well to the treatment with anakinra [6], as in the case of the patient we present. Case report

Expanding the phenotype of CIAS1 related autoinflammatory syndrome

Dominant mutations in the CIAS1 gene cause a spectrum of autoinflammatory diseases such as CINCA (chronic, infantile, neurologic, cutaneous, articular) syndrome, Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS) which is characterized by episodes of urticaria, arthralgia, fever, and conjunctivitis after generalized exposure to cold. We here describe patients of two German families with the 592G→A, V198M mutation within the CIAS1 gene, which has been described to induce FCAS before. However, in our patients the clinical phenotype was very different from this disease. They never had urticaria, cold induced fever or conjunctivitis; instead the following symptoms occurred: Very regular periodic fever, irregular severe febrile episodes, relatively mild arthralgia, dry cough, cardiomyopathy, nephropathy, and euthyroid thyroiditis all being reversible. We conclude that the clinical phenotype associated with mutations in the CIAS1 gene is much broader than assumed before.

Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare disorder of unknown aetiology with neonatal onset, characterized by severe arthropathy, persistent skin rash and central nervous system disease. Joint involvement may vary from minimal swelling to destructive arthritis, with inability to stand or walk. The most striking findings of CINCA syndrome are cartilage anomalies with epiphyseal modifications and abnormal ossification, for which a pathogenetic role of tumour necrosis factor‐α (TNF‐α) is postulated. We describe a 4‐year‐old child affected with CINCA syndrome and presenting progressive joint disease, in whom non‐steroidal anti‐inflammatory drugs (NSAID) and systemic corticosteroidal therapy had been ineffective. Etanercept, anti‐TNF‐α therapy, was administered over a 6‐month‐period resulting in a dramatic improvement of the arthropathy. This good response to anti‐cytokine treatment supports our hypothesis that TNF‐α might play an important role in the pathogenesis of CINCA syndrome, which needs to be evaluated and confirmed in further studies.

Two German CINCA (NOMID) patients with different clinical severity and response to anti-inflammatory treatment.

Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a deforming arthritis. In the CIAS1 gene of many but not all CINCA patients, disease-associated mutations have been found recently. We here describe two such patients from Germany. One of them, a 3-yr-old boy, has a 1709A-->G, Y570C, mutation, which has previously been described to cause CINCA syndrome. His clinical course is very severe and no satisfying response has been achieved even with high doses of local and systemic steroids. The other patient has a somewhat milder clinical course and considerable improvement could be accomplished with moderate and low doses of steroids. In her CIAS1 gene we have found a 1043C-->T, T348M, mutation, which has only been detected in Muckle-Wells syndrome before. Our results suggest that the severity of symptoms in CINCA patients may be influenced by the underlying mutation in the CIAS1 gene. Furthermore, our observations support the view that CINCA syndrome and Muckle-Wells syndrome are essentially the same disease with different degrees of severity.