International Journal of Rheumatic Diseases 2014; 17: 346–348
CORRESPONDENCE
CINCA syndrome in an infant presenting with hydrocephalus
Dear Editor, Chronic infantile neurologic, cutaneous and arthritis (CINCA) syndrome, also called neonatal-onset multisystem inflammatory disease (NOMID), is a very rare congenital auto-inflammatory disease.1 Children suffering from CINCA present with urticarial-like rash, recurrent fever, central nervous system (CNS) involvement, chronic arthropathy and peculiar facial and morphological features.1,2 Local and systemic manifestations of disease develop as a result of elevated interleukin (IL)-1b production. Missense mutations within the CIAS1/NLRP3 gene encoding cryopyrin are found in 50–60% of patients.2 We report an infant with CINCA syndrome presenting with hydrocephalus to emphasize awareness of this rare condition. A 7-month-old boy attended to hospital for investigation of hydrocephalus. He was born by normal vaginal delivery following an unremarkable pregnancy. He had urticarial rash with waxes and wanes beginning from birth, and recurrent attacks of high fever without a definite source. Progressive enlargement of head developed after 3 months. The parents were healthy and non-consanguineous. On admission the patient was afebrile, awake and alert. He had an open, bulging fontanel and eyes appeared to gaze downward. Other vital signs were stable. Cranial computerized tomography (CT) revealed bilateral enlargement of lateral ventricles and cerebral atrophy in frontal, temporal and partially in parietal lobes. Investigations for intrauterine infections and metabolic diseases were negative. Immunological workup did not reveal any congenital immunodeficiency. A ventriculo-peritoneal (VP) shunt was inserted on the 26th day of admission and he was discharged after 10 days. Five days later he was readmitted with fever. Physical examination revealed a fully alert child with body temperature of 38°C. Blood test showed leukocytes 40 000/mm3, hemoglobin 7.8 mg/dL, hematocrit 28.7% and C reactive protein 8 mg/dL. Cerebrospinal fluid (CSF) examination revealed 30 leukocytes/mm³, glucose
41 mg/dL and protein 69 mg/dL. Blood and CSF cultures remained sterile. He experienced fluctuating episodes of high fever and high inflammation markers during his stay in hospital. VP shunt revision was performed multiple times and finally a ventriculo-atrial (VA) shunt was inserted. Recurrent episodes of unexplained elevation of inflammatory markers and fever raised the suspicion of an auto-inflammatory disease. Urticaria-like rash attacks beginning from birth, chronic meningitis and cerebral atrophy led us to consider CINCA as the most probable diagnosis. He had no articular or bone deformities but pain on mobilization of lower limbs and joints was declared by his mother. Search for mutations in NLRP3 gene revealed that the proband was heterozygous for the mutation p.Gly569Arg (G569R) located in exon 3. Anakinra, an IL-1 receptor antagonist, was started at a dose of 2 mg/kg/day as subcutaneous injections. Following the initiation of anakinra, his constitutional symptoms, fever and acute phase reactant levels were promptly alleviated. Fever and urticarial rash did not recur during the following 3 months. Bilateral hearing impairment was detected by otoacoustic emission and a brainstem response evoked audiometry is planned. CINCA syndrome is a well-defined clinical condition but its early identification is often missed. Neven et al.3 defined three major criteria for the diagnosis of CINCA syndrome: (i) early-onset urticarial skin rash variably associated with episodic fever; (ii) CNS involvement; and (iii) inflammatory or deforming arthropathy. In younger subjects (< 4 years old), typical facies in addition to two major criteria is enough for the early diagnosis. Aseptic meningitis and increased intracranial pressure are common. Torbiak et al.4 summarized clinical finding in 32 NOMID patients and reported that the incidence of sensorineural hearing loss, seizures, intellectual impairment, hydrocephalus/atrophy and chronic meningitis ranged from 22–93% of cases in ascending frequencies. In a recent report, ventriculomegaly was detected on brain magnetic resonance
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
imaging (MRI) in 42% of patients with NOMID.5 Osteoarthropathy, mainly of the large joints and overgrowth of epimetaphyseal cartilage, particularly of the long bones, is also a distinctive feature. Among 26 patients with NOMID, bone overgrowth, joint contractures and limb length discrepancies were present in 38%, 69% and 23% of patients, respectively.5 The volume of the bony lesions increased significantly despite anakinra therapy. The uniqueness of our case is presentation with pronounced ventriculomegaly, absence of cartilaginous or bony overgrowth and diagnosis at an early age. NOMID/CINCA syndrome is the most severe clinical phenotype in the spectrum of cryopyrin-associated periodic syndromes (CAPS) which also include the Muckle–Wells syndrome (MWS) and the familial cold autoinflammatory syndrome (FCAS).2 Cryopyrin (also known as PYPAF1 or NALP3) is a member of the cytoplasmic protein family caterpillar, which is involved in inflammasome molecular platform assembly, leading to inflammatory immune response and apoptosis regulation.6 In the presence of a still unknown stimulus, cryopyrin oligomerizes and binds the adaptor protein ASC (apoptosis-associated speck-like protein). This association directly activates the IL-converting enzyme (ICE)/caspase-1 and through other inflammasome components, the nuclear factor kappa B (NF-jB).7 Therefore, activated cryopyrin induces both the release of IL-1b and the transcription of pro-inflammatory and anti-apoptotic genes. Chronic IL-1b overproduction leads to the auto-inflammatory phenotype observed in CINCA syndrome and organ damage. More than 90 mutations associated with a CAPS phenotype have been reported. For CINCA patients, a study reports no difference in clinical phenotype between patients with and those without mutations.8 However, severity gradient of disease may be related to amount of IL-1 production. The mutation p.Gly569Arg (G569R) carried by our patient was previously reported in a MWS patient9 and subsequently found in a CINCA patient (L. Cuisset, personnal communication). Specific inhibition of IL-1 by anakinra, IL-1 receptor antagonist, has given good results in CINCA.10 The two longer-acting IL-1 blocking agents, rilonacept and canakinumab were efficacious in treatment of FCAS and MWS.11,12 Studies for IL-1b blocking therapies targeting a broad spectrum of new indications are underway. Pediatricians should be aware of this rare condition in order to prevent progression to irreversible organ damage and disability. Rapid clinical response to IL-1
International Journal of Rheumatic Diseases 2014; 17: 346–348
blocking therapy has made it imperative to treat patients early and aggressively.
CONFLICT OF INTEREST The study was not funded by any source. Ozden TUREL1, Nilufer GOKNAR1, Selcuk UZUNER1, Ozgur KASAPCOPUR2 and Laurence CUISSET3,4 1
Department of Pediatrics, Faculty of Medicine, Bezmialem Vakif University, 2Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul, Turkey; 3Assistance Publique Hoˆpitaux de Paris, H^opital Cochin, and 4Institut Cochin, Universite Paris Descartes, Inserm, Paris, France Correspondence: Dr Ozden Turel, email: [email protected]
REFERENCES 1 Prieur AM (2001) A recently recognized chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol 19, 103–6. 2 Goldbach-Mansky R (2011) Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep 13, 123–31. 3 Neven B, Callebaut I, Prieur AM et al. (2004) Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell mediated auto-inflammatory disorders (CINCA/NOMID, MWS, FCU). Blood 103, 2809–15. 4 Torbiak RP, Dent PB, Cockshott WP (1989) NOMID-a neonatal syndrome of multisystem inflammation. Skeltal Radiol 18, 359–64. 5 Sibley CH, Plass N, Snow J et al. (2012) Sustained response and prevention of damage progression in patients with neonatal onset multisystem inflammatory disease treated with Anakinra. Arthritis Rheum 64, 2375–86. 6 Tschopp J, Martinon F, Burns K (2003) NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4, 95–104. 7 Manji GA, Wang L, Geddes BJ et al. (2002) PYPAF1, a pyrin-containing Apaf1-like protein that assembles with ASC and regulates activation of NFjB. J Biol Chem 277, 11570–5. 8 Caroli F, Pontillo A, D’Osualdo A et al. (2007) Clinical and genetic characterization of Italian patients affected by CINCA syndrome. Rheumatology 46, 473–8. 9 Dode C, Le D^ u N, Cuisset L et al. (2002) New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 70, 1498–506.
347
Correspondence
10 Granel B, Serratrice J, Disdier P, Weiller P-J (2005) Dramatic improvement with anakinra in a case of chronic infantile neurological cutaneous and articular (CINCA) syndrome. Rheumatology 44, 689–90. 11 Gillespie J, Mathews R, McDermott MF (2010) Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS). J Inflamm Res 3, 1–8.
348
12 Kuemmerle-Deschner JB, Hachulla E, Cartwright R et al. (2011) Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis 70, 2095–102.
International Journal of Rheumatic Diseases 2014; 17: 346–348
CORRESPONDENCE
CINCA syndrome in an infant presenting with hydrocephalus
Dear Editor, Chronic infantile neurologic, cutaneous and arthritis (CINCA) syndrome, also called neonatal-onset multisystem inflammatory disease (NOMID), is a very rare congenital auto-inflammatory disease.1 Children suffering from CINCA present with urticarial-like rash, recurrent fever, central nervous system (CNS) involvement, chronic arthropathy and peculiar facial and morphological features.1,2 Local and systemic manifestations of disease develop as a result of elevated interleukin (IL)-1b production. Missense mutations within the CIAS1/NLRP3 gene encoding cryopyrin are found in 50–60% of patients.2 We report an infant with CINCA syndrome presenting with hydrocephalus to emphasize awareness of this rare condition. A 7-month-old boy attended to hospital for investigation of hydrocephalus. He was born by normal vaginal delivery following an unremarkable pregnancy. He had urticarial rash with waxes and wanes beginning from birth, and recurrent attacks of high fever without a definite source. Progressive enlargement of head developed after 3 months. The parents were healthy and non-consanguineous. On admission the patient was afebrile, awake and alert. He had an open, bulging fontanel and eyes appeared to gaze downward. Other vital signs were stable. Cranial computerized tomography (CT) revealed bilateral enlargement of lateral ventricles and cerebral atrophy in frontal, temporal and partially in parietal lobes. Investigations for intrauterine infections and metabolic diseases were negative. Immunological workup did not reveal any congenital immunodeficiency. A ventriculo-peritoneal (VP) shunt was inserted on the 26th day of admission and he was discharged after 10 days. Five days later he was readmitted with fever. Physical examination revealed a fully alert child with body temperature of 38°C. Blood test showed leukocytes 40 000/mm3, hemoglobin 7.8 mg/dL, hematocrit 28.7% and C reactive protein 8 mg/dL. Cerebrospinal fluid (CSF) examination revealed 30 leukocytes/mm³, glucose
41 mg/dL and protein 69 mg/dL. Blood and CSF cultures remained sterile. He experienced fluctuating episodes of high fever and high inflammation markers during his stay in hospital. VP shunt revision was performed multiple times and finally a ventriculo-atrial (VA) shunt was inserted. Recurrent episodes of unexplained elevation of inflammatory markers and fever raised the suspicion of an auto-inflammatory disease. Urticaria-like rash attacks beginning from birth, chronic meningitis and cerebral atrophy led us to consider CINCA as the most probable diagnosis. He had no articular or bone deformities but pain on mobilization of lower limbs and joints was declared by his mother. Search for mutations in NLRP3 gene revealed that the proband was heterozygous for the mutation p.Gly569Arg (G569R) located in exon 3. Anakinra, an IL-1 receptor antagonist, was started at a dose of 2 mg/kg/day as subcutaneous injections. Following the initiation of anakinra, his constitutional symptoms, fever and acute phase reactant levels were promptly alleviated. Fever and urticarial rash did not recur during the following 3 months. Bilateral hearing impairment was detected by otoacoustic emission and a brainstem response evoked audiometry is planned. CINCA syndrome is a well-defined clinical condition but its early identification is often missed. Neven et al.3 defined three major criteria for the diagnosis of CINCA syndrome: (i) early-onset urticarial skin rash variably associated with episodic fever; (ii) CNS involvement; and (iii) inflammatory or deforming arthropathy. In younger subjects (< 4 years old), typical facies in addition to two major criteria is enough for the early diagnosis. Aseptic meningitis and increased intracranial pressure are common. Torbiak et al.4 summarized clinical finding in 32 NOMID patients and reported that the incidence of sensorineural hearing loss, seizures, intellectual impairment, hydrocephalus/atrophy and chronic meningitis ranged from 22–93% of cases in ascending frequencies. In a recent report, ventriculomegaly was detected on brain magnetic resonance
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
imaging (MRI) in 42% of patients with NOMID.5 Osteoarthropathy, mainly of the large joints and overgrowth of epimetaphyseal cartilage, particularly of the long bones, is also a distinctive feature. Among 26 patients with NOMID, bone overgrowth, joint contractures and limb length discrepancies were present in 38%, 69% and 23% of patients, respectively.5 The volume of the bony lesions increased significantly despite anakinra therapy. The uniqueness of our case is presentation with pronounced ventriculomegaly, absence of cartilaginous or bony overgrowth and diagnosis at an early age. NOMID/CINCA syndrome is the most severe clinical phenotype in the spectrum of cryopyrin-associated periodic syndromes (CAPS) which also include the Muckle–Wells syndrome (MWS) and the familial cold autoinflammatory syndrome (FCAS).2 Cryopyrin (also known as PYPAF1 or NALP3) is a member of the cytoplasmic protein family caterpillar, which is involved in inflammasome molecular platform assembly, leading to inflammatory immune response and apoptosis regulation.6 In the presence of a still unknown stimulus, cryopyrin oligomerizes and binds the adaptor protein ASC (apoptosis-associated speck-like protein). This association directly activates the IL-converting enzyme (ICE)/caspase-1 and through other inflammasome components, the nuclear factor kappa B (NF-jB).7 Therefore, activated cryopyrin induces both the release of IL-1b and the transcription of pro-inflammatory and anti-apoptotic genes. Chronic IL-1b overproduction leads to the auto-inflammatory phenotype observed in CINCA syndrome and organ damage. More than 90 mutations associated with a CAPS phenotype have been reported. For CINCA patients, a study reports no difference in clinical phenotype between patients with and those without mutations.8 However, severity gradient of disease may be related to amount of IL-1 production. The mutation p.Gly569Arg (G569R) carried by our patient was previously reported in a MWS patient9 and subsequently found in a CINCA patient (L. Cuisset, personnal communication). Specific inhibition of IL-1 by anakinra, IL-1 receptor antagonist, has given good results in CINCA.10 The two longer-acting IL-1 blocking agents, rilonacept and canakinumab were efficacious in treatment of FCAS and MWS.11,12 Studies for IL-1b blocking therapies targeting a broad spectrum of new indications are underway. Pediatricians should be aware of this rare condition in order to prevent progression to irreversible organ damage and disability. Rapid clinical response to IL-1
International Journal of Rheumatic Diseases 2014; 17: 346–348
blocking therapy has made it imperative to treat patients early and aggressively.
CONFLICT OF INTEREST The study was not funded by any source. Ozden TUREL1, Nilufer GOKNAR1, Selcuk UZUNER1, Ozgur KASAPCOPUR2 and Laurence CUISSET3,4 1
Department of Pediatrics, Faculty of Medicine, Bezmialem Vakif University, 2Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul, Turkey; 3Assistance Publique Hoˆpitaux de Paris, H^opital Cochin, and 4Institut Cochin, Universite Paris Descartes, Inserm, Paris, France Correspondence: Dr Ozden Turel, email: [email protected]
REFERENCES 1 Prieur AM (2001) A recently recognized chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol 19, 103–6. 2 Goldbach-Mansky R (2011) Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep 13, 123–31. 3 Neven B, Callebaut I, Prieur AM et al. (2004) Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell mediated auto-inflammatory disorders (CINCA/NOMID, MWS, FCU). Blood 103, 2809–15. 4 Torbiak RP, Dent PB, Cockshott WP (1989) NOMID-a neonatal syndrome of multisystem inflammation. Skeltal Radiol 18, 359–64. 5 Sibley CH, Plass N, Snow J et al. (2012) Sustained response and prevention of damage progression in patients with neonatal onset multisystem inflammatory disease treated with Anakinra. Arthritis Rheum 64, 2375–86. 6 Tschopp J, Martinon F, Burns K (2003) NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4, 95–104. 7 Manji GA, Wang L, Geddes BJ et al. (2002) PYPAF1, a pyrin-containing Apaf1-like protein that assembles with ASC and regulates activation of NFjB. J Biol Chem 277, 11570–5. 8 Caroli F, Pontillo A, D’Osualdo A et al. (2007) Clinical and genetic characterization of Italian patients affected by CINCA syndrome. Rheumatology 46, 473–8. 9 Dode C, Le D^ u N, Cuisset L et al. (2002) New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 70, 1498–506.
347
Correspondence
10 Granel B, Serratrice J, Disdier P, Weiller P-J (2005) Dramatic improvement with anakinra in a case of chronic infantile neurological cutaneous and articular (CINCA) syndrome. Rheumatology 44, 689–90. 11 Gillespie J, Mathews R, McDermott MF (2010) Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS). J Inflamm Res 3, 1–8.
348
12 Kuemmerle-Deschner JB, Hachulla E, Cartwright R et al. (2011) Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis 70, 2095–102.
International Journal of Rheumatic Diseases 2014; 17: 346–348
