TNF-α gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response.

OBJECTIVE: To investigate the genetic contribution of TNF-α gene polymorphisms on the disease course and therapeutic response in patients with juvenile idiopathic arthritis (JIA). METHODS: 74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at positions -163, -244, -238, -376, and -308. RESULTS: No SNPs at position -163 were observed, while we observed only SNPs at positions -244 and -376 in the controls. No differences were observed in the prevalence of SNPs at -238 and -308 between JIA and controls. In JIA patients no significant differences were observed between the -238 and -308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of -308 GG genotype with respect to GA and AA genotypes after 6 (p = 0.008 and p = 0.013, respectively) and 12 months of disease (p = 0.02 and p = 0.08, respectively). Also the -238 GG genotypes showed a better disease course after 12 months of disease. Moreover, the -238/-308 GG genotypes presented the higher reduction of disease activity both after 6 (p < 0.01 vs GA and p < 0.01 vs AA) and 12 months from baseline (p < 0.01 vs GA and p < 0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype -308 AA respect to both GA (p = 0.012) and GG (p = 0.016). CONCLUSIONS: JIA patients carrying the TNF-α -308 GA/AA and -238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-α drugs.

Serum calprotectin: review of its usefulness and validity in paediatric rheumatic diseases.

In most childhood rheumatic diseases, specific diagnostic markers are not yet available. Therefore, a major emphasis in medical research today is directed to the discovery of new inflammation molecules, like calprotectin. Calprotectin (MRP8/MRP14) is a complex of calcium- and zinc-binding proteins that belong to the S100 protein family. This protein is directly released by leukocytes during the interaction with inflammatory activated endothelium at the site of inflammation. Increased plasma calprotectin levels have been found in inflammatory chronic diseases such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel diseases (IBD), multiple sclerosis, cystic fibrosis and systemic lupus erythematosus (SLE). In these diseases, serum calprotectin has been shown to correlate with disease activity and laboratory variables of inflammation such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). This review outlines the validity and the possible applications of calprotectin as a new inflammation marker in paediatric rheumatic diseases.

Prolonged sporadic hemiplegic migraine associated with a novel de novo missense ATP1A2 gene mutation.

Hemiplegic migraine is a rare form of migraine characterized by periodic attacks of migraine with neurologic aura and transient hemiplegia. There are familial and sporadic cases, both on a genetic basis; we describe the case of a 6-year-old boy affected by sporadic hemiplegic migraine, showing a novel ATP1A2 gene missense mutation (p.Gly715Arg) in exon 16. Long-term treatment with flunarizine resulted in good clinical response and prevention of further attacks.

Autoinflammatory syndromes: diagnosis and management.

During the last decades the description of autoinflammatory syndromes induced great interest among the scientific community. Mainly rheumatologists, immunologists and pediatricians are involved in the discovery of etiopathogenesis of these syndromes and in the recognition of affected patients. In this paper we will discuss the most important clues of monogenic and non-genetic inflammatory syndromes to help pediatricians in the diagnosis and treatment of these diseases.

Gradenigo's syndrome with lateral venous sinus thrombosis: successful conservative treatment.

Gradenigo's syndrome (GS) is a rare disease characterised by the triad otitis media, pain in the region innervated by the first and the second division of trigeminal nerve and abducens nerve palsy. Septic sinus thrombosis is one of the most frequent and relevant complication of GS; it is often due to persistent damage and late diagnosis. Computed tomography (CT) scan and magnetic resonance imaging (MRI) allow the correct diagnosis in most cases. Surgical therapy may be necessary for a better and more rapid resolution of the disease. We report the case of a 4-year-old child that was admitted for facial nerve palsy and abducens nerve palsy subsequent to a 2-week persistent pain in the right ear. MRI showed infective acute process of the right mastoid and partial ipsilateral sinus thrombophlebitis. The child was treated with high-dose intravenous antibiotics and with oral anticoagulants. A complete resolution of symptoms and radiological alterations were observed within 7 weeks. In conclusion, lateral sinus thrombosis and Gradenigo's syndrome are rare but potential fatal complications of otitis media and mastoiditis. High-dose intravenous antibiotics and a low dose of anticoagulant can achieve a complete recovery without surgery.

Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update.

OBJECTIVES: We reviewed the literature to evaluate the role of common laboratory tests and to examine the recent progress in the laboratory diagnosis of pediatric rheumatic diseases. METHODS: We used the PubMed database (1950-2008) to search for the keywords "laboratory," "erythrocyte sedimentation rate" (ESR), "C-reactive protein" (CRP), "blood cytology," "procalcitonin" (PCT), "complement system," "ferritin," "antistreptolysin O titer" (ASO), "autoantibodies," "genetic studies," in conjunction with "rheumatic disease in children" and "pediatric autoimmune diseases." All relevant original and review articles in English were reviewed as well as textbooks of pediatric rheumatology. RESULTS: Laboratory tests (ESR, CRP, blood cytology, complement system, ferritin, ASO titer) play an important role in confirming a diagnosis and in the follow-up of rheumatic diseases in the pediatric age group. The ESR is probably the most widely measured index of the acute phase response. Measurement of CRP is very useful in the rapid diagnosis of infection as a progressive increase can be shown in the first 48 hours. Also, the subsequent fall in serum CRP concentration on resolution of inflammation is useful for monitoring the efficacy of treatment. In chronic diseases, a combination of CRP and ESR may provide the most useful information. Cytopenia and different forms of anemia can be encountered in many rheumatic diseases: they can be related to disease activity or to therapeutic side effects. Determination of complement levels (C3 and/or C4) is useful in the follow-up of systemic lupus erythematosus (SLE) and membranoproliferative glomerulonephritis. Ferritin is a laboratory hallmark of primary and secondary hemophagocytic lymphohistiocytosis. ASO titer should be obtained to confirm a diagnosis of acute rheumatic fever; other important antibody markers of streptococcal infection include antihyaluronidase, antideoxyribonuclease B, and antistreptokinase antibodies. We also found that, in the pediatric age, the main indication for synovial fluid analysis is suspected joint infection. Antinuclear antibodies, anti-Smith antigen, and anti-double-stranded DNA antibodies are important in the diagnosis of SLE, are useful prognostic markers, and facilitate clinical and treatment follow-up. Anti-SSA/Ro and anti-SSB/La antibodies are associated with Sjögren's syndrome and congenital heart block, while the anti-U1 small nuclear ribonucleoprotein antibodies show high specificity for mixed connective tissue disease. Repetitive spontaneous abortions, thrombocytopenia, and many types of venous or arterial thrombosis are associated with antiphospholipid antibodies. The presence of cytoplasmic antineutrophil antibodies is essential in the diagnosis of Wegener granulomatosis. The discovery of underlying single causative gene defects led to the identification of several autoinflammatory diseases, a group of genetic disorders characterized by recurrent attacks of inflammation (hereditary periodic fever syndromes). These include familial Mediterranean fever due to mutations in the Mediterranean fever (MEFV) gene, hyperimmunoglobulinemia D syndrome due to mutations in the MK gene for mevalonate kinase, cryopyrinopathies such as Muckle-Wells syndrome or neonatal-onset multisystemic inflammatory disease (neonatal-onset multisystemic inflammatory disease or chronic infantile neurological cutaneous and articular (CINCA)) associated with cold-induced autoinflammatory syndrome 1 gene mutations, and tumor necrosis factor receptor-associated periodic syndrome due to mutation of TNF receptor I gene. CONCLUSIONS: Laboratory investigations play an important role in the diagnosis and follow-up of inflammatory rheumatic diseases in children. A good history and a complete physical examination are the best screening tests. Routine laboratory tests are useful to confirm a suspected diagnosis, to assess disease activity, and to measure the response and toxicity to treatment. Only a few tests represent diagnostic criteria such as antinuclear antibodies and anti-double-stranded DNA in SLE or cytoplasmic antineutrophil cytoplasmic autoantibodies in Wegener's granulomatosis. Recent advances in molecular genetics have impacted diagnosis, pathogenesis, and treatment in genetic fever syndromes.

Non-tuberculous mycobacterial osteomyelitis: an unusual cause of hip pain in immunocompetent children.

Non-tuberculous mycobacteria (NTM) are an unusual cause of osteomyelitis in immunocompetent children. Diagnosis is often difficult due to the paucity of clinical symptoms and a subtle course of the disease. NTM comprise a group of about 91 identified species of environmental mycobacteria that cause infections most frequently in immunocompromised individuals or in patients with predisposing factors. Cervical lymphadenitis is the most common presentation of NTM infection in children. Invasive and recurrent infections with these organisms have been associated with a genetic defect of the interferon gamma-receptor. We report a 3-year-old immunocompetent girl who presented a NTM osteomyelitis of the left femur. Four months before she had been treated with medical and surgical therapy for a mycobacterium avium complex cervical lymphadenitis. Polymerase chain reaction assay on bone aspirate specimens confirmed the diagnosis of mycobacterium avium osteomyelitis. The patient was treated successfully with clarithromycin and rifampicin for 6 months.