RESUMEN
BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease. METHODS: Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel. RESULTS: These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon. CONCLUSIONS: X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.
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Linfohistiocitosis Hemofagocítica , Trastornos Linfoproliferativos , Humanos , Masculino , Mutación , Linfocitos T , Proteína Inhibidora de la Apoptosis Ligada a X/genéticaRESUMEN
Although acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are well-known complications of group A streptococcus infection, concomitant occurrence of both diseases is rare. We report an 11-year-old Japanese girl with primary Sjögren's syndrome complicated by acute renal failure about 2 weeks after the onset of pharyngitis. Although histopathological findings of the kidney were not confirmative, APSGN was suggested by the spontaneous recovery of her renal function, typical latent period with high levels of antistreptolysin O and low serum levels of C3 but not of C4. In addition, cardiac hypomotility and regurgitation of the 4 valves progressed in the convalescent phase of APSGN, which was accompanied by elevation of serum C-reactive protein and plasma brain natriuretic peptide (BNP) levels. Myocarditis was suggested by delayed gadolinium-enhancement of cardiac walls on cardiac magnetic resonance imaging. She was diagnosed with APSGN and ARF and was treated with a combination of short course prednisolone and prophylactic penicillin G. There is no relapse of renal or cardiac symptoms during 6 years follow-up. Unexpected elevation of plasma BNP in a convalescent stage of APSGN suggests the development of ARF. Underlying Sjögren's syndrome (SS) may modify the histopathological findings and make it difficult to differentiate APSGN from CTD-associated nephritis such as lupus nephritis (LN) even by renal biopsy.
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Glomerulonefritis/diagnóstico , Glomerulonefritis/etiología , Fiebre Reumática/diagnóstico , Fiebre Reumática/etiología , Síndrome de Sjögren/complicaciones , Infecciones Estreptocócicas/complicaciones , Enfermedad Aguda , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Biomarcadores , Niño , Susceptibilidad a Enfermedades , Femenino , Glomerulonefritis/tratamiento farmacológico , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética , Fiebre Reumática/terapia , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/tratamiento farmacológico , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Hereditary folate malabsorption (HFM) is an autosomal recessive disease caused by mutations in SLC46A1 encoding the proton-coupled folate transporter (PCFT). HFM patients present with various clinical features including megaloblastic anemia, thrombocytopenia, combined immunodeficiency and neurodevelopmental disorders. In this study, we report the same deep intronic mutation of c.1166-285â¯Tâ¯>â¯G shared by four unrelated Japanese patients with HFM. This mutation was shown to generate a cryptic splice donor site for a 168-bp insertion of intron 3 sequences, leading to premature termination in the middle of this insertion. This mutation could be a founder mutation in the Japanese population, but also could be a hot-spot and could be present in undiagnosed HFM patients worldwide because of the difficulty to detect this mutation.
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Deficiencia de Ácido Fólico/genética , Síndromes de Malabsorción/genética , Transportador de Folato Acoplado a Protón/genética , Pueblo Asiatico/genética , Femenino , Humanos , Lactante , Masculino , MutaciónRESUMEN
OBJECTIVES: The purpose of this study is to evaluate systemic disease activity of pediatric Sjögren's syndrome (SS) using European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI). METHODS: We retrospectively reviewed medical records of patients with SS who have been diagnosed according to 1999 Japanese diagnostic criteria for SS before 16 years old at KKR Sapporo Medical Center, Hokkaido University Hospital, and affiliated hospitals. We analyzed clinical and laboratory data and calculated ESSDAI at both diagnosis and peak activity. RESULTS: Twenty-five patients (2 boys and 23 girls) were enrolled. Only 4 patients had sicca symptoms at diagnosis. Mean ESSDAI scores at diagnosis and peak activity were 12.68 (2-31) and 15.08 (2-38), respectively. Only 3 patients were inactive (ESSDAI score <5) at diagnosis. Frequently involved domains at diagnosis were the biological (96%) followed by the constitutional (68%), glandular (44%), articular (44%), cutaneous domains (28%), renal (16%), and central nervous system (12%). At peak activity, biological domain (96%) was followed by the constitutional (72%), glandular (60%), articular (44%), cutaneous (28%), central nervous system (20%), and renal domains (16%). CONCLUSION: Pediatric SS is suspected from active systemic manifestations. The items of ESSDAI are useful clues to the diagnosis of pediatric SS.
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Síndrome de Sjögren , Adolescente , Factores de Edad , Niño , Femenino , Humanos , Japón/epidemiología , Masculino , Gravedad del Paciente , Proyectos de Investigación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Síndrome de Sjögren/fisiopatologíaRESUMEN
OBJECTIVES: The aim of our study is to clarify the association of myositis-specific autoantibodies (MSAs) with clinical and laboratory features in Japanese patients with juvenile idiopathic inflammatory myopathies (JIIMs). METHODS: We retrospectively analyzed the frequency of MSAs and their association with clinical or laboratory findings in 25 Japanese patients with JIIMs in Hokkaido district. RESULTS: Eighteen of the 25 patients (72%) were positive for MSAs; seven with anti-melanoma differentiation associated gene (MDA) 5 (28%), five with anti-transcriptional intermediary factor (TIF)-1γ (20%), four with anti-MJ/nuclear matrix protein (NXP)-2 (16%), two with anti-Jo-1 (8%), one with anti- HMG-CoA reductase, one with anti-signal recognition peptide (SRP) antibodies (4% each), including co-existence and transition of MSAs in one patient each. Anti-MDA5 antibodies were related to interstitial lung disease (ILD) and arthritis but not to amyopathic juvenile dermatomyositis. Drug-free remission was achieved, once ILD was overcome in this group. Anti-TIF-1γ antibodies were associated with typical rashes and mild myositis. Anti-MJ/NXP2 and anti-SRP antibodies were associated with severe muscle weakness. No patient was complicated with malignancy. CONCLUSION: Anti-MDA5 antibodies are prevalent and closely associated with ILD in our series compared with other countries. There was no apparent difference in clinical features associated with other MSAs among races.
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Artritis , Autoanticuerpos , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales , Miositis , Adolescente , Artritis/epidemiología , Artritis/etiología , Artritis/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/clasificación , Niño , Preescolar , Correlación de Datos , Proteínas de Unión al ADN/inmunología , Femenino , Histidina-ARNt Ligasa/inmunología , Humanos , Hidroximetilglutaril-CoA Reductasas/inmunología , Japón/epidemiología , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Miositis/complicaciones , Miositis/inmunología , Miositis/fisiopatología , Prevalencia , Estudios Retrospectivos , Factores de Transcripción/inmunologíaRESUMEN
Palindromic rheumatism (PR), a rare disease in children, is characterized by recurrent arthritis or periarthritis and asymptomatic interval. We report evolution of PR to juvenile idiopathic arthritis in a Japanese girl with heterozygous complex L110P-E148Q allele of MEFV gene. Poor response to colchicine alone suggests that the MEFV substitution could increase the susceptibility to arthritis rather than caused arthritis associated with atypical Familial Mediterranean Fever. Weekly methotrexate is a choice for such cases.
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Artritis Juvenil/complicaciones , Artritis Reumatoide/etiología , Mutación , Pirina/genética , Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/genética , Artritis Juvenil/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Preescolar , Colchicina/uso terapéutico , Femenino , Heterocigoto , HumanosAsunto(s)
Artralgia , Médula Ósea , Imagen por Resonancia Magnética/métodos , Policondritis Recurrente , Adolescente , Artralgia/diagnóstico , Artralgia/etiología , Biopsia/métodos , Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Diagnóstico Diferencial , Pabellón Auricular/patología , Femenino , Fluorodesoxiglucosa F18/farmacología , Humanos , Policondritis Recurrente/diagnóstico , Policondritis Recurrente/inmunología , Policondritis Recurrente/fisiopatología , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacologíaRESUMEN
OBJECTIVES: Acute leukemia often causes osteoarthralgia. The aim of this study is characterization of leukemia-associated osteoarthralgia in comparison with juvenile idiopathic arthritis (JIA). METHODS: We retrospectively reviewed clinical records of 31 patients with acute leukemia and 13 patients with articular JIA diagnosed between January 2008 and March 2013. Clinical and laboratory findings at the initial examination were compared among the three groups; 10 leukemia with and 21 leukemia without osteoarthralgia and 13 JIA groups. RESULTS: Eleven of the 31 leukemic patients (35%) had osteoarthralgia before the diagnosis of leukemia. Peripheral leukemic cells were initially absent in 10 of the 31 leukemia patients including three with osteoarthralgia. Platelet counts over 300 × 109/L were common in JIA, but not in osteoarthralgia group. Mean serum lactate dehydrogenase levels were higher in both of the leukemia groups than JIA group but often within normal or near-normal levels in the leukemia groups. Magnetic resonance imaging was examined in three leukemic patients and demonstrated osteomyelitis-like bone marrow edema in two and periarticular infiltration similar to synovitis in one patient. Three leukemic patients with osteoarthralgia showed partial and transient responses to antibiotic therapy. CONCLUSIONS: Leukemia-associated osteoarthralgia is often indistinguishable from rheumatic diseases by imaging and laboratory findings and should be confirmed by bone marrow examination.
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Artralgia/diagnóstico por imagen , Artritis Juvenil/diagnóstico por imagen , Médula Ósea/diagnóstico por imagen , Edema/diagnóstico por imagen , Leucemia/diagnóstico por imagen , Dolor/diagnóstico por imagen , Artralgia/etiología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Leucemia/complicaciones , Imagen por Resonancia Magnética/métodos , Masculino , Dolor/etiología , Estudios RetrospectivosRESUMEN
Heterozygous dominant-negative mutations of STAT1 are responsible for autosomal-dominant Mendelian susceptibility to mycobacterial diseases (AD-MSMD). So far, only 7 mutations have been previously described and are localized to 3 domains: the DNA-binding domain, the SH2 domain, and the tail segment. In this study, we demonstrated the first coiled-coil domain (CCD) mutation of c.749G>C, p.G250A (G250A) in STAT1 as a genetic cause of AD-MSMD in a patient with mycobacterial multiple osteomyelitis. This de novo heterozygous mutation was shown to have a dominant-negative effect on the gamma-activated sequence (GAS) transcriptional activity following IFN-γ stimulation, which could be attributable to the abolished phosphorylation of STAT1 from the wild-type (WT) allele. The three-dimensional structure of STAT1 revealed the G250 residue was located distant from a cluster of residues affected by gain-of-function mutations responsible for chronic mucocutaneous candidiasis.
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Predisposición Genética a la Enfermedad , Infecciones por Mycobacterium/genética , Factor de Transcripción STAT1/genética , Preescolar , Femenino , Humanos , Mutación , Dominios ProteicosRESUMEN
[Purpose] The aims of the present study were to investigate the most suitable location for vibroarthrography measurements of the knee joint to distinguish a healthy knee from knee osteoarthritis using Wavelet transform analysis. [Subjects and Methods] Participants were 16 healthy females and 17 females with severe knee osteoarthritis. Vibroarthrography signals were measured on the medial and lateral epicondyles, mid-patella, and tibia using stethoscopes with a microphone while subjects stood up from a seated position. Frequency and knee flexion angles at the peak wavelet coefficient were obtained. [Results] Peak wavelet coefficients at the lateral condyle and tibia were significantly higher in patients with knee osteoarthritis than in the control group. Knee joint angles at the peak wavelet coefficient were smaller (more extension) in the osteoarthritis group compared to the control group. The area under the receiver operating characteristic curve on tibia assessment with the frequency and knee flexion angles was higher than at the other measurement locations (both area under the curve: 0.86). [Conclusion] The tibia is the most suitable location for classifying knee osteoarthritis based on vibroarthrography signals.
RESUMEN
Recent advances in biologic therapy have enabled reduction of the progression of destructive arthritis in rheumatoid arthritis. Once destroyed, however, the affected bones and cartilage are not fully repaired. We describe the case of an 8-year-old girl with anti-citrullinated peptide antibody (ACPA)-positive polyarticular juvenile idiopathic arthritis (p-JIA). Destructive arthritis progressed during combination therapy with infliximab, methotrexate, mizoribine and prednisolone. Clinical remission was achieved, however, after switching the biologic agent to tocilizumab, a humanized monoclonal antibody to interleukin-6 receptor. Both bone erosion and bone marrow edema on magnetic resonance imaging were repaired in association with restoration of joint spaces. Furthermore, there was no relapse of arthritis on weekly methotrexate alone for 2 years after discontinuation of the tocilizumab. Tocilizumab led to radiological repair of both bone and cartilage destruction and long-term biologics-free remission in a patient with ACPA-positive p-JIA, and should be considered for tumor necrosis factor inhibitor-resistant cases.