A Case of Familial Spondyloenchondrodysplasia with Immune Dysregulation Masquerading as Moyamoya Syndrome

No abstract available.

The First Report on Clinical Manifestation of Cryopyrin-Associated Periodic Syndrome in Korean Children

PURPOSE: The aim of this study was to evaluate the clinical characteristics of children diagnosed as cryopyrin-associated periodic syndrome (CAPS) in Korea. METHODS: Diagnosis was made based on clinical features and confirmed by a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene. Especially, osteocartilaginous overgrowth in the patella or distal femur was so characteristic that its presence warranted a diagnosis of chronic infantile neurologic cutaneous and articular/NOMID. RESULTS: We observed the clinical features of 9 Korean CAPS patients. All the patients suffered from an urticarial rash with recurrent fever. Among the 9 patients, 6 presented with rash and 4 with fever on the 1st or 2nd days of birth. Eight patients showed myalgia, and 7 patients showed arthralgia in the joints, and 6 patients showed radiologic findings of arthropathy including cupping of the metaphysis, excessive growth of the epiphysis, osteopenia or overgrowth of the cartilage. Four patients showed brain atrophy, enlarged ventricles or leptomeningeal enhancement on magnetic resonance imaging. Intellectual disability was observed in 1 patient. Five patients had eye involvement as conjunctivitis, uveitis, chorioretinitis, avascular area or papillary edema, and 3 patients showed progressive hearing loss. All 9 patients showed increased C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). CONCLUSIONS: All the patients carried a mutation on exon 3 of the CIAS1 gene. After the anakinra (interleukin-1 receptor antagonist) therapy, the fever and rash immediately disappeared, and CRP and ESR were improved.

Clinical Manifestations and Treatment in Korean Patients with X-Linked Agammaglobulinemia

PURPOSE: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The aim of this study was to investigate the clinical manifestations, molecular features, and treatment status of XLA in Korean patients at Seoul National University Children's Hospital. METHODS: Fourteen Korean boys with XLA showing serum agammaglobulinemia, non-detectable to less than 2% of peripheral B-cells, and mutation of the Btk gene were enrolled. We observed the clinical features, laboratory findings, status of treatment, and complications in these XLA patients. RESULTS: All XLA patients had a history of recurrent bacterial infections before diagnosis, and 20% of them had a neutropenia. Of the XLA patients 35.7% had a family history of XLA and 75% of their mothers were carriers. Btk gene analysis showed variable gene mutations in Xq22 including 9 amino acid substitutions, 3 frameshifts, 1 premature stop codon, and 1 splice defect. After intravenous immunoglobulin replacement therapy, infection episodes decreased, but complications such as bronchiectasis and chronic sinusitis remained. CONCLUSIONS: In patients less than 4 years of age with recurrent infection, analysis of serum gamma globulin levels and the Btk gene are recommended for the early diagnosis of XLA and for the appropriate prevention of recurrent infection.

Clinical Manifestations and Treatment in Korean Patients with X-Linked Agammaglobulinemia

PURPOSE: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The aim of this study was to investigate the clinical manifestations, molecular features, and treatment status of XLA in Korean patients at Seoul National University Children's Hospital. METHODS: Fourteen Korean boys with XLA showing serum agammaglobulinemia, non-detectable to less than 2% of peripheral B-cells, and mutation of the Btk gene were enrolled. We observed the clinical features, laboratory findings, status of treatment, and complications in these XLA patients. RESULTS: All XLA patients had a history of recurrent bacterial infections before diagnosis, and 20% of them had a neutropenia. Of the XLA patients 35.7% had a family history of XLA and 75% of their mothers were carriers. Btk gene analysis showed variable gene mutations in Xq22 including 9 amino acid substitutions, 3 frameshifts, 1 premature stop codon, and 1 splice defect. After intravenous immunoglobulin replacement therapy, infection episodes decreased, but complications such as bronchiectasis and chronic sinusitis remained. CONCLUSIONS: In patients less than 4 years of age with recurrent infection, analysis of serum gamma globulin levels and the Btk gene are recommended for the early diagnosis of XLA and for the appropriate prevention of recurrent infection.

Targeted busulfan and fludarabine-based conditioning for bone marrow transplantation in chronic granulomatous disease / 소아과

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by impaired phagocytic function. Hematopoietic stem cell transplantation (HSCT) is a definitive cure for CGD; however, the use of HSCT is limited because of associated problems, including transplantation-related mortality and engraftment failure. We report a case of a patient with CGD who underwent successful HSCT following a targeted busulfan and fludarabine reduced-toxicity myeloablative conditioning. Intravenous busulfan was administered once daily for 4 consecutive days (days –8 to –5), and the target area under the curve was 75,000 µg·hr/L. Fludarabine (40 mg/m2) was administered once daily for 6 consecutive days from days –8 to –3. Antithymocyte globulin (2.5 mg/kg/day) was administered from days –4 to –2. The patient underwent successful engraftment and did not have any severe toxicity related to the transplantation. Conditioning with a targeted busulfan and fludarabine regimen could provide a better outcome for HSCT in CGD, with close regulation of the busulfan dose.

A Case of Esophageal Obstruction Complicated in a Patient with Chronic Granulomatous Disease: Esophageal obstruction in Chronic Granulomatous Disease / 소아감염

Chronic granulomatous disease (CGD) is an inherited immunodeficient disease characterized by recurrent infections and granuloma formation. Granulomatous obstruction of esophagus is one of the rare complications of CGD. The use of steroids and antimicrobials for esophageal obstruction by granuloma in CGD patients has been controversial due to the possibility of concomitant inapparent infection. We report a case of esophageal obstruction in an 8-year-old CGD patient showing the poor response to antibiotics therapy. However, dramatic improvement of symptoms and radiologic findings of esophageal obstruction were achieved after steroid therapy. One month after discontinuation of steroid, esophageal obstruction recurred and the patient was re-treated with steroid. After that time, he experienced one more recurrence of esophageal obstruction. This symptom subsided after antibiotics therapy without steroid and he has been followed up to the present without further relapse.

Prevalence of Primary Immunodeficiency in Korea

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis / 소아과

Juvenile rheumatoid arthritis (JRA) is the most common rheumatic childhood disease; its onset is before 16 years of age and it persists for at least 6 weeks. JRA encompasses a heterogeneous group of diseases that is classified according to 3 major presentations: oligoarthritis, polyarthritis, and systemic onset diseases. These presentations may originate from the same or different causes that involve interaction with specific immunogenetic predispositions, and result in heterogeneous clinical manifestations. An arthritic joint exhibits cardinal signs of joint inflammation, such as swelling, pain, heat, and loss of function; any joint can be arthritic, but large joints are more frequently affected. Extra-articular manifestations include high fever, skin rash, serositis, and uveitis. The first 2 types of JRA are regarded as T helper 1 (Th1) cell-mediated inflammatory disorders, mainly based on the abundance of activated Th1 cells in the inflamed synovium and the pathogenetic role of proinflammatory cytokines that are mainly produced by Th1 cell-stimulated monocytes. In contrast, the pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, including the lack of association with human leukocyte antigen type and the absence of autoantibodies or autoreactive T cells. Although the precise mechanism that leads to JRA remains unclear, proinflammatory cytokines are thought to be responsible for at least part of the clinical symptoms in all JRA types. The effectiveness of biologic therapy in blocking the action of these cytokines in JRA patients provides strong evidence that they play a fundamental role in JRA inflammation.

Unrelated Bone Marrow Transplantation with a Reduced Toxicity Myeloablative Conditioning Regimen in Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is an X-linked congenital immune-deficiency syndrome, and bone marrow transplantation (BMT) has become a curative modality. However, the transplant with the alternative donor needed more intensive conditioning with increased treatment-related toxicities. Recently, fludarabine-based reduced toxicity myeloablative conditioning regimens have been developed for adult myeloid malignancies with promising results of good engraftment and low treatment-related toxicities. To increase the engraftment potential without serious complications, a boy with WAS received successful unrelated BMT with a reduced toxicity myeloablative conditioning regimen composed of fludarabine (40 mg/m(2) on days -8, -7, -6, -5, -4, -3), busulfan (0.8 mg/kg i. v. q 6 hr on days -6, -5, -4, -3), and thymoglobulin (2.5 mg/kg on days -4, -3, -2). This novel conditioning regimen could improve the outcome of allogeneic transplantation for other non-malignant diseases such as congenital immune-deficiency syndromes or metabolic storage diseases.

A Case of X-linked Chronic Granulomatous Disease Diagnosed in Identical Twin

Chronic granulomatous disease (CGD) is a rare, inherited congenital immunodeficiency disease, characterized by severe and recurrent infections at epithelial surfaces or in more vital organs such as the liver, lung or brain. There are two types of inheritance: X-linked recessive and autosomal recessive. The disease is caused by mutations of proteins, which compose the NADPH oxidase of phagocytes. The most common X-linked CGD type exhibits defect in CYBB encoding gp91phox. It rarely arise from intronic mutations within CYBB. This report describes identical twin patients with X-linked form CGD that showed mutations at intron 1.

A Case of X-linked Chronic Granulomatous Disease Diagnosed in Identical Twin

Chronic granulomatous disease (CGD) is a rare, inherited congenital immunodeficiency disease, characterized by severe and recurrent infections at epithelial surfaces or in more vital organs such as the liver, lung or brain. There are two types of inheritance: X-linked recessive and autosomal recessive. The disease is caused by mutations of proteins, which compose the NADPH oxidase of phagocytes. The most common X-linked CGD type exhibits defect in CYBB encoding gp91phox. It rarely arise from intronic mutations within CYBB. This report describes identical twin patients with X-linked form CGD that showed mutations at intron 1.

Autoimmunity / 소아과

Self/non-self discrimination and unresponsiveness to self is the fundamental properties of the immune system. Self-tolerance is a state in which the individual is incapable of developing an immune response to an individual's own antigens and it underlies the ability to remain tolerant of individual's own tissue components. Several mechanisms have been postulated to explain the tolerant state. They can be broadly classified into two groups: central tolerance and peripheral tolerance. Several mechanisms exist, some of which are shared between T cells and B cells. In central tolerance, the recognition of self-antigen by lymphocytes in bone marrow or thymus during development is required, resulting in receptor editing (revision), clonal deletion, anergy or generation of regulatory T cells. Not all self-reactive B or T cells are centrally purged from the repertoire. Additional mechanisms of peripheral tolerance are required, such as anergy, suppression, deletion or clonal ignorance. Tolerance is antigen specific. Generating and maintaining the self-tolerance for T cells and B cells are complex. Failure of self-tolerance results in immune responses against self-antigens. Such reactions are called autoimmunity and may give rise to autoimmune diseases. Development of autoimmune disease is affected by properties of the genes of the individual and the environment, both infectious and non-infectious. The host's genes affect its susceptibility to autoimmunity and the environmental factors promote the activation of self-reactive lymphocytes, developing the autoimmunity. The changes in participating antigens (epitope spreading), cells, cytokines or other inflammatory mediators contribute to the progress from initial activation to a chronic state of autoimmune diseases.

A clinical analysis of juvenile dermatomyositis; focus on clinical manifestations at diagnosis / 소아과

PURPOSE: Juvenile dermatomyositis (JDM) is the most common of the idiopathic inflammatory myopathies in children. The purpose of this study is to observe demographic, initial presentations, duration of time between disease onset and diagnosis, clinical manifestations and laboratory findings at diagnosis of patients with JDM. METHODS: Forty seven patients identified at Seoul National University Children's Hospital from January 1986 to May 2007. Medical records were reviewed retrospectively focusing on initial presentations, clinical manifestations and laboratory findings at the time of diagnosis of patients with JDM. RESULTS: Male and female patients were 25 and 22, respectively and sex ratio was 1.14:1. The average age at the time of diagnosis was 6.51 years. Skin rash (94%) was the most common symptom, followed by the proximal muscle weakness (89%). The disease activity score was 10.8. The duration between the onset of the skin rash and the muscle weakness and diagnosis was 7.18 and 4.70 months, respectively. The serum muscle enzymes, LDH, AST, CK and aldolase, were elevated in the patient with JDM. Autoimmune antibodies, antinuclear antibody, anti SSA antibody and anti SSB antibody, were negative findings. Electromyography findings were consistent with JDM in 88% of the patients, the muscle biopsy was in 91% and all MRI findings were compatible with those of patients with JDM. The most common symptom besides musculocutaneous lesions was the calcinosis (62.5%). The most common site of calcinosis was the pelvic area and buttocks. CONCLUSION: This study shows that the major symptoms are proximal muscle weakness and cutaneous lesion, and they are important to diagnose JDM.

A Case of Orbital Myositis Secondary to Systemic Lupus Erythematosus / 대한류마티스학회지

A 17-year-old girl with 12-year history of systemic lupus erythematosus (SLE) was presented with one month history of diplopia and headache. She had experienced acute cerebral infarction due to multiple cerebral arterial stenosis one year before, and fully recovered except right-side central facial nerve palsy. When she visited pediatric emergency room, ophthalmologic examination showed ophthalmoplegia of the left eye ball; limitation of medial gaze, supra-adduction and infra-adduction. Neurologic examination didn't show any newly developed neurologic defect. There was no newly developed intra-cranial lesion on the brain MRI. But, the brain MRI revealed irregularly enhanced thickened left medial rectus muscle, and that was compatible with orbital myositis. There was no definite evidence of infection or other autoimmune disease. Her condition responded to high dose intravenous methylprednisone therapy (1 g/day for 3 days) and continued oral prednisolone.

Association of Diagnostic Criteria and Autoantibodies with Juvenile Dermatomyositis in Newly Diagnosed Children

PURPOSE: To determine the clinical association of diagnostic criteria and the prevalence of autoantibodies in newly diagnosed children with juvenile dermatomyositis(JDM). METHODS: Thirty-two children with JDM were identified at Seoul National University Children's Hospital from March 1985 to March 1999 by retrospective review. The diagnosis of JDM was based of the criteria proposed by Bohan and Peter. We investigated for the presence of several autoanti bodies: antinuclear(ANA), double-stranded DNA, anti-Sm, anti-ribonucleoprotein(RNP), anti-SSA/ SSB, anti-Jo1, anti-Scl-70 antibodies and rheumatoid factor(RF). RESULTS: Sex ratio and age at diagnosis were similar to data published in other studies. All the newly diagnosed children with JDM had a typical rash(100%) and proximal muscle weakness(100%); 17(53%) had muscle pain or tenderness; 10(31%) calcinosis; eight(25%) dysphagia; eight(25%) arthritis, and seven(22%) fever. Muscle enzymes were elevated in 90% of the patients. Of the 27 patients who had an electromyogram, 20(70%) had diagnostic results. Sixteen(70%) of biopsied patients had appropriated results for JDM. Patients were negative for all autoantibodies except ANA and RF. ANA and RF were detected in 47% and 7% of the patients respectively. CONCLUSION: Although the sensitivity of the criteria proposed by Bohan and Peter is superior, each of these criteria has possible confounding factors. Additional criteria may be needed for early diagnosis of JDM. Based on our findings of autoantibodies in JDM, we do not recommend routine testing for autoantibodies in children with typical JDM.

Are the Germinal Center T Cells the Memory Ones? / 대한해부학회지

Germinal center (GC) is a critical site where the humoral immune responses take place. Especially memory cells are known to be generated from the GC. In this experiment, T cells observed in the GC were studied in the aspect of memory T cells. T cells responding to myelin basic protein (MBP) antigen usually have their own specific T cell receptor complex (TCR) consisting of V 2 and V 8. Therefore, MBP antigen enables to trace specific T cells reacting to MBP antigen. This experiment, in which balb/c mice were injected with MBP into footpad and the popliteal lymph nodes were removed, showed that most of V 2 +/- cells were L3T4 +/- cells, and that initially they were located in the deep cortex near the B cell follicles and later they were observed in the GC. In case of the primary injection of MBP, IL -4 +/- cells were observed for the first time, followed by appearance of CD69 and CD2R. In case of the secondary injection, all of IL -4, CD25, CD69, CD2R and CTLA -4 were observed from the 1st day after injection. However IL -4, CD25 and CD69 among them were not observed any more since 2 wks after the secondary injection. These results strongly suggest that T cells observed in the GC during the immune responses for MBP might be memory T helper cells.

The Regulation of Cytokine and Chemokine Expressions in Skin Xenograft by Aminoguanidine / 대한이식학회지

PURPOSE: Previous reports demonstrated that nitric oxide (NO) plays immuno-regulatory role in immune responses including allograft rejection response. However, its possible role in xenograft rejection has not been examined. The purpose of this study is to elucidate possible immunoregulatory role of NO in skin xenograft rejection by determining the expressions of chemokines and cytokines in the presence or absence of iNOS inhibitors. METHODS: C57BL/6J mice were grafted with Lewis rat tail skin. The mice were injected intraperitoneally with potent inhibitor of iNOS, aminoguanidine (AMG, 200 mg/kg). Graft survival was monitored and cytokine and chemokine mRNA expressions were measured by real-time RT-PCR in context with iNOS expression on day 3, 5, 7 and 9. These data were compared with those of control mice (saline injected). RESULTS: Compared with the control mice, the AMG treated mice showed delayed xenograft rejection by approximately 3 days (8.9+/-0.7 days vs 11.7+/-1.2 days). Infiltrations of CD11b+, MOMA-2+ cells and neutrophils were significantly reduced but not CD4+ and CD8+ cells in AMG treated graft. The expression of cytokines such as IL-1beta, IL-2, IL-6, IL-12, IFN-gamma in AMG treated graft significantly decreased (P<0.01) whereas IL- 10, TNF-alpha and TGF-beta1 were not changed or enhanced. Additionally, the expression of CC-chemokines such as RANTES and MIP-1alpha significantly reduced (P<0.01) whereas CXC-chemokines such as IP-10 and MIG did not change. CONCLUSION: These data imply that NO suppression by iNOS inhibitor may prolong rat to mouse skin xenograft survival through a selective inhibition of pro-inflammatory cytokines and chemokines. The possible role of NO in transplant rejection can be, therefore, extended to regulation of cytokine and chemokine expressions.

The Ocular Manifestations of the Korean Juvenile Rheumatoid Arthritis Children

PURPOSE: To investigate the ocular findings, risk factors, and clinical outcomes in juvenile rheumatoid arthritis (JRA) patients. METHODS: JRA patients were classified to polyarticular, pauciarticular and systemic-onset type. We retrospectively analyzed the incidence of uveitis, cataract, elevation of intraocular pressure, and compared them to the type of JRA, gender, the presence of HLA B27 and antinuclear antibody. RESULTS: Acute uveitis in 14 patients (23.7%) of 59 patients manifested 20~37.5% evenly in JRA type except polyarticular rheumatoid factor positive type and systemic-onset type. Chronic uveitis occurred only in 2 pauciarticular type patients. In female, antinuclear antibody positive, HLA B27 positive and pauciarticular type the uveitis was more frequently occured. Cataract was occured in 7 patients (11 eyes, 10.2%), preceded by uveitis in 3 patients (3 eyes) and no history of uveitis in the others (8 eyes). The cataract surgery was performed in 3 patients (4 eyes) due to visual disturbance and then corrected visual acuities were more than 0.7 except one eye with band keratopathy. CONCLUSIONS: This study suggests that the ocular examinations are regularly required in cases of female, the presence of antinuclear antibody and pauciarticular type of JRA patients. Cataract surgery combined with posterior chamber intraocular lens implantation can be done with a good visual results in cases of poor vision.

Immunotherapy for Rheumatoid Arthritis

No abstract available

Preparation of Collagen Modified Hyaluronan Microparticles as Antibiotics Carrier

Hyaluronan (HA), a natural glycoaminoglycan featuring an extracellular matrix, has been suggested as an effective biocompatible material. In this study, the effectiveness of HA microparticles as a carrier system for antibiotics was evaluated, and their physicochemical characteristics were determined. Microparticles were fabricated by the gelation of sulfadiazine (SD) loaded HA solution with calcium chloride through either a granulation (GR-microparticles) or encapsulation (EN-microparticles) process, and atelocollagen was incorporated into the microparticles as an additive in order to improve their physical properties. The characteristics of the microparticles were examined by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and swelling test. In vitro release experiments were performed for 7 days and the released amount of SD was determined using high-performance liquid chromatography (HPLC). Microscopic observations revealed that the collagen incorporated HA particles had a more compact surface than the HA particles. DSC analysis determined a loss of SD crystallinity in the particles. Calcium chloride retarded the swelling of particles, whereas the loaded drug contents did not affect this property. Both GR-and EN-microparticles sustained SD release with initial bursting effect. SD release from EN-microparticles was faster than from GR- microparticles. In addition, the release rate was dependent on the SD content in the microparticles. These results suggest that collagen modified HA microparticles have a potential as a release rate controlling material for crystalline drugs such as SD.