Hidemasa Sakai

Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.

OBJECTIVE Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappaB activity predict the Blau syndrome/EOS clinical phenotype. METHODS Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB activity with muramyldipeptide. RESULTS All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappaB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappaB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. CONCLUSION NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.

Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein.

Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially lethal genetic disorder of immune dysregulation that requires prompt and accurate diagnosis to initiate life-saving immunosuppressive therapy and to prepare for hematopoietic stem cell transplantation. In the present study, 85 patients with hemophagocytic lymphohistiocytosis were screened for FHL3 by Western blotting using platelets and by natural killer cell lysosomal exocytosis assay. Six of these patients were diagnosed with FHL3. In the acute disease phase requiring platelet transfusion, it was difficult to diagnose FHL3 by Western blot analysis or by lysosomal exocytosis assay. In contrast, the newly established flow cytometric analysis of intraplatelet Munc13-4 protein expression revealed bimodal populations of normal and Munc13-4-deficient platelets. These findings indicate that flow cytometric detection of intraplatelet Munc13-4 protein is a sensitive and reliable method to rapidly screen for FHL3 with a very small amount of whole blood, even in the acute phase of the disease.

Familial Cases of Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome

We report three familial cases of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome, including a pair of monozygotic twins and their mother. It suggests that periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome may have a certain monogenetic background.

Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency

Somatic mosaicism has been described in several primary immunodeficiency diseases and causes modified phenotypes in affected patients. X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the NF-κB essential modulator (NEMO) gene and manifests clinically in various ways. We have previously reported a case of XL-EDA-ID with somatic mosaicism caused by a duplication mutation of the NEMO gene, but the frequency of somatic mosaicism of NEMO and its clinical impact on XL-EDA-ID is not fully understood. In this study, somatic mosaicism of NEMO was evaluated in XL-EDA-ID patients in Japan. Cells expressing wild-type NEMO, most of which were derived from the T-cell lineage, were detected in 9 of 10 XL-EDA-ID patients. These data indicate that the frequency of somatic mosaicism of NEMO is high in XL-ED-ID patients and that the presence of somatic mosaicism of NEMO could have an impact on the diagnosis and treatment of XL-ED-ID patients.

The CD40-CD40L axis and IFN-γ play critical roles in Langhans giant cell formation

The presence of Langhans giant cells (LGCs) is one of the signatures of systemic granulomatous disorders such as tuberculosis and sarcoidosis. However, the pathophysiological mechanism leading to LGC formation, especially the contribution of the T cells abundantly found in granulomas, has not been fully elucidated. To examine the role of T cells in LGC formation, a new in vitro method for the induction of LGCs was developed by co-culturing human monocytes with autologous T cells in the presence of concanavalin A (ConA). This system required close contact between monocytes and T cells, and CD4+ T cells were more potent than CD8+ T cells in inducing LGC formation. Antibody inhibition revealed that a CD40-CD40 ligand (CD40L) interaction and IFN-γ were essential for LGC formation, and the combination of exogenous soluble CD40L (sCD40L) and IFN-γ efficiently replaced the role of T cells. Dendritic cell-specific transmembrane protein (DC-STAMP), a known fusion-related molecule in monocytes, was up-regulated during LGC formation. Moreover, knock-down of DC-STAMP by siRNA inhibited LGC formation, revealing that DC-STAMP was directly involved in LGC formation. Taken together, these results demonstrate that T cells played a pivotal role in a new in vitro LGC formation system, in which DC-STAMP was involved, and occurred via a molecular mechanism that involved CD40-CD40L interaction and IFN-γ secretion.

Rapid Improvement of Paraplegia Caused by Epidural Involvements of Burkitt’s Lymphoma With Chemotherapy

Study Design. Case report. Objective. The authors present a case of atypical Burkitt’s lymphoma with multiple epidural involvements. Summary of Background Data. Spinal cord compression in children is an emergency that requires urgent attention to minimize neurologic dysfunction. Although it is not life-threatening in most patients, cord compression can cause severe neurologic morbidity. Materials and Methods. Because the patient showed rapid neurologic deterioration, we started chemotherapy and high-dose steroids without laminectomy or radiotherapy immediately after a tumor biopsy from the left mandible. Result. The combined therapies were very effective and his neurologic symptoms improved immediately. The epidural involved masses disappeared in imaging studies after the first course of chemotherapy including methylprednisolone (20 mg/kg per day for 3 consecutive days and gradually tapered off over 2 weeks), vincristine (1.5 mg/m2 per day), cyclophosphamide (2 g/m2 per day for 2 days) and pirarubicin (40 mg/m2 per day). After completing seven courses of chemotherapy, the patient is now fully ambulant. Conclusion. Considering the severe late effects of laminectomy and radiotherapy, chemotherapy should be considered as a first choice of treatment for spinal cord compression caused by malignant lymphoma.

A case of early-onset sarcoidosis with a six-base deletion in the NOD2 gene

ted patients. Efficacy was better than that of nifedipine and amlodipine (33 vs 25% response rate, respectively), but small numbers and retrospective analysis does not allow statistical comparison. Response was similar in primary and secondary RP. Children with severe RP had a better response to nifedipine and amlodopine than children with moderate disease. The sub-group with severe disease was more likely to be using a diseasemodifying drug, which may have had an impact. However, numbers are too small for any conclusion to be drawn from this. Application of GTN patches allows removal if adverse events occur. Together with absence of tablets, this may make treatment with GTN attractive in paediatric practice. All patients received Deponit GTN patches. Alternative brands may not have adequate skin adhesion when cut into quarters for this off-license use. GTN patches, nifedipine and amlodipine offer symptomatic relief for patients with moderate primary/secondary RP. Further studies, including head-to-head trials, are needed to determine if one agent is superior. Meanwhile, GTN patches offer an alternative to oral calcium channel blockers for symptomatic relief of paediatric RP.

Cardiac infiltration in early-onset sarcoidosis associated with a novel heterozygous mutation, G481D, in CARD15

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Targeted use of prednisolone with the second IVIG dose for refractory Kawasaki disease

Prednisolone (PSL) has been suggested to be useful for the treatment of Kawasaki disease (KD) resistant to i.v. immunoglobulin (IVIG), but much remains to be elucidated regarding its use.

National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics

Abstract Objectives: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan. Methods: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed. Results: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs. Conclusion: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.