Akihiro Hoshino

Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome

Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well‐characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS‐dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS‐like phenotype. Objective The aim of the present study was to elucidate the genetic cause of the ALPS‐like phenotype. Methods Candidate genes associated with the ALPS‐like phenotype were screened by using whole‐exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of TNF‐&agr;–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor &kgr;B pathway, was identified in one of the patients exhibiting the ALPS‐like phenotype. Increased activity of the nuclear factor &kgr;B pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

X-Linked Agammaglobulinemia Associated with B-Precursor Acute Lymphoblastic Leukemia

X-linked agammaglobulinemia (XLA) is clinically characterized by reduced number of peripheral B cells and diminished levels of serum immunoglobulins, and caused by a mutation in the Bruton’s tyrosine kinase (BTK) gene, which play a pivotal role in signal transduction of pre-B-cell receptor (BCR) and BCR. B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children, and it may be associated with gene alterations that regulate B-cell development. Here we described a first case of XLA associated BCP-ALL. The whole-exome sequencing revealed a somatic mutation in MLL2 in the sample from the onset of BCP-ALL. This study suggests that the alterations of BTK and MLL2 synergistically function as leukemogenesis.

A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan

BackgroundX-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.AimTo investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.MethodsA spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.ResultsUp to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.ConclusionThe RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

Flow cytometry-based diagnosis of primary immunodeficiency diseases

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.

Neutropenia and myeloid dysplasia in a patient with delayed-onset adenosine deaminase deficiency.

Approximately 15% of ADA deficiency cases are diagnosed later than infancy, which are referred to as delayed-onset type. At the age of 2 years, the patient was admitted for acute disseminated encephalomyelitis. At the age of 3 years, laboratory study revealed lymphopenia (580/ml) and neutropenia (600/ml), and he was suspected of primary immunodeficiency because of recurrent infections and autoimmune neutropenia and thyroiditis. The patient showed a decreased level of ADA (1.0 mmol/hours/ mg protein; normal, 26.4 10.0 mmol/hours/mg protein) and

Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases

PurposePrimary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs.MethodsFifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Immunophenotyes were evaluated by multicolor flow cytometry using seven different panels that allowed the detection of major leukocyte populations in peripheral blood.ResultsMulticolor flow cytometry revealed distinct leukocyte populations and immunological features of patients with X-SCID, XLA, X-HIGM, AT, WAS, HIES, and CMCD.ConclusionsImmunophenotyping by multicolor flow cytometry is useful to evaluate immune status and contributes to the diagnosis and management of patients with PIDDs.

A case of primary adenocarcinoma of the cervical esophagus arising from the ectopic gastric mucosa

Adenocarcinoma of the cervical esophagus arising from the ectopic gastric mucosa is a rare form of tumor, and only 25 cases have been reported previously. We present a case of a 74-year-old man who complained of dysphagia. Esophagogastroduodenoscopy revealed an elevated lesion located on the right posterior wall of the cervical and upper thoracic esophagus. Total esophagectomy and three-field lymph node dissection was performed. The tumor was 7.3 cm × 4.5 cm in size and of an ulcerative and localized type. Microscopic examination revealed a papillary adenocarcinoma with invasion to the adventitial layer. Its origin was diagnosed as ectopic gastric mucosa in the cervical esophagus, which lay adjacent to the tumor.

Allogeneic Bone Marrow Transplantation Appears to Ameliorate IgA Nephropathy in a Patient with X-linked Thrombocytopenia

Wiskott-Aldrich syndrome (WAS) is caused by a mutation in the WAS gene, and it is clinically characterized by the triad of thrombocytopenia, eczema and immunodeficiency. X-linked thrombocytopenia (XLT), which is a clinically mild form of WAS, is also caused by a WAS gene mutation. Patients with WAS/XLT sometimes also have autoimmune diseases such as IgA nephropathy. Progression of IgA nephropathy may lead to chronic renal failure with a poor prognosis. Here, we describe an XLT patient who also had IgA nephropathy. The patient underwent bone marrow transplantation (BMT) because of an associated-lymphoproliferative disorder, and clinical and histological improvement in his IgA nephropathy was observed after BMT. The amount of galactose-deficient IgA in the patient’s serum markedly decreased after BMT. Therefore, immunological reconstitution might improve autoimmune diseases in patients with WAS/XLT.

Aggressive transformation of anaplastic large cell lymphoma with increased number of ALK-translocated chromosomes

Pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) usually has a benign clinical course. A small fraction of patients with ALCL develops an aggressive clinical course; however, its etiology remains unclear. Here we report on an ALK-positive ALCL patient, who had complex translocations with TPM3-ALK revealed by RNA sequencing, with a very aggressive clinical course. On admission, the patient had extraordinarily high white blood cell count with double ALK-translocated chromosomes, and subsequently developed a more aggressive transformation with invasion into multiple organs with triple ALK-translocated chromosomes. The aggressive clinical course may have been related to these additional chromosomal aberrations. Our report provides new insights into the clonal evolution in ALCL and suggests the importance of monitoring examinations including fluorescence in situ hybridization analysis.