Shin-ichiro Miyagawa

Insulin and insulin‐like growth factor I support the proliferation of erythroid progenitor cells in bone marrow through the sharing of receptors

The effects of insulin and insulin‐like growth factor I (IGF‐I) on the proliferation of erythroid progenitor cells in bone marrow were studied in serum‐deprived culture. Primitive human bone marrow cells were purified by cell sorting on the basis of the expression of CD34 and the Kit receptor. Insulin and IGF‐I with erythropoietin (EPO) dose dependently supported the formation of erythroid colonies of CD34+/Kit+ cells in bone marrow. The direct effect of insulin and IGF‐I on the stimulation of primitive erythroid progenitor cells was confirmed by single‐cell proliferation studies in serum‐deprived liquid suspension culture. The addition of insulin and/or IGF‐I to stem cell factor (SCF) resulted in an additive increase in the number of erythroid colonies. The erythroid colonies formed by insulin and IGF‐I with EPO were different in size from those formed by SCF with EPO. These findings imply that erythroid progenitor cells responding to insulin and IGF‐I might be at a different developmental stage of erythropoiesis from those responding to SCF in CD34+/Kit+ cells. Similarly, insulin and IGF‐I with EPO supported the proliferation of the mature erythroid progenitor cells in light‐density bone marrow mononuclear cells (LDBMCs). The addition of the anti‐receptor antibody to IGF‐I receptor or insulin receptor partially suppressed erythroid colony formation supported with insulin or IGF‐I in both CD34+/Kit+ cells and LDBMCs. The simultaneous addition of both receptor antibodies completely abrogated the erythroid colony formation. These results suggest that insulin and IGF‐I directly stimulate the proliferation of the late stage of primitive erythroid progenitor cells and mature erythroid progenitor cells through the sharing of receptors.

Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia

We examined the expression of granule constituent genes in myeloid progenitor cells during proliferation and differentiation in patients with severe congenital neutropenia (SCN). The heterozygous mutation of the neutrophil elastase gene was identified in two of four patients. The CD34+/granulocyte‐colony stimulating factor receptor (G‐CSFR)+ cells of SCN patients showed defective responsiveness to G‐CSF in serum‐deprived culture. The CD34+/G‐CSFR+ cells expressed low levels of the granule constituent mRNAs. The transcription levels of primary granule enzyme genes in CD34+/G‐CSFR+ cells were gradually enhanced and then decreased when cells were induced toward myeloid lineage with G‐CSF in normal subjects. However, the primary up‐regulation and the following down‐regulation of these enzyme transcriptions were not clearly observed in SCN patients. No differences in expressions of the lactoferrin gene were seen between normal subjects and patients with SCN. We hypothesize that the abnormal regulation of the transcription in primary granule constituents might involve the defective proliferation and differentiation of myeloid cells in patients with SCN.

Steroid-Dependent ACTH-Produced Thymic Carcinoid: Regulation of POMC Gene Expression by Cortisol via Methylation of Its Promoter Region

Aims: Metyrapone causes a decrease in the serum cortisol level without affecting ACTH production in ectopic tumors. We report a case who presented with Cushing’s syndrome due to an ectopic ACTH-producing thymic carcinoid. In the present case, it was demonstrated that metyrapone administration resulted in a significant decrease in the plasma ACTH and serum cortisol levels. We hypothesized that the steroid hormone may promote proopiomelanocortin (POMC) gene expression in the carcinoid cells. Methods: An 11-year-old boy presented with Cushing’s syndrome. Prior to the detection of a thymic tumor, metyrapone was administered to ameliorate the symptoms of Cushing’s syndrome. Interestingly, plasma ACTH as well as serum cortisol levels immediately decreased after metyrapone administration. The levels of cortisol and ACTH were observed to be normal after complete surgical resection of the tumor. Biological characterization of the tumor cells was by in vitro analysis. Results: Thein vitro culture of the tumor cells showed an increased expression of POMC in the presence of cortisol. A CpG methylation assay showed that the demethylation of the POMC promoter was induced by a steroid hormone. Conclusion: These findings suggest that the ectopic ACTH-producing tumor may partly be regulated by the elevated levels of cortisol.

Clinical Characteristics of Perinatal Lethal Hypophosphatasia: A Report of 6 Cases

Hypophosphatasia is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase activity. It is classified into 6 subtypes, and the perinatal lethal form of hypophosphatasia is the most severe. Patients with this form suffer from various symptoms, including respiratory failure, premature craniosynostosis, rachitic changes in the metaphyses, convulsions and hypercalcemia. This report presents 6 cases of the perinatal lethal form of hypophosphatasia. All of the patients showed shortening of the long bones in utero in ultrasonographic examinations. Two of the six patients died at birth because they could not establish spontaneous breathing. Three of the remaining four patients also died before 1 yr of age. The major cause of death was respiratory failure due to hypoplastic lung. All of the patients, except for the two who died at birth, experienced convulsions in their clinical courses. Vitamin B6 therapy effectively reduced the frequency and severity of convulsions. However, it could not always make the patients convulsion free. Three patients underwent a genetic analysis. The 1559delT mutation, which abolishes Alkaline Phosphatase (ALP) activity, was a hot spot. A homozygous 1559delT mutation was observed in two patients. However, they differed in severity of symptoms. Although a good genotype-phenotype correlation has been reported in hypophosphatasia, the genotype alone does not always predict the life span of the patients. These cases therefore suggested the importance of genetic counseling.

A Case of Adolescent Primary Adrenal Natural Killer Cell Lymphoma

Primary adrenal lymphoma is uncommon, and the majority cases of this disorder are found in elderly individuals. We describe a 17-year-old boy with persistent fever, hemophagocytic lymphohistiocytosis, and a bilateral tumor of the adrenal glands. The disease was progressive and did not respond to treatment such as immunosuppression therapy or plasma exchange. Postmortem analysis revealed nasal-type natural killer cell lymphoma in association with Epstein-Barr virus infection. To our knowledge, this case is the first of primary adrenal lymphoma with the natural killer cell phenotype to be reported. The characterization of this unusual case should be included in the differential diagnosis of adrenal gland tumors.

Successful bone marrow transplantation in chronic granulomatous disease

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Individual Clinically Diagnosed with CHARGE Syndrome but with a Mutation in KMT2D, a Gene Associated with Kabuki Syndrome: A Case Report

We report a Japanese female patient presenting with classic features of CHARGE syndrome, including choanal atresia, growth and development retardation, ear malformations, genital anomalies, multiple endocrine deficiency, and unilateral facial nerve palsy. She was clinically diagnosed with typical CHARGE syndrome, but genetic analysis using the TruSight One Sequence Panel revealed a germline heterozygous mutation in KMT2D with no pathogenic CHD7 alterations associated with CHARGE syndrome. Kabuki syndrome is a rare multisystem disorder characterized by five cardinal manifestations including typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate intellectual disability, and postnatal growth deficiency. Germline mutations in KMT2D underlie the molecular pathogenesis of 52–76% of patients with Kabuki syndrome. This is an instructive case that clearly represents a phenotypic overlap between Kabuki syndrome and CHARGE syndrome. It suggests the importance of considering the possibility of a diagnosis of Kabuki syndrome even if patients present with typical symptoms and meet diagnostic criteria of CHARGE syndrome. The case also emphasizes the impact of non-biased exhaustive genetic analysis by next-generation sequencing in the genetic diagnosis of rare congenital disorders with atypical manifestations.

Management of advanced-stage neuroblastoma in a patient with 21-hydroxalase deficiency

A 2‐year‐old boy presented with a 21‐hydroxylase deficiency, associated with advanced‐stage neuroblastoma primarily occurring in the left adrenal gland. He required intensive chemotherapy with polypharmacy, followed by cord blood stem cell transplantation to treat the neuroblastoma. The precise adjustment of cortisol levels was crucial in this patient to prevent adrenal crisis. We administered hydrocortisone by continuous infusion while monitoring blood cortisol levels. As there are no published reports on the target cortisol levels for children, we used two control infants with advanced‐stage neuroblastoma, also undergoing chemotherapy and cord blood stem cell transplantation, to guide the continuous hydrocortisone therapy. The daily dose of hydrocortisone during chemotherapy required about threefold the normal treatment to avoid adrenal insufficiency. Continuous hydrocortisone therapy is feasible for preventing adrenal crisis and this report may provide an effective management for hydrocortisone replacement in 21‐hydroxylase‐deficient patients undergoing chemotherapy and hematopoietic stem cell transplantation.