Ryuji Fukuzawa

Tokyo Metropolitan Children's Medical Center, Edo, Tōkyō, Japan

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Publications (50)261.01 Total impact

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    ABSTRACT: Intramural bronchogenic cysts are extremely rare. We describe the case of an intramural bronchogenic cyst in a 2 year old boy who underwent tracheal resection and end-to-end anastomosis.
    SpringerPlus 01/2014; 3:262.
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    ABSTRACT: Abstract Intralobar sequestration of the lung (ILS) is generally considered to be an acquired anomaly due to the obliteration of the bronchial connection from the main bronchi by chronic infection, while a minority of congenital cases have been reported. The current case was a 4-year-old boy who presented with pneumonia. CT demonstrated a multicystic mass at the posteromedial segments of bilateral lower lobes which were connected by a bronchus behind the heart. Enhanced CT revealed that an anomalous artery arose from the left gastric artery, and inserted into the left sequestrated lung and branched to the right one. The diagnosis of bilateral ILS with a bridging isthmus was made. We thought that this extremely rare variant of ILS could provide an opportunity to address another pathogenetic mechanism of ILS. After removal of the bilateral ILS, radiological and pathological approaches were undertaken to reconstruct the vascular and bronchial architectures within both ILSs. The following observations were made: 1) A pulmonary hilus-like structure was histologically identified near the anomalous artery insertion site. 2) The shape and course of the bronchi within the ILS indicated a distinct bronchial origin that arose from the hilus-like structure. 3) Those bronchi ran along with the anomalous artery which histologically resembles a pulmonary artery. These features led us to conclude that a minority of ILS could originate from an accessory lung tissue.
    Pediatric and Developmental Pathology 10/2013; · 0.86 Impact Factor
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    ABSTRACT: Background: Individuals with NR5A1 mutations encoding steroidogenic factor-1 (SF1) develop a phenotypically broad range of disorders of sexual development (DSD). Based on a literature review, we noted that hypoplastic seminiferous tubules and the emergence of Leydig cells with vacuolar cytoplasms are seen predominantly in the majority of individuals with NR5A1 mutations. Aim: The aim of this study was to address whether the histopathological characteristics of the testis can be a biomarker for 46,XY individuals with NR5A1 mutations. Design: In order to ascertain whether or not the histological features were the characteristics of NR5A1 mutations, we screened the testicular histology of 242 patients with 46,XY DSD and then subsequently assessed NR5A1 mutations. Result: Of 242 patients with 46,XY DSD, 6 patients matched histological testicular features: a reduced number of thin seminiferous tubules and focal aggregations of Leydig cells that contained cytoplasmic lipid droplets. All 6 patients had NR5A1 mutations. These histological features were distinct from those of other DSD. Thus, this unique testicular histology is useful for identifying NR5A1 mutations in 46,XY patients with DSD before puberty.
    Hormone Research in Paediatrics 08/2013; · 1.55 Impact Factor
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    ABSTRACT: Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR.European Journal of Human Genetics advance online publication, 13 March 2013; doi:10.1038/ejhg.2013.45.
    European journal of human genetics: EJHG 03/2013; · 3.56 Impact Factor
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    ABSTRACT: We herein demonstrate a case of a gastric-type duplication cyst of the pancreas with a bifid tail in a 1-year-old girl, who presented as relapsing pancreatitis with pseudocyst formation. We reviewed the literature concerning pancreatic enteric duplication cysts with and without pancreatitis to search for causes of pancreatitis. The following new information was obtained: 1) The presence of a communication between the pancreatic duct system and enteric duplication cysts is the major cause, but it does not always lead to pancreatitis. 2) Enteric duplication cysts are occasionally connected to abnormal pancreatic lobes or ducts. We suggest that a duplication cyst associated with bifid pancreas is in the same category as the association of enteric cyst formation and pancreatic lobe maldevelopment. Since an aberrant lobe associated with an enteric duplication cyst often evokes pancreatitis, its surgical resection should be considered.
    Journal of Pediatric Surgery Case Reports. 01/2013; 1(10):368–372.
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    ABSTRACT: OBJECTIVE: NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus-specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from 2 families) with NR5A1 mutations, showing psychiatric symptoms. DESIGN AND METHODS: We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localisation, and transactivation assays. RESULTS: We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localisation and impaired transcriptional activation without dominant negative effects in both mutations. CONCLUSIONS: We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations. © 2012 Blackwell Publishing Ltd.
    Clinical Endocrinology 10/2012; · 3.40 Impact Factor
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    ABSTRACT: Epigenetic abnormalities at the IGF2/H19 locus play a key role in the onset of Wilms tumor. These tumors can be classified into three molecular subtypes depending on the events occurring at this locus: loss of imprinting (LOI), loss of hetero-zygosity (LOH), or retention of imprinting (ROI). As IGF2 LOI is a consequence of aberrant methylation, we hypothesized that this subtype of Wilms tumors might display global abnormalities of methylation. We therefore analyzed the methyla-tion status of satellite DNA, as a surrogate for global methylation in 50 Wilms tumor patients. Satellite methylation was quantified by a methylation-sensitive quantitative PCR. We confirmed hypomethylation of both satellite a (Sat a) and satel-lite 2 (Sat 2) DNA in Wilms tumor samples compared with normal kidney. In addition, we found that LOI tumors, unlike ROI or LOH ones, showed concordant hypomethylation of both Sat a and Sat 2 DNA. This would suggest that the LOI subtype of Wilms tumor, which unlike other subtypes results from an epimutation, has a global deregulation of methylation mechanisms. V V C 2012 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 10/2012; 00:0-0. · 3.55 Impact Factor
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    ABSTRACT: Prolyl 3-hydroxylase 1 (P3H1), encoded by the LEPRE1 gene, forms a molecular complex with cartilage-associated protein (CRTAP) and cyclophilin B (encoded by PPIB) in the endoplasmic reticulum (ER). This complex is responsible for one step in collagen post-translational modification, the prolyl 3-hydroxylation of specific proline residues, specifically α1(I) Pro986. P3H1 provides the enzymatic activity of the complex and has a Lys-Asp-Glu-Leu (KDEL) ER-retrieval sequence at the carboxyl terminus. Loss of function mutations in LEPRE1 lead to the Pro986 residue remaining unmodified and lead to slow folding and excessive helical post-translational modification of type I collagen, which is seen in both dominant and recessive osteogenesis imperfecta (OI). Here, we present the case of siblings with non-lethal OI due to novel compound heterozygous mutations in LEPRE1 (c.484delG and c.2155dupC). The results of RNA analysis and real-time PCR suggest that mRNA with c.2155dupC escapes from nonsense-mediated RNA decay. Without the KDEL ER- retrieval sequence, the product of the c.2155dupC variant cannot be retained in the ER. This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact. Our study shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality and that a defect in KDEL is sufficient for disease onset.
    PLoS ONE 01/2012; 7(5):e36809. · 3.73 Impact Factor
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    ABSTRACT: Heterozygous inactivating PAX8 mutations cause congenital hypothyroidism. Although more than 30 mutation carriers have been reported, no histological examination of the thyroid has been conducted. The objective of this study was to document the histological characteristics of the thyroid tissue harboring a PAX8 mutation. The patient was a 40-yr-old female, whose two children had congenital hypothyroidism and an inactivating PAX8 mutation (p.K80_A84dup). She had normal thyroid function but had a thyroid nodule and received right hemithyroidectomy at age 28 yr. Mutation analyses using DNA derived from multiple sources, namely lymphocytes, nails, and laser capture microdissected thyroid samples, were performed. The PAX8 mutation was detected in the lymphocytes; however, the level of the mutant allele was significantly lower than that of the wild-type allele. This finding was compatible with her somatic mosaic state. We reviewed the histology of her resected thyroid and found a characteristic lesion in the nonneoplastic tissue: dense aggregates of thyrocytes with absent or very small follicles, resembling a fetal thyroid in the late phase of development. Mutation analyses of laser capture microdissected thyroid samples revealed that the fetal-like tissue carried the PAX8 mutation, whereas surrounding morphologically normal tissue and adenoma tissue did not. In our case, the histology of PAX8 mutation-carrying thyroid tissue was characterized by the lack of follicular growth. Our observations provide the first evidence suggesting that the late phase of thyroid development is sensitive to the PAX8 gene dosage and can be disturbed by heterozygous inactivating PAX8 mutations.
    The Journal of clinical endocrinology and metabolism 12/2011; 96(12):E2039-44. · 6.50 Impact Factor
  • The Journal of pediatrics 11/2011; 160(3):524-524.e1. · 4.02 Impact Factor
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    ABSTRACT: Osteogenesis imperfecta type IIC (OI IIC) is a rare variant of lethal OI that has been considered to be an autosomal recessive trait. Twisted, slender long bones with dense metaphyseal margins and normal vertebral bodies in OI IIC contrast with crumpled, thick long bones and multiple vertebral compression fractures in OI IIA. Here, we report on two sporadic patients with classical OI IIC and a pair of siblings, with features of OI IIC but less distortion of the tubular bones (OI dense bone variant). One case with OI IIC and the sibs had novel heterozygous mutations in the C-propeptide region of COL1A1, while the second patient with clear-cut OI IIC had no mutation in this region. Histological examination in the two sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyses. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Our experience sheds light on the genetics and etiology of OI IIC and on its phenotypic spectrum.
    American Journal of Medical Genetics Part A 09/2011; 155A(9):2269-73. · 2.30 Impact Factor
  • Ryuji Fukuzawa, Miki Toma, Aya Nomura
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    ABSTRACT: We report a case of gastroschisis in which a paraumbilical band was found at the right margin of the abdominal wall defect and extended into the antimesenteric side of the small intestine. The band consisted of 2 thin cords. Microscopically, 1 band showed a fibrous tissue, and the other 1 revealed a unique vascular structure resembling the vitelline artery and vein, suggesting that the paraumbilical band represents a remnant of the yolk stalk that failed to be incorporated into the umbilical stalk. The origin of the paraumbilical band and an associated pathogenetic hypothesis of gastroschisis are discussed.
    Pediatric and Developmental Pathology 08/2011; 14(6):493-5. · 0.86 Impact Factor
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    ABSTRACT: We report the cases of 3 children with plastic bronchitis associated with 2009 H1N1 influenza virus infection. These 3 children shared common clinical and radiologic features: rapid and progressive respiratory distress with whole lung atelectasis on chest radiograph. In children with severe respiratory symptoms accompanied by H1N1 influenza, plastic bronchitis should be considered.
    The Pediatric Infectious Disease Journal 01/2011; 30(1):80-2. · 3.57 Impact Factor
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    ABSTRACT: Somatic mutations in the X-linked tumour suppressor gene WTX have been observed in 6- 30% of sporadic cases of Wilms tumour. Germline mutations in the same gene cause the sclerosing skeletal dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS). No evidence points towards a susceptibility to the development of tumours in individuals with OSCS, suggesting that there are unrecognised additional determinants that influence the phenotypic outcome associated with germline mutations in WTX. One explanation may be that a somatic mutation in WTX may need to occur late in tumour development to contribute to tumourigenesis. Here a panel of four sporadic Wilms tumours with associated nephrogenic rest tissue and characterised WTX and CTNNB1 mutations is studied to ascertain the temporal sequence of acquisition of these mutations. Additionally, a family with OSCS is described segregating a germline mutation in WTX and manifesting a lethal phenotype in males. One male from this family had bilateral multifocal nephrogenic rests at autopsy. In one of the four tumours the WTX mutation was present in both tumour and rest tissue indicating it had arisen early in tumour development. In the remaining three tumours, the WTX mutation was present in the tumour only indicating late acquisition of these mutations. These data indicate that WTX mutations can arise both early and late in Wilms tumour development. WTX mutations may predispose to nephrogenic rest development rather than Wilms tumour per se.
    Journal of Medical Genetics 11/2010; 47(11):791-4. · 5.70 Impact Factor
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    ABSTRACT: Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC. Immunochemistry for c-Src and other cancer-related molecules was performed on archived tissue specimens from 57 LBC patients. Relative c-Src activity was estimated by comparing fluorescence intensity of ILC with that of adjacent ALH/LCIS and nonneoplastic epithelia after staining with an antibody against active c-Src. Expression of active c-Src was correlated with markers of invasion and malignancy and with relapse among LBC patients. Levels of activated c-Src were increased in ILC relative to ALH/LCIS (1.63-fold +/- 0.24 SD) and nonneoplastic epithelia (1.47 +/- 0.18 SD). Increased c-Src levels correlated with the activation of c-Src downstream targets (Fak, Stat-3) and the expression of mesenchymal markers. ILC cells with activated c-Src co-expressed metastatic markers (Opn, Cxcr4) and included cells positive for the cancer stem cell marker Aldh1. A tendency for high c-Src levels (P = 0.072) was observed among the seven LBC patients with relapsed disease. Our data indicate elevated c-Src activity in ILC relative to noninvasive neoplastic tissue. The associated molecular changes suggest that c-Src promotes LBC invasiveness by inducing an epithelial-mesenchymal transition. Therefore, c-Src antagonists might counteract the acquisition of invasiveness during LBC progression. Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth. Together with the possible association between high c-Src levels and disease recurrence, our findings encourage the evaluation of c-Src antagonists for the treatment of LBC.
    Breast cancer research: BCR 08/2009; 11(4):R45. · 5.87 Impact Factor
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    ABSTRACT: Wilms tumours (WTs) have two distinct types of histology with or without ectopic mesenchymal elements, suggesting that WTs arise from either the mesenchymal or epithelial nephrogenic lineages. Regardless of the presence or absence of CTNNB1 mutations, nuclear accumulation of beta-catenin is often observed in WTs with ectopic mesenchymal elements. Here, we addressed the relationship between the WNT-signalling pathway and lineage in WTs by examining CTNNB1 and WT1 mutations, nuclear accumulation of beta-catenin, tumour histology and gene expression profiles. In addition, we screened for mutations in WTX, which has been proposed to be a negative regulator of the canonical WNT-signalling pathway. Unsupervised clustering analysis identified two classes of tumours: mesenchymal lineage WNT-dependent tumours, and epithelial lineage WNT-independent tumours. In contrast to the mesenchymal lineage specificity of CTNNB1 mutations, WTX mutations were surprisingly observed in both lineages. WTX-mutant WTs with ectopic mesenchymal elements had nuclear accumulation of beta-catenin, upregulation of WNT target genes and an association with CTNNB1 mutations in exon 7 or 8. However, epithelial lineage WTs with WTX mutations had no indications of active WNT signalling, suggesting that the involvement of WTX in the WNT-signalling pathway may be lineage dependent, and that WTX may have an alternative function to its role in the canonical WNT-signalling pathway.
    Oncogene 02/2009; 28(8):1063-75. · 7.36 Impact Factor
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    ABSTRACT: Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373). This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11-29% of cases of Wilms tumor. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.
    Nature Genetics 01/2009; 41(1):95-100. · 35.21 Impact Factor
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    ABSTRACT: The association between cell proliferation and the malignant potential of colon cancer is not well understood. Here, we evaluated this association using a colon-specific gene proliferation signature (GPS). The GPS was derived by combining gene expression data obtained from the analysis of a cancer cell line model and a published colon crypt profile. The GPS was overexpressed in both actively cycling cells in vitro and the proliferate compartment of colon crypts. K-means clustering was used to independantly stratify two cohorts of colon tumours into two groups with high and low GPS expression. Notably, we observed a significant association between reduced GPS expression and an increased likelihood of recurrence (P < 0.05), leading to shorter disease-free survival in both cohorts. This finding was not a result of methodological bias as we verified the well-established association between breast cancer malignancy and increased proliferation, by applying our GPS to public breast cancer data. In this study, we show that reduced proliferation is a biological feature characterizing the majority of aggressive colon cancers. This contrasts with many other carcinomas such as breast cancer. Investigating the reasons underlying this unusual observation may provide important insight into the biology of colon cancer progression and putative novel therapy options.
    British Journal of Cancer 10/2008; 99(6):966-73. · 5.08 Impact Factor
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    ABSTRACT: Wilms tumor (WT) is the most frequent renal neoplasm of childhood; a myogenic component is observed in 5% to 10% of tumors. We demonstrate for the first time that myogenic WTs are associated with expression of PAX3, a transcription factor known to specify myoblast cell fate during muscle development. In a panel of 20 WTs, PAX3 was identified in 13 of 13 tumor samples with myogenic histopathology but was absent in 7 of 7 tumors lacking a myogenic component. Furthermore, we show that PAX3 is expressed in the metanephric mesenchyme and stromal compartment of developing mouse kidney. Modulation of endogenous PAX3 expression in human embryonic kidney (HEK293) cells influenced cell migration in in vitro assays. Mutations of WT1 were consistently associated with PAX3 expression in WTs, and modulation of WT1 expression in HEK293 cells was inversely correlated with the level of endogenous PAX3 protein. We demonstrate abundant PAX3 and absence of PAX2 expression in a novel cell line (WitP3) isolated from the stromal portion of a WT bearing a homozygous deletion of the WT1 gene. We hypothesize that PAX3 sets stromal cell fate in developing kidney but is normally suppressed by WT1 during the mesenchyme-to-epithelium transition leading to nephrogenesis. Loss of WT1 permits aberrant PAX3 expression in a subset of WTs with myogenic phenotype.
    Pediatric and Developmental Pathology 08/2008; 12(5):347-54. · 0.86 Impact Factor
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    ABSTRACT: Current models of Wilms tumour development propose that histological features of the tumours are programmed by the underlying molecular aberrations. For example, tumours associated with WT1 mutations arise from intralobar nephrogenic rests (ILNR), concur with CTNNB1 mutations and have distinct histology, whereas tumours with IGF2 loss of imprinting (LOI) often arise from perilobar nephrogenic rests (PLNR). Intriguingly, ILNR and PLNR are found simultaneously in Wilms tumours in children with overgrowth who have constitutional IGF2 LOI. We therefore examined whether the precursor lesions or early epigenetic changes are the primary determinant of Wilms tumour histology. We examined the histological features and gene expression profiles of IGF2 LOI tumours and WT1-mutant tumours which are associated with PLNR and/or ILNR. Two distinct types of IGF2 LOI tumours were identified: the first type had a blastemal-predominant histology associated with PLNR, while the second subtype had a myogenic histology, increased expression of mesenchymal lineage genes and an association with ILNR, similar to WT1-mutant tumours. These ILNR-associated IGF2 LOI tumours also showed signatures of activation of the WNT signalling pathway: differential expression of beta-catenin targets (MMP2, RARG, DKK1) and WNT antagonist genes (DKK1, WIF1, SFRP4). Unexpectedly, the majority of these tumours had CTNNB1 mutations, which are normally only seen in WT1-mutant tumours. The absence of WT1 mutations in tumours with IGF2 LOI indicated that CTNNB1 mutations occur predominantly in tumours arising from ILNR independent of the presence or absence of WT1 mutations. Thus, even though these two classes of tumours with IGF2 LOI have the same underlying predisposing epigenetic error, the tumour histology and the gene expression profiles are determined by the nature of the precursor cells within the nephrogenic rests and subsequent CTNNB1 mutations.
    The Journal of Pathology 08/2008; 215(4):377-87. · 7.59 Impact Factor

Publication Stats

529 Citations
261.01 Total Impact Points

Institutions

  • 2012–2014
    • Tokyo Metropolitan Children's Medical Center
      Edo, Tōkyō, Japan
  • 1998–2012
    • Keio University
      • • Department of Pediatrics
      • • Department of Pathology
      Tokyo, Tokyo-to, Japan
  • 2002–2010
    • University of Otago
      • • Department of Women's and Children's Health (WCH) (Dunedin)
      • • Department of Biochemistry
      Dunedin, Otago, New Zealand