[Show abstract][Hide abstract] ABSTRACT: Mixed gonadal dysgenesis (MGD) is a disorder of sexual development that typically has a mosaic 45,X/46,XY karyotype.
A 1-year-old infant with 46,XY identified by peripheral blood karyotype demonstrated clinical manifestations and gonadal pathologic features of MGD. Fluorescence in situ hybridization (FISH) for X and Y chromosomes and immunofluorescence for SRY along with testicular and ovarian lineage markers SOX9 and FOXL2, respectively, were performed on paraffin sections from the gonad to ascertain the somatic mosaic state for 45,X monosomy and 46,XY cells. The gonad consisted of cells with X and XY signals, which were further quantified in comparison with a normal control testis by a digital image analysis program.
The average percentages of 45,X cells of this patient's gonad and a control testis were 39.0% and 5.7%, respectively (χ2 test, P < 0.001). SRY expression was absent in approximately 10% of precursor granulosa cells (FOXL2 positive) and precursor Sertoli/granulosa cells (both SOX9 and FOXL2 positive) within gonadoblastomas, confirming the involvement of 45,X cells.
A combination of analysis of FISH and immunofluorescence for SRY in the gonadal tissue could identify 45,X cells in MGD with 46,XY.
[Show abstract][Hide abstract] ABSTRACT: C3 glomerulonephritis (C3GN) is a recently described disease that is related to membranoproliferative glomerulonephritis (MPGN). We retrospectively compared the frequencies, clinical characteristics, treatment modalities, and outcomes of C3GN and MPGN in a cohort of Japanese children.
Children who were pathologically diagnosed with MPGN (type I or III) in our hospital were divided into two groups based on immunofluorescence imaging of renal biopsies: children with MPGN induced by classical complement pathway activation (classical MPGN) and children with C3GN.
Of 14 children with MPGN (five boys), four had classical MPGN, eight had C3GN, and two had unclassifiable glomerulonephritis. Four children with classical MPGN and seven with C3GN received methylprednisolone pulse therapy followed by oral prednisolone for 2 years (MPT+PSL therapy). Subsequently, six of seven children with C3GN received combined therapy (prednisolone, azathioprine, and anticoagulants) for 2 years because they responded poorly to MPT+PSL therapy. At the last follow-up visit, two children with classical MPGN and seven with C3GN had not achieved remission. One child with classical MPGN and five with C3GN had hypocomplementemia at the last follow-up. None of the children had renal impairment.
More than half of the patients previously diagnosed with MPGN fulfilled the criteria for C3GN in children. C3GN may be more refractory than classical MPGN to immunosuppressant therapy.
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[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
No preview · Article · Oct 2013 · Pediatric and Developmental Pathology
[Show abstract][Hide abstract] 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.
Preview · Article · Oct 2013 · Journal of Pediatric Surgery Case Reports
[Show abstract][Hide abstract] 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.
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.
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.
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.
Full-text · Article · Aug 2013 · Hormone Research in Paediatrics
[Show abstract][Hide abstract] 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.
No preview · Article · Mar 2013 · European journal of human genetics: EJHG
[Show abstract][Hide abstract] 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.
Full-text · Article · Feb 2013 · Genes Chromosomes and Cancer
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The myocardial bridge (MB) is an anatomical structure consisting of myocardium covering a part of the left anterior descending coronary artery (LAD). The extent and spatial distribution of atherosclerosis in the LAD with an MB is influenced by the anatomical properties of the MB. In this study, the relationship between the overall anatomical framework of the MB including the periarterial adipose tissue as well as fibrosis of the MB itself and coronary atherosclerosis was histomorphometrically examined.
Full-length LADs with an MB from 180 autopsied hearts were cross-sectioned at 5-mm intervals. Together with measurements of MB - length, thickness, and location, proportional decrease of the atherosclerosis ratio of LAD segments beneath MB for that of LAD segments proximal to MB was defined as the atherosclerosis suppression ratio. The area ratio of adipose tissue in the periarterial area beneath MB and area ratio of fibrosis in the MB muscle were also measured.
The atherosclerosis suppression ratio was significantly proportional to MB length and thickness. Periarterial adipose tissue beneath MB was detected in all cases (100%), and fibrosis within MB muscle for 136 cases (75.6%). The amount of adipose tissue beneath MB and MB fibrosis did not statistically affect the atherosclerosis suppression ratio. Multivariate analysis revealed MB length and thickness were the independent factors affecting the atherosclerosis suppression ratio.
The anatomical properties of an MB, especially of its length and thickness, play decisive roles as regulators of atherosclerosis in the LAD regardless of the amount of adipose tissue around LAD and MB fibrosis.
[Show abstract][Hide abstract] ABSTRACT: 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 two families) with NR5A1 mutations, showing psychiatric symptoms.
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 localization and transactivation assays.
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 localization and impaired transcriptional activation without dominant-negative effects in both mutations.
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.
Full-text · Article · Oct 2012 · Clinical Endocrinology
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Full-text · Article · Dec 2011 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] 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.
No preview · Article · Sep 2011 · American Journal of Medical Genetics Part A
[Show abstract][Hide abstract] 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.
No preview · Article · Aug 2011 · Pediatric and Developmental Pathology
[Show abstract][Hide abstract] ABSTRACT: Three children with plastic bronchitis associated with 2009 H1N1 influenza virus infection.
Terano C1, Miura M, Fukuzawa R, Saito Y, Arai H, Sasaki M, Ariyasu D, Hasegawa Y.
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.
No preview · Article · Jan 2011 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] 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.
No preview · Article · Jan 2011 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] 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.
No preview · Article · Nov 2010 · Journal of Medical Genetics
[Show abstract][Hide abstract] 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.
Full-text · Article · Aug 2009 · Breast cancer research: BCR