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1.
Mol Genet Metab ; 108(3): 161-5, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23403242

ABSTRACT

BACKGROUND: Urea cycle disorders (UCD) are caused by genetic defects in enzymes that constitute the hepatic ammonia detoxification pathway. Patients may present with variable clinical manifestations and with hyperammonaemia. Liver abnormalities have been associated with UCD, but only a few reports on the histopathological findings in the liver of UCD patients have been published. METHODS: We conducted a retrospective review of liver biopsies, ex-planted livers and livers at post-mortem of patients with UCD. A single pathologist reviewed all specimens. RESULTS: There were 18 liver samples from 13 patients with confirmed UCD: four ex-planted livers from patients with Ornithine Transcarbamylase (OTC) (n=3) and Carbamoyl Phosphate Synthetase 1 (CPS 1) (n=1) deficiencies, eight post-mortem samples from patients with CPS 1 (n=2), OTC (n=4), Argininosuccinate Synthetase (ASS) (n=1) and Argininosuccinate Lyase (ASL) (n=1) deficiencies, and six liver biopsies, three of which came from one patient with ASL deficiency. The other three liver biopsies were from patients who subsequently received liver transplantation. Histopathological findings in samples from neonates were non-specific. Samples from three late onset OTC deficient and one ASL deficient patients showed thin fibrous septa with portal to portal bridging fibrosis and focal marked enlargement and pallor of the hepatocytes due to accumulation of glycogen particles, resembling glycogenosis and resulting in a prominent nodular pattern. Serial liver biopsies in four UCD patients with interval between samples ranging from 1 year 2 months to 17 years showed progression in fibrosis in one OTC and one ASL deficient patients. Moderate fatty changes to no progression in liver disease were noted in the two patients (OTC=1 and CPS=1). A variety of non-specific features such as fatty change, mild inflammation, cholestasis and focal necrosis were seen in the other UCD patients. CONCLUSIONS: Histopathological changes in livers from neonates with UCD are non-specific. Older patients with UCD seem to show variable hepatic fibrosis compared to those who died early. Some of these patients also show focal and superficial resemblance to a glycogen storage disorder and cirrhosis. However, progression of these changes seems to be slow. To clarify the long term consequence of these changes, more extensive periods of follow up in a larger population series is needed.


Subject(s)
Argininosuccinate Synthase/deficiency , Argininosuccinic Aciduria/pathology , Carbamoyl-Phosphate Synthase (Ammonia)/deficiency , Hepatocytes/pathology , Hyperammonemia/pathology , Liver/pathology , Ornithine Carbamoyltransferase Deficiency Disease/pathology , Argininosuccinic Aciduria/complications , Argininosuccinic Aciduria/metabolism , Autopsy , Biopsy , Child , Child, Preschool , Fatty Acids/metabolism , Female , Hepatocytes/metabolism , Histocytochemistry , Humans , Hyperammonemia/complications , Hyperammonemia/metabolism , Infant , Infant, Newborn , Liver/metabolism , Liver Transplantation , Male , Ornithine Carbamoyltransferase Deficiency Disease/complications , Ornithine Carbamoyltransferase Deficiency Disease/metabolism
2.
Australas J Dermatol ; 53(1): 61-5, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22309335

ABSTRACT

Ectodermal dysplasia-skin fragility syndrome (ED-SFS) is a rare autosomal recessive genodermatosis resulting from mutations in the PKP1 gene, encoding the desmosomal plaque protein plakophilin-1 (PKP1). Mutations in PKP1 may manifest with skin fragility and erosions, patches of scale crust on the trunk and limbs, peri-oral cracking and inflammation, hypotrichosis, palmoplantar keratoderma with painful fissuring and other somewhat variable ectodermal anomalies. Ten cases of the syndrome have been reported. We report a further case of this desmosomal genodermatosis. A 14-month old child, born to consanguineous parents, presented with a history of neonatal bullae and subsequent development of dystrophic nails, sparse eyelashes and eyebrows, woolly scalp hair, abnormal dental development and a desquamating erythematous rash at sites of trauma. A clinical diagnosis of ED-SFS was supported by skin biopsy findings of suprabasal intraepidermal clefting and a loss of immunoreactivity for PKP1. Sequencing of genomic DNA revealed a homozygous 5 base pair deletion in exon 5 of the PKP1 gene, designated c.897del5 (CAACC). This new mutation creates a frameshift, leading to a downstream premature termination codon, p.Pro299fsX61. This case highlights the clinicopathological consequences of inherited mutations in the PKP1 gene and illustrates the key role of desmosomes in skin biology.


Subject(s)
Base Sequence , Ectodermal Dysplasia/genetics , Plakophilins/genetics , Sequence Deletion , Skin Diseases/genetics , Ectodermal Dysplasia/pathology , Female , Homozygote , Humans , Infant , Skin Diseases/pathology
3.
J Med Genet ; 48(7): 458-61, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21357941

ABSTRACT

BACKGROUND: McCune Albright syndrome (MAS), a disorder caused by somatic activating mutations in the GNAS gene, usually presents with cutaneous, skeletal, and endocrine manifestations. While focal lesions involving multiple tissues have been identified in MAS, almost nothing is known about gastrointestinal lesions in this disease. METHODS: Two MAS patients with perioral freckling, resembling Peutz-Jeghers syndrome (PJS), and two MAS patients without similar pigmentation underwent gastrointestinal endoscopy to establish if they had coexisting hamartomatous polyposis. Three of 4 subjects had documented GNAS mutations in peripheral blood. Genetic testing for STK11 and PRKAR1A genes was performed to exclude presence of coexistent PJS and Carney complex. Genetic testing of biopsy material was also performed. RESULTS: Hamartomatous gastrointestinal polyps with histological features similar to those in PJS were observed in all 4 subjects, only in the stomach and/or upper duodenum. Activating GNAS mutations were found in the polyps or adjacent mucosa in 3 of 4 subjects. One patient each had mutation only in the blood or tissue, while 2 patients had both. No subject harboured any detectable PRKARIA or STK11 mutation as determined by direct DNA sequencing and copy number variation analysis. CONCLUSIONS: These findings confirm that gastrointestinal polyps are a common manifestation of MAS, indicate an overlap between MAS and PJS, and point towards a putative interaction between the GNAS and STK11 genes in the pathogenesis of these two disorders. The findings suggest a need for routine gastrointestinal endoscopy in patients with MAS, to establish the true incidence of polyps in these patients.


Subject(s)
Duodenum/pathology , Fibrous Dysplasia, Polyostotic/complications , Fibrous Dysplasia, Polyostotic/pathology , Polyps/complications , Polyps/pathology , Stomach/pathology , Adolescent , Adult , Child , Child, Preschool , Chromogranins , Fibrous Dysplasia, Polyostotic/genetics , GTP-Binding Protein alpha Subunits, Gs/genetics , Genotype , Humans , Infant , Male , Mouth/pathology , Mutation/genetics , Phenotype , Polyps/genetics , Young Adult
4.
BMC Cancer ; 9: 437, 2009 Dec 13.
Article in English | MEDLINE | ID: mdl-20003390

ABSTRACT

BACKGROUND: Rhabdoid tumors are rare cancers of early childhood arising in the kidney, central nervous system and other organs. The majority are caused by somatic inactivating mutations or deletions affecting the tumor suppressor locus SMARCB1 [OMIM 601607]. Germ-line SMARCB1 inactivation has been reported in association with rhabdoid tumor, epitheloid sarcoma and familial schwannomatosis, underscoring the importance of accurate mutation screening to ascertain recurrence and transmission risks. We describe a rapid and sensitive diagnostic screening method, using high resolution melting (HRM), for detecting sequence variations in SMARCB1. METHODS: Amplicons, encompassing the nine coding exons of SMARCB1, flanking splice site sequences and the 5' and 3' UTR, were screened by both HRM and direct DNA sequencing to establish the reliability of HRM as a primary mutation screening tool. Reaction conditions were optimized with commercially available HRM mixes. RESULTS: The false negative rate for detecting sequence variants by HRM in our sample series was zero. Nine amplicons out of a total of 140 (6.4%) showed variant melt profiles that were subsequently shown to be false positive. Overall nine distinct pathogenic SMARCB1 mutations were identified in a total of 19 possible rhabdoid tumors. Two tumors had two distinct mutations and two harbored SMARCB1 deletion. Other mutations were nonsense or frame-shifts. The detection sensitivity of the HRM screening method was influenced by both sequence context and specific nucleotide change and varied from 1: 4 to 1:1000 (variant to wild-type DNA). A novel method involving digital HRM, followed by re-sequencing, was used to confirm mutations in tumor specimens containing associated normal tissue. CONCLUSIONS: This is the first report describing SMARCB1 mutation screening using HRM. HRM is a rapid, sensitive and inexpensive screening technology that is likely to be widely adopted in diagnostic laboratories to facilitate whole gene mutation screening.


Subject(s)
Chromosomal Proteins, Non-Histone/genetics , DNA Mutational Analysis/methods , DNA-Binding Proteins/genetics , Rhabdoid Tumor/genetics , Transcription Factors/genetics , Freezing , Humans , Mutation , SMARCB1 Protein , Sensitivity and Specificity
5.
Pathology ; 41(2): 155-60, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19152188

ABSTRACT

AIMS: To review the clinicopathological features and highlight the problems in the diagnosis and management of low grade fibromyxoid sarcomas (LGFMS). METHODS: Three cases of LGFMS were studied with histology and immunohistochemistry, and cytogenetics in one. The features and problems were compared with those in the literature. RESULTS: Two LGFMS had typical fibrotic and myxoid patterns showing abrupt transition from one to the other. Cellularity was low to moderate. Nuclei were medium sized and regular. In one of these the correct diagnosis was not made in the original needle biopsy resulting in inappropriate management. In the third tumour only myxoid areas were seen and the diagnosis was supported by cytogenetics showing a complex previously unreported translocation, t(7;18;16). One tumour recurred, one metastasised, and one has possible metastasis on imaging of the lungs. CONCLUSION: LGFMS is a tumour with low grade histological features but a high risk of local recurrence and a significant risk of metastasis which can be very late. There should be a high index of suspicion for this rare tumour and a low threshold for sending tissue for cytogenetics and/or molecular genetics. Special precautions should be exercised in the interpretation of small biopsies of a spindle cell lesion with bland cytological features in children. If the diagnosis is unclear there must be a detailed follow up plan with a person responsible for monitoring the plan.


Subject(s)
Fibrosarcoma/pathology , Soft Tissue Neoplasms/pathology , Child , Child, Preschool , Chromosome Aberrations , Female , Fibrosarcoma/genetics , Fibrosarcoma/surgery , Humans , Immunohistochemistry , Male , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/surgery , Translocation, Genetic
6.
Pathology ; 40(2): 188-95, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18203041

ABSTRACT

The prevalence of eosinophilic oesophagitis appears to be increasing in many countries, sometimes rapidly, although this may be partly due to increased disease recognition. Histological methods of assessment and diagnostic criteria vary considerably between major clinical centres. Oesophagitis with over 20 intraepithelial eosinophils per high power field is more likely to be due to allergy than gastro-oesophageal reflux induced acid-peptic mucosal injury. Typical eosinophilic oesophagitis shows involvement of the entire oesophagus, with basal cell proliferation occupying more than 50% of the thickness of the surface epithelium, and high numbers of intraepithelial eosinophils, sometimes concentrated on the surface or as contiguous clusters. Ulceration and prominent neutrophils are atypical and should suggest an alternative or co-existent disease. On endoscopy, the oesophagus may display the typical 'corrugated' mucosal appearance. Clinically, dysphagia or food impaction are the most characteristic symptoms. There is a strong association with other atopic diseases, especially asthma and eczema. To date no evidence has emerged of an increased malignancy risk. Patients with eosinophilic oesophagitis typically fail to respond to acid suppressive medications but respond well to either elemental/elimination diets or aerosolised swallowed corticosteroids. Long-term uncontrolled oesophageal eosinophilic inflammation may lead to progressive subepithelial fibrosis, potentially resulting in strictures or oesophageal narrowing.


Subject(s)
Esophagitis/etiology , Gastroesophageal Reflux/complications , Hypersensitivity, Immediate/complications , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Eosinophilia/diagnosis , Eosinophilia/etiology , Eosinophilia/pathology , Esophagitis/diagnosis , Esophagitis/pathology , Gastroesophageal Reflux/diagnosis , Gastroesophageal Reflux/pathology , Humans , Hypersensitivity, Immediate/diagnosis , Hypersensitivity, Immediate/pathology , Infant , Infant, Newborn
7.
J Pediatr Surg ; 42(12): 2035-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18082703

ABSTRACT

BACKGROUND: Squamous cell carcinomas (SCCs) seem to have become more common recently. This study aims to check whether the increase is real and to review possible etiologic factors and problems in diagnosis. METHODS: Patients with SCC were identified from anatomical pathology files over 30 years. The number and primary sites seen in the first 15 years were compared with those in the second. Histories were reviewed for predisposing factors. Mucosal tumors were tested for human papillomavirus (HPV) and Epstein-Barr virus by polymerase chain reaction. RESULTS: One cutaneous SCC and 2 nasopharyngeal carcinomas (NPCs) were seen in the first period, and 2 cutaneous SCCs and 3 nasopharyngeal carcinomas in the second. Another 9 patients with mucosal SCCs were seen in the second period, many with history of cancer treatment or immunosuppression. Two laryngeal SCCs were HPV16-positive. Histologic diagnosis was difficult in 3 patients. CONCLUSION: Squamous cell carcinomas have become more common in the last 15 years. Causes include improved survival of cancer patients, therapeutic irradiation, immunosuppression, and possibly, increased prevalence of HPV in the community. Awareness of this increase in children, early biopsy in susceptible patients, repeat wider biopsy, and consultation with adult pathologists may reduce the diagnostic delay.


Subject(s)
Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/pathology , Nasopharyngeal Neoplasms/epidemiology , Nasopharyngeal Neoplasms/pathology , Skin Neoplasms/epidemiology , Skin Neoplasms/pathology , Adolescent , Adult , Age Distribution , Australia/epidemiology , Biopsy, Needle , Carcinoma, Squamous Cell/therapy , Child , Combined Modality Therapy , Early Diagnosis , Female , Humans , Immunohistochemistry , Incidence , Male , Mouth Mucosa/pathology , Nasal Mucosa/pathology , Nasopharyngeal Neoplasms/therapy , Neoplasm Staging , Rare Diseases , Registries , Retrospective Studies , Risk Assessment , Sex Distribution , Skin Neoplasms/therapy , Survival Analysis
9.
J Heart Lung Transplant ; 26(3): 293-5, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17346634

ABSTRACT

We report a case of familial contracted endocardial fibroelastosis (EFE) in a young boy presenting at 14 months of age with severe heart failure. A previous echocardiogram showed normal left ventricular (LV) size and systolic function. The family history was suggestive of X-linked cardiomyopathy. These findings are assessed in light of earlier reports of contracted EFE.


Subject(s)
Cardiomyopathies/complications , Cardiomyopathies/genetics , Endocardial Fibroelastosis/etiology , Genes, X-Linked , Cardiac Output, Low/etiology , Cardiomyopathies/diagnostic imaging , Echocardiography , Endocardial Fibroelastosis/pathology , Fatal Outcome , Humans , Infant , Male , Pedigree , Severity of Illness Index
10.
Biometals ; 20(5): 751-7, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17136311

ABSTRACT

Wilson's disease carriers constitute 1% of the human population. It is unknown whether Wilson's disease carriers are at increased susceptibility to copper overload when exposed to chronically high levels of ingested copper. This study investigated the effect of chronic excess copper in drinking water on the heterozygous form of the Wilson's disease mouse model--the toxic milk (tx) mouse. Mice were provided with drinking water containing 300 mg/l copper for 4-7, 8-11, 12-15 or 16-20 months. At the completion of the study liver, spleen, kidney and brain tissue were analyzed by atomic absorption spectroscopy to determine copper concentration. Plasma ceruloplasmin oxidase activity and liver histology were also assessed. Chronic copper loading resulted in significantly increased liver copper in both tx heterozygous and tx homozygous mice, while wild type mice were resistant to the effects of copper loading. Copper loading effects were greatest in tx homozygous mice, with increased extrahepatic copper deposition in spleen and kidney - an effect absent in heterozygote and wild type mice. Although liver histology in homozygous mice was markedly abnormal, no histological differences were noted between heterozygous and wild type mice with copper loading. Tx heterozygous mice have a reduced ability to excrete excess copper, indicating that half of the normal liver Atp7b copper transporter activity is insufficient to deal with large copper intakes. Our results suggest that Wilson's disease carriers in the human population may be at increased risk of copper loading if chronically exposed to elevated copper in food or drinking water.


Subject(s)
Copper/metabolism , Disease Models, Animal , Genetic Carrier Screening , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/metabolism , Adenosine Triphosphatases/genetics , Animals , Cation Transport Proteins/genetics , Copper-Transporting ATPases , Female , Hepatolenticular Degeneration/pathology , Male , Mice , Mutation, Missense
11.
Australas J Dermatol ; 47(3): 198-203, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16867004

ABSTRACT

A female infant presented at 3 months of age with vascular lesions involving the left lower limb and left side of the vulva. At birth, the left leg was thinner than the right, but equal in length. She had macular, reticulate, bluish discolouration covering most of the skin of the involved leg with superimposed cherry-red papules, most dense over the proximal portion. The macular component showed evidence of improvement within the first few months of life. Papular and nodular components over the leg and the vulva progressively increased in size and thickness until the age of 10 months. These elements had the appearance and behaviour typical of haemangioma of infancy. Regression of these lesions started at the age of 15 months. By the age of 6.5 months, the involved leg was no longer thinner than the right, but the left leg and foot had grown longer. Leg length discrepancy peaked at 2.4 cm at the age of 2 years. The most rapid phase of relative growth discrepancy of left and right leg bones was contemporaneous with the growth phase of the haemangioma. Radiological investigations and histopathology have been consistent with haemangioma of infancy. GLUT-1 immunostaining of the lesion was positive.


Subject(s)
Hemangioma/complications , Leg Length Inequality/etiology , Female , Femur , Follow-Up Studies , Hemangioma/diagnosis , Hemangioma/radiotherapy , Humans , Infant , Leg Length Inequality/diagnosis , Leg Length Inequality/therapy , Low-Level Light Therapy/methods , Tibia , Treatment Outcome
12.
Pediatr Dev Pathol ; 9(1): 56-60, 2006.
Article in English | MEDLINE | ID: mdl-16808642

ABSTRACT

Suction rectal biopsies in a newborn and a 10-month-old infant presenting with intestinal obstruction showed marked increase in neurons and nerve bundles in the submucosa. Although there were no syndromic features or a positive family history, mutation analysis of the RET proto-oncogene showed a de novo germline Met918Thr mutation in both patients, confirming the diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). Thyroidectomy was performed at 9 and 14 months, showing medullary carcinoma and focal prominent C-cell hyperplasia, respectively. These 2 cases are presented to emphasize that when the submucosal plexus is obviously and prominently increased in suction rectal biopsies, diffuse intestinal ganglioneuromatosis should be considered. As this can be associated with genetic conditions, especially MEN 2B, it is crucial that further investigations be performed to ensure proper patient management, such as early thyroidectomy.


Subject(s)
Biopsy, Needle/methods , Multiple Endocrine Neoplasia Type 2b/diagnosis , Rectum/pathology , DNA Mutational Analysis , Humans , Hyperplasia , Infant , Infant, Newborn , Intestinal Obstruction/etiology , Intestinal Obstruction/pathology , Male , Multiple Endocrine Neoplasia Type 2b/complications , Multiple Endocrine Neoplasia Type 2b/surgery , Mutation , Nerve Fibers/pathology , Neurons/pathology , Proto-Oncogene Mas , Proto-Oncogene Proteins c-ret/genetics , Submucous Plexus/pathology , Suction/instrumentation , Suction/methods , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Thyroidectomy
13.
Zhonghua Bing Li Xue Za Zhi ; 35(2): 97-100, 2006 Feb.
Article in Chinese | MEDLINE | ID: mdl-16630484

ABSTRACT

OBJECTIVE: To study the clinicopathologic features of metanephric stromal tumor (MST), with emphasis on diagnostic criteria. METHODS: The clinicopathologic findings in 2 cases of MST were analyzed and the literature of this entity was reviewed. RESULTS: Cases of MST were unilateral and mostly centered in renal medulla. The tumor was separated from adjacent renal tissue by sharp and scalloped borders. Entrapped tubules and glomeruli were commonly seen within the lesion. The tumor cells were spindle to stellate in shape and arranged in a nodular pattern. On low power examination, alternating areas of high and low tumor cellularity were noted. Characteristically, there were onion skin-like concentric cuffs of tumor cells around entrapped tubules. The small intratumoral vasculatures showed irregular thickening ("angiodysplasia"). Immunohistochemical study demonstrated that the tumor cells diffusely expressed CD34. CONCLUSIONS: Which the tumor cells around the entrapped renal tubules and blood vessels imparts a nodular appearance, as well as the tumor cells labbed for CD34 are the highly characteristic pathologic findings of MST.


Subject(s)
Antigens, CD34/metabolism , Kidney Neoplasms/pathology , Kidney/pathology , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Infant, Newborn , Kidney Neoplasms/immunology , Kidney Neoplasms/surgery , Male , Nephrectomy , Stromal Cells/pathology
14.
Pediatr Dev Pathol ; 8(5): 541-9, 2005.
Article in English | MEDLINE | ID: mdl-16211456

ABSTRACT

Primary intestinal lymphangiectasia and intestinal lymphatic hypoplasia are 2 causes of protein-losing enteropathy in children and share many common clinical features. For the diagnosis of lymphatic hypoplasia on endoscopic biopsies of the intestine, i.e., based on a negative finding in a small specimen, a very sensitive and specific method for identifying lymphatics is essential. In the present study, lymphatic vessels were labelled using D2-40 immunostaining in mucosal biopsy specimens of the alimentary tract of children in whom no histologic abnormality was noted and of those who had different relatively common pediatric conditions, including inflammatory and neoplastic diseases. Using this method, lymphatic vessels were well visualized even in young infants and not destroyed by diseases. The presence of the muscularis mucosae in specimens was important for adequate assessment. In the duodenum and esophagus, lymphatics were observed in every single section; in the stomach, ileum, and colon, they were less regular and several sections were sometimes required. The extreme sensitivity of this method for demonstrating lymphatic vessels in the duodenum makes it ideal for the histologic diagnosis of intestinal lymphatic hypoplasia. In 4 patients who were considered to have this diagnosis based on clinical features, full-thickness intestinal biopsies and electron microscopy, D2-40 immunostaining confirmed the absence or marked paucity of lymphatics.


Subject(s)
Antibodies, Monoclonal , Biomarkers, Tumor , Gastrointestinal Tract/pathology , Lymphatic System/pathology , Lymphatic Vessels/pathology , Mucous Membrane/pathology , Antibodies, Monoclonal, Murine-Derived , Biopsy , Child , Child, Preschool , Endoscopy, Gastrointestinal , Fluorescent Antibody Technique, Indirect , Humans , Infant , Lymphatic System/physiology , Lymphatic System/physiopathology , Lymphatic Vessels/metabolism , Mucous Membrane/metabolism
15.
Cancer ; 104(10): 2092-8, 2005 Nov 15.
Article in English | MEDLINE | ID: mdl-16206293

ABSTRACT

BACKGROUND: The NANOG gene, a member of the homeobox family of DNA binding transcription factors, was recently identified in a screen for pluripotency-promoting genes. NANOG overexpression in murine embryonic stem cells is sufficient to maintain self-renewal and to block differentiation. The NANOG gene is located on human chromosome 12p13, a region frequently duplicated in human tumors of germ cell origin and in cultured human embryonic stem cells. Here we investigate the expression and gene copy number of NANOG in human germ cells and tumors of germ cell origin. METHODS: Immunohistochemistry and quantitative polymerase chain reaction (QPCR) were used to examine the expression and gene copy number of the human NANOG gene in germ cell tumors. RESULTS: NANOG protein was detected in germline stem cells (gonocytes) within the developing testis. Immunohistochemistry and quantitative real-time PCR analysis were used to demonstrate that NANOG is highly and specifically expressed in carcinoma in situ (CIS), embryonal carcinomas, and seminomas, but not in teratomas and yolk sac tumors. CONCLUSIONS: NANOG expression in germline stem cells (gonocytes), CIS, embryonal carcinoma, and seminoma reveals a molecular and developmental link between germ cell tumors and the embryonic cells from which they arise. Identification of NANOG as a molecular marker of undifferentiated germ cell tumors provides a novel tool for identifying and classifying tumors of germ cell origin.


Subject(s)
Biomarkers, Tumor/analysis , DNA-Binding Proteins/biosynthesis , Homeodomain Proteins/biosynthesis , Neoplasms, Germ Cell and Embryonal/metabolism , Spermatozoa/metabolism , DNA-Binding Proteins/genetics , Fetus , Gene Dosage , Gene Expression , Gene Expression Profiling , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Humans , Immunohistochemistry , Male , Nanog Homeobox Protein , Neoplasms, Germ Cell and Embryonal/genetics , Octamer Transcription Factor-3/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic
16.
J Pediatr Surg ; 40(3): 478-83, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15793721

ABSTRACT

PURPOSE: Chronic idiopathic constipation (CIC) with soiling in children may result from slow colonic transit (SCT) or anorectal dysfunction and/or psychological problems known as functional fecal retention (FFR). Evidence is accumulating that SCT and FFR need different treatments, but they are poorly distinguished by solid marker studies. The authors used radionuclear transit scintigraphy to categorize children with CIC as having either FFR or SCT. METHODS: Children (N = 101) with CIC (and soiling) who were referred for further investigation after failure of standard treatments (diet, laxatives) received radiolabeled colloid orally, and scintillation images were collected at 0 to 2, 6, 24, 30 and 48 hours (total radiation dosage = 2 standard x-rays). Radioactivity in 6 regions (precolonic, ascending, transverse, descending, rectosigmoid, and evacuated feces) was measured, and the median position (geometric center) of radioactivity at each time was determined. RESULTS: In children, meals normally reach the cecum at 6 hours and are evacuated in 30 to 58 hours. Fifty patients had retention of radioactivity in the proximal colon at 48 hours, indicating SCT. Analysis of the images and the geometric center showed that passage through the ascending colon and transverse colon was delayed in SCT. In 24 patients, radioactivity was passed by 30 hours, indicating normal transit or possible FFR. Twenty-two patients had retention in the rectum, indicating definite FFR. Five studies were borderline. CONCLUSIONS: Radionuclear transit scintigraphy is useful for categorizing patients with CIC as having either FFR or SCT, allowing for different treatments. Radionuclear transit scintigraphy provides more detail and greater sensitivity than solid marker studies in diagnosing CIC. Radionuclear transit scintigraphy showed that half of our patients had SCT.


Subject(s)
Constipation/diagnostic imaging , Gastrointestinal Diseases/diagnostic imaging , Gastrointestinal Transit , Cecum/diagnostic imaging , Child , Child, Preschool , Chronic Disease , Colon/diagnostic imaging , Constipation/etiology , Constipation/psychology , Diagnosis, Differential , Encopresis/etiology , Fecal Incontinence/etiology , Female , Gastrointestinal Diseases/complications , Gastrointestinal Diseases/psychology , Humans , Intestine, Small/diagnostic imaging , Male , Radionuclide Imaging , Rectum/diagnostic imaging , Retrospective Studies
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