46 results on '"Hoei-Hansen, Christina E"'
Search Results
2. Severe Congenital Heart Defects and Cerebral Palsy
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Garne, Ester, Goldsmith, Shona, Barisic, Ingeborg, Braz, Paula, Dakovic, Ivana, Gibson, Catherine, Hansen, Michele, Hoei-Hansen, Christina E., Hollung, Sandra Julsen, Klungsøyr, Kari, Smithers-Sheedy, Hayley, Virella, Daniel, Badawi, Nadia, Watson, Linda, and McIntyre, Sarah
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- 2023
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3. The BrainDrugs-epilepsy study: A prospective open-label cohort precision medicine study in epilepsy
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Marstrand-Joergensen, Maja R., Dam, Vibeke H., Vinter, Kirsten, Ip, Cheng-Teng, Jensen, Kristian Reveles, Jørgensen, Martin Balslev, Hoei-Hansen, Christina E., Ozenne, Brice, Fisher, Patrick M., Knudsen, Gitte M., and Pinborg, Lars H.
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- 2023
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4. The effect of gestational age on major neurodevelopmental disorders in preterm infants
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Larsen, Mads L., Wiingreen, Rikke, Jensen, Andreas, Rackauskaite, Gija, Laursen, Bjarne, Hansen, Bo M., Hoei-Hansen, Christina E., and Greisen, Gorm
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- 2022
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5. Unexpected marked seizure improvement in paediatric epilepsy surgery candidates
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Hoei-Hansen, Christina E., Mathiasen, René, and Uldall, Peter
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- 2017
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6. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy
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Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Angel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van der Zwaag, Bert, Aleck, Kyrieckos A, Fazenbaker, Andrew C, Balciuniene, Jorune, Dubbs, Holly A, Marsh, Eric D, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina E, Deardorff, Matthew A, Raca, Gordana, Quindipan, Catherine, Van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjorg, Moller, Rikke S, Whitney, Andrea, Douglas, Andrew GL, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argilli, Emanuela, Sherr, Elliot H, Dobyns, William B, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew
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neurodevelopmental disorders ,ATP6V0C ,VMA3 ,V-ATPase ,Neurology (clinical) ,epilepsy genetics - Abstract
The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms. ispartof: BRAIN vol:146 issue:4 ispartof: location:England status: Published online
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- 2023
7. Children in Denmark with cerebral palsy rarely complete elementary school.
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Pedersen, Signe V., Wiingreen, Rikke, Hansen, Bo M., Greisen, Gorm, Larsen, Mads L., and Hoei‐Hansen, Christina E.
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CHILDREN with cerebral palsy ,ELEMENTARY schools ,MANN Whitney U Test ,GRADE point average ,ODDS ratio - Abstract
Aim: To investigate how children with cerebral palsy (CP) perform in the Danish school system and which factors are associated with school performance. Method: This was a population‐based cohort study including 463 126 children born from 1997 to 2003. Data were extracted from seven national registries. The study encompassed 818 children with CP (483 [59.0%] males, 335 [41.0%] females) and 417 731 without CP (214 535 [51.4%] males, 203 196 [48.6%] females). We evaluated two primary outcomes: not completing 10 years of elementary school, defined as attending fewer than eight final mandatory exams; and grade point averages (GPAs). Mann–Whitney U tests were used to analyse differences in GPAs and logistic regressions were used to calculate odds ratios (ORs). Results: Among children with and without CP, 62.6% and 12.4% did not complete elementary school respectively (OR = 11.85 [10.28–13.66]). Additionally, children with CP who attended all final exams achieved lower overall GPAs than children without CP (6.6 vs 7.3, p = 0.001). In children with CP, comorbidities, maternal education, severity of motor impairments, and intellectual deficits were associated with increased odds of not completing elementary school. Notably, one‐third of children with CP with apparent normal intelligence did not complete school, despite special educational measures. Interpretation: Danish children with CP rarely complete elementary school despite initiatives for a more supportive educational system. The complexity of individual needs in children with CP may be challenging for an inclusive school environment. What this paper adds: Children with cerebral palsy (CP) have a high risk of not completing elementary school.Children with CP achieve lower overall grades than children without CP.Motor impairment, comorbidities, and maternal education are associated with poor school performance.Intellectual impairment is the most important predictor of poor school performance. What this paper adds: Children with cerebral palsy (CP) have a high risk of not completing elementary school.Children with CP achieve lower overall grades than children without CP.Motor impairment, comorbidities, and maternal education are associated with poor school performance.Intellectual impairment is the most important predictor of poor school performance. This original article is commented on by Lebeer on pages 1273–1274 of this issue. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
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Johannesen, Katrine M., Liu, Yuanyuan, Gjerulfsen, Cathrine E., Koko, Mahmoud, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Au, P. Y. Billie, Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, S.Verhoeven, Judith, van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Schmidt-Petersen, Mette U., Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
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Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] - Abstract
We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3.In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.
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- 2021
9. Nutrition and preparation of blenderized tube feeding in children and adolescents with neurological impairment: A scoping review.
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Brekke, Ghita, Raun, Anne Mette Terp, Sørensen, Sarah B., Kok, Karin, Sørensen, Jette L., Born, Alfred P., Mølgaard, Christian, and Hoei‐Hansen, Christina E.
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- 2022
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10. Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: Implications for the anti-tumor barrier concept and treatment
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Bartkova, Jirina, Hoei-Hansen, Christina E., Krizova, Katerina, Hamerlik, Petra, Skakkebæk, Niels E., Rajpert-De Meyts, Ewa, and Bartek, Jiri
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- 2014
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11. Declining prevalence of cerebral palsy in children born at term in Denmark.
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Larsen, Mads L., Rackauskaite, Gija, Greisen, Gorm, Laursen, Bjarne, Uldall, Peter, Krebs, Lone, and Hoei‐Hansen, Christina E.
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- 2022
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12. Identity of M2A (D2-40) antigen and gp36 (Aggrus, T1A-2, podoplanin) in human developing testis, testicular carcinoma in situ and germ-cell tumours
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Sonne, Si Brask, Herlihy, Amy S., Hoei-Hansen, Christina E., Nielsen, John E., Almstrup, Kristian, Skakkebaek, Niels E., Marks, Alexander, Leffers, Henrik, and Rajpert-De Meyts, Ewa
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- 2006
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13. Genomic and gene expression signature of the pre-invasive testicular carcinoma in situ
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Almstrup, Kristian, Ottesen, Anne Marie, Sonne, Si Brask, Hoei-Hansen, Christina E., Leffers, Henrik, Rajpert-De Meyts, Ewa, and Skakkebaek, Niels E.
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- 2005
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14. Molecular Characteristics of Malignant Ovarian Germ Cell Tumors and Comparison With Testicular Counterparts: Implications for Pathogenesis
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Kraggerud, Sigrid Marie, Hoei-Hansen, Christina E., Alagaratnam, Sharmini, Skotheim, Rolf I., Abeler, Vera M., Rajpert-De Meyts, Ewa, and Lothe, Ragnhild A.
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- 2013
15. Using both electromyography and movement disorder assessment improved the classification of children with dyskinetic cerebral palsy.
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Lorentzen, Jakob, Born, Alfred P., Svane, Christian, Forman, Christian, Laursen, Bjarne, Langkilde, Annika R., Uldall, Peter, and Hoei‐Hansen, Christina E.
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CHILDREN with cerebral palsy ,MOVEMENT disorders ,ELECTROMYOGRAPHY ,MAGNETIC resonance imaging ,GENETIC disorders - Abstract
Aim: Children with dyskinetic cerebral palsy (CP) are often severely affected and effective treatment is difficult, due to different underlying disease mechanisms. Comprehensive systematic movement disorder evaluations were carried out on patients with this disorder. Methods: Patients born from 1995 to 2007 were identified from the Danish Cerebral Palsy Register and referrals to the neuropaediatric centre, Rigshospitalet, Copenhagen. They were classified by gross motor function, manual functional ability, communication ability, dystonia and spasticity. Electromyography was carried out on the upper and lower limbs. Magnetic resonance imaging scans were revised, and aetiological searches for underlying genetic disorders were performed. Results: We investigated 25 patients with dyskinetic CP at a mean age of 11.7 years. Dystonia, spasticity and rigidity were found in the upper limbs of 21, four and six children, respectively, and in the lower limbs of 18, 18 and three children. The mean total Burke‐Fahn‐Marsden score for dystonia was 45.02, and the mean Disability Impairment Scale level was 38% for dystonia and 13% for choreoathetosis. Sustained electromyography activity was observed in 20/25 children. Stretching increased electromyography activity more in children with spasticity. There were 10 re‐classifications. Conclusion: The children had heterogenic characteristics, and 40% were reclassified after systematic movement disorder evaluation. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children.
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Hoei-Hansen, Christina E., Tygesen, Marie L. B., Dunø, Morten, Vissing, John, Ballegaard, Martin, and Born, Alfred P.
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NEUROMUSCULAR diseases , *DIAGNOSIS , *CONGENITAL myasthenic syndromes , *GENERAL anesthesia , *NEMALINE myopathy , *GENETIC disorder diagnosis - Abstract
Aim The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality. Materials and Methods Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years). Results Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in ACTA1 , NEB , SELENON , GRIN2B , SCN8A , and COMP genes. Conclusion Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease. [ABSTRACT FROM AUTHOR]
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- 2021
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17. Does more than one biopsy of the contralateral testis in men with a germ cell tumor add value?
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Hoei-Hansen, Christina E, Rajpert-De Meyts, Ewa, Daugaard, Gedske, Rorth, Mikael, Jorgensen, Niels, and Skakkebaek, Niels E
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- 2007
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18. From Gonocytes to Testicular Cancer: The Role of Impaired Gonadal Development
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RAJPERT-DE MEYTS, EWA and HOEI-HANSEN, CHRISTINA E.
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- 2007
19. Testicular carcinoma in situ in subfertile Danish men
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Olesen, Inge A., Hoei-Hansen, Christina E., Skakkebæk, Niels E., Petersen, Jørgen H., Rajpert-De Meyts, Ewa, and Jørgensen, Niels
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- 2007
20. Current approaches for detection of carcinoma in situ testis
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Hoei-Hansen, Christina E., Olesen, Inge A., Jorgensen, Niels, Carlsen, Elisabeth, Holm, Mette, Almstrup, Kristian, Leffers, Henrik, and Rajpert-De Meyts, Ewa
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- 2007
21. Immunoexpression of Androgen Receptor and Nine Markers of Maturation in the Testes of Adolescent Boys with Klinefelter Syndrome: Evidence for Degeneration of Germ Cells at the Onset of Meiosis
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Wikström, Anne M., Hoei-Hansen, Christina E., Dunkel, Leo, and Rajpert-De Meyts, Ewa
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- 2007
22. CDH1 (E-cadherin) in testicular germ cell neoplasia: suppressed translation of mRNA in pre-invasive carcinoma in situ but increased protein levels in advanced tumours
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SONNE, SI B., HOEI-HANSEN, CHRISTINA E., NIELSEN, JOHN E., HERLIHY, AMY S., ANDERSSON, ANNA-MARIA, ALMSTRUP, KRISTIAN, DAUGAARD, GEDSKE, SKAKKEBAEK, NIELS E., LEFFERS, HENRIK, and RAJPERT-DE MEYTS, EWA
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- 2006
23. From embryonic stem cells to testicular germ cell cancer – should we be concerned?
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Almstrup, Kristian, Sonne, Si Brask, Hoei-Hansen, Christina E., Ottesen, Anne Marie, Nielsen, John E., Skakkebæk, Niels E., Leffers, Henrik, and Meyts, Ewa Rajpert-De
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- 2006
24. A rare diagnosis: testicular dysgenesis with carcinoma in situ detected in a patient with ultrasonic microlithiasis
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Hoei-Hansen, Christina E., Sommer, Peter, Meyts, Ewa Rajpert-De, and Skakkebaek, Niels E.
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- 2005
25. The emerging phenotype of the testicular carcinoma in situ germ cell
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RAJPERT-DE MEYTS, EWA, BARTKOVA, JIRINA, SAMSON, MICHEL, HOEI-HANSEN, CHRISTINA E., FRYDELUND-LARSEN, LONE, BARTEK, JIRI, and SKAKKEBÆK, NIELS E.
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- 2003
26. Increased Risk of Carcinoma In Situ In Patients With Testicular Germ Cell Cancer With Ultrasonic Microlithiasis In the Contralateral Testicle
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HOLM, METTE, HOEI-HANSEN, CHRISTINA E., RAJPERT-DE MEYTS, EWA, and SKAKKEBÆK, NIELS E.
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- 2003
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27. Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers
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Kærn Janne, Abeler Vera M, Kraggerud Sigrid M, Hoei-Hansen Christina E, Rajpert-De Meyts Ewa, and Lothe Ragnhild A
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. Results We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2γ) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13–40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. Conclusion This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.
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- 2007
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28. The diagnosis of cerebral palsy in two Danish national registries: a validation study.
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Larsen, Mads L., Hoei-Hansen, Christina E., and Rackauskaite, Gija
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To determine the quality of prospectively collected data from the highly specialized Danish Cerebral Palsy Follow-up Program (CPOP), and to establish the validity of a reported cerebral palsy (CP) diagnosis in the Danish National Patient Registry (NPR), regularly used as a proxy for neurodevelopmental disorders in epidemiological research.We compared data from the two registries on children with registered CP, born in Denmark between 2008 and 2009, with information from medical records verified by two experienced physicians specializing in pediatric neurology. Data accuracy was estimated by completeness, correctness, and reliability. Completeness was calculated as the number of cases with correctly registered CP diagnoses divided by the total number of true CP diagnoses (similar to sensitivity). Correctness was calculated as the number of cases with correct registrations divided by the total number of cases (similar to positive predictive value). Reliability was estimated using kappa statistics.Registered CP diagnoses in the CPOP had high accuracy, with 94% correctness and 91% completeness. Furthermore, most key variables in the CPOP showed excellent reliability, especially variables defining the severity of the condition. In the Danish NPR, only 225 of 348 children with a noted CP diagnosis fulfilled the diagnostic criteria for CP, resulting in 65% correctness.
Danish CPOP data are a valid source for epidemiological research. Conversely, a noted CP diagnosis in the Danish NPR was, at best, correct in only two out of three patients. [ABSTRACT FROM AUTHOR]- Published
- 2024
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29. Danish experience with paediatric epilepsy surgery
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Underbjerg, Ebba von Celsing, Hoei-Hansen, Christina E, Madsen, Flemming Find, Madsen, Camilla Gøbel, Høgenhaven, Hans, and Uldall, Peter
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INTRODUCTION: Epilepsy surgery is increasingly used to treat children with medically intractable epilepsy. This study investigates the aetiology and seizure outcome in Danish children operated between 1996 and 2010.METHODS: Retrospectively collected data on structural magnetic resonance imaging (MRI) diagnoses, surgical procedures and seizure outcomes classified according to the Engel Classification were used. Changes over time grouped as 1996-2000, 2001-2005 and 2006-2010 were analysed.RESULTS: A total of 95 children underwent epilepsy surgery. Sixty-three operations were performed in Denmark and 50 abroad. In all, 14 children needed reoperation. The median follow-up period was four years. At the latest follow-up, Engel class I (indicating no disabling seizures) was found in 67% of the patients. Cortical dysplasia, mesial temporal sclerosis and tumour were the most common MRI findings. The percentage of tumours operated decreased over time, and frontal lobe resections increased. In the 2006-2010 period, resections with normal MRI were performed, resulting in a less favourable Engel outcome. Persistent, unexpected complications were seen in three of 113 operations.CONCLUSIONS: The majority of children who undergo epilepsy surgery have a good, worthwhile seizure outcome. The seizure outcome for Danish children corresponds to that of other epilepsy surgery centres. The clinical criteria for selection of patients changed over time.FUNDING: none.TRIAL REGISTRATION: The Danish Data Protection Agency approved the project with record number: 2013-41-2459.
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- 2015
30. Children with dyskinetic cerebral palsy are severely affected as compared to bilateral spastic cerebral palsy.
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Préel, Marie, Rackauskaite, Gija, Larsen, Mads L., Laursen, Bjarne, Lorentzen, Jakob, Born, Alfred Peter, Langhoff‐Roos, Jens, Uldall, Peter, and Hoei‐Hansen, Christina E.
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CHILDREN with cerebral palsy ,CEREBRAL palsy ,VISION disorders ,BASAL ganglia ,SEIZURES (Medicine) - Abstract
Aim: We aimed at describing clinical findings in children with dyskinetic as compared to bilateral spastic cerebral palsy (CP). Methods: Data were extracted from the Danish nationwide CP register. Participants were born in 1999–2007 and were 5–6 years at ascertainment. Results: The total number of CP cases was 1165 of which 92 had dyskinetic and 540 bilateral spastic CP. Prevalence of dyskinetic CP was 0.16 per 1000 live births. In participants with dyskinetic compared to bilateral spastic CP, there was more frequently an Apgar level less than five at five minutes (22.7% vs. 11.2%) and neonatal seizures (43.5% vs. 28.5%), but less respiratory deficiency, hyperbilirubinaemia and sepsis. Impairment based on gross motor function classification was more severe in dyskinetic CP (level III–V 90.0% vs. 66.0%). In dyskinetic CP, there was a high rate of reduced developmental quotient (68.1%), visual impairment (39.3%) and epilepsy (51.6%). Basal ganglia lesions were more prevalent in dyskinetic compared to bilateral spastic CP (27.7% vs. 12.8%). Conclusion: Cases of dyskinetic CP had overlapping clinical features with cases of bilateral spastic CP, but differed significantly in several perinatal risk factors. The children with dyskinetic CP had experienced more peri‐ or neonatal adverse events, and neurodevelopmental impairment was severe. [ABSTRACT FROM AUTHOR]
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- 2019
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31. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability.
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Liu, Yuanyuan, Schubert, Julian, Sonnenberg, Lukas, Helbig, Katherine L, Hoei-Hansen, Christina E, Koko, Mahmoud, Rannap, Maert, Lauxmann, Stephan, Huq, Mahbubul, Schneider, Michael C, Johannesen, Katrine M, Kurlemann, Gerhard, Gardella, Elena, Becker, Felicitas, Weber, Yvonne G, Benda, Jan, Møller, Rikke S, and Lerche, Holger
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INTELLECTUAL disabilities ,EPILEPSY ,ACTION potentials ,DISABILITIES - Abstract
Ion channel mutations can cause distinct neuropsychiatric diseases. We first studied the biophysical and neurophysiological consequences of four mutations in the human Na+ channel gene SCN8A causing either mild (E1483K) or severe epilepsy (R1872W), or intellectual disability and autism without epilepsy (R1620L, A1622D). Only combined electrophysiological recordings of transfected wild-type or mutant channels in both neuroblastoma cells and primary cultured neurons revealed clear genotype-phenotype correlations. The E1483K mutation causing mild epilepsy showed no significant biophysical changes, whereas the R1872W mutation causing severe epilepsy induced clear gain-of-function biophysical changes in neuroblastoma cells. However, both mutations increased neuronal firing in primary neuronal cultures. In contrast, the R1620L mutation associated with intellectual disability and autism-but not epilepsy-reduced Na+ current density in neuroblastoma cells and expectedly decreased neuronal firing. Interestingly, for the fourth mutation, A1622D, causing severe intellectual disability and autism without epilepsy, we observed a dramatic slowing of fast inactivation in neuroblastoma cells, which induced a depolarization block in neurons with a reduction of neuronal firing. This latter finding was corroborated by computational modelling. In a second series of experiments, we recorded three more mutations (G1475R, M1760I, G964R, causing intermediate or severe epilepsy, or intellectual disability without epilepsy, respectively) that revealed similar results confirming clear genotype-phenotype relationships. We found intermediate or severe gain-of-function biophysical changes and increases in neuronal firing for the two epilepsy-causing mutations and decreased firing for the loss-of-function mutation causing intellectual disability. We conclude that studies in neurons are crucial to understand disease mechanisms, which here indicate that increased or decreased neuronal firing is responsible for distinct clinical phenotypes. [ABSTRACT FROM AUTHOR]
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- 2019
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32. Unexpected marked seizure improvement in paediatric epilepsy surgery candidates.
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Hoei-Hansen, Christina E, Mathiasen, René, and Uldall, Peter
- Abstract
Purpose: Epilepsy surgery is performed based on the assumption that medical refractory epilepsy will continue. Rarely seizure freedom occurs before surgery is performed, while the patient is being evaluated as an epilepsy surgery candidate. The aim of this study was to describe the number of children withdrawn from an epilepsy surgery programme due to unexpected seizure improvement.Methods: We retrospectively studied 173 children under 18 years with medical refractory epilepsy referred for epilepsy surgery between 1996 and 2010. Medical records were reviewed in 2012 and 2015.Results: At the first evaluation point in 2012, 13 patients were withdrawn from the epilepsy surgery programme due to unexpected marked improvement. In 2015, 6 of them were still seizure free. They had unexpected seizure freedom due to change in AED treatment (n=3) or after a febrile episode (n=3). The mean number of years they had had seizures was 3.4 years (range 0.6-6.2 years) and the number of seizures at inclusion was 209 per month (range 6-750 per month). The duration of follow-up was 6.6 years after inclusion into the epilepsy surgery programme (range 4.0-13.0 years). The aetiology of the epilepsy for these patients was heterotopia (n=1), focal cortical dysplasia (n=3), infarction (n=1) and unknown, with normal MRI (n=1). They all had an IQ in the normal range. Two of the remaining 7 children were operated later.Conclusion: Unexpected seizure control may occur during epilepsy surgery evaluation. [ABSTRACT FROM AUTHOR]- Published
- 2016
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33. Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers
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Hoei-Hansen, Christina E, Kraggerud, Sigrid M, Abeler, Vera M, Kærn, Janne, Rajpert-De Meyts, Ewa, and Lothe, Ragnhild A
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Pluripotent Stem Cells ,Embryonal Carcinoma Stem Cells ,Cell Cycle Proteins ,Gestational Age ,Dysgerminoma ,lcsh:RC254-282 ,Oogonia ,Antigens, Neoplasm ,Carcinoma, Embryonal ,Biomarkers, Tumor ,Humans ,Cell Lineage ,Carcinoma, Small Cell ,Homeodomain Proteins ,Ovarian Neoplasms ,Research ,Ovary ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Cell Differentiation ,Nanog Homeobox Protein ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Neoplasm Proteins ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-kit ,Cell Transformation, Neoplastic ,Transcription Factor AP-2 ,Mutation ,Neoplastic Stem Cells ,Female ,Gonadoblastoma ,Octamer Transcription Factor-3 - Abstract
Background Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. Results We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2γ) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13–40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. Conclusion This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.
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- 2007
34. Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors.
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Mosbech, Christiane H., Rechnitzer, Catherine, Brok, Jesper S., Rajpert-De Meyts, Ewa, and Hoei-Hansen, Christina E.
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- 2014
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35. Alternating hemiplegia of childhood in Denmark: Clinical manifestations and ATP1A3 mutation status.
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Hoei-Hansen, Christina E., Dali, Christine í, Lyngbye, Troels J.B., Duno, Morten, and Uldall, Peter
- Abstract
Abstract: Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by early-onset recurrent distinctive hemiplegic episodes commonly accompanied by other paroxysmal features and developmental impairment. De novo mutations in ATP1A3 were recently identified as a genetic cause of AHC. To describe the entire Danish cohort of paediatric AHC patients we approached neuropaediatricians nationwide. All currently acknowledged Danish patients ≤16 years with AHC were genetically tested and seen by the same child neurologist (PU). Ten patients; seven girls and three boys were identified. Mean present age was 10.0 years (range 1–16). Mean age at presentation was 7.4 months (range 1–18 months). Sequencing of ATP1A3 in all ten patients revealed a pathogenic mutation in seven. Two females with moderate psychomotor impairment were heterozygous for the known p.G947R mutation, whereas one severely retarded boy was heterozygous for the common p.E815K mutation. The prevalent p.D801N mutation was identified in two moderate to severely retarded children. Interestingly, in a set of monochorionic male twins a novel p.D801E mutation was identified, underscoring that the asparagine at position 801 is a mutation hotspot. Three girls aged 5–13 years did not reveal any ATP1A3 mutations. They were rather mildly clinically affected and displayed a normal or near-normal psychomotor development. This is the first study of AHC in the Danish paediatric population. The patients harboured a wide range of psychomotor difficulties. Patients with no mutation detected tended to be less severely affected. Prevalence was approximately 1 per 100,000 children. [Copyright &y& Elsevier]
- Published
- 2014
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36. Optimizing Staining Protocols for Laser Microdissection of Specific Cell Types from the Testis Including Carcinoma In Situ.
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Sonne, Si Brask, Dalgaard, Marlene D., Nielsen, John Erik, Hoei-Hansen, Christina E., Meyts, Ewa Rajpert-De, Gjerdrum, Lise Mette, and Leffers, Henrik
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MICRODISSECTION -- Instruments ,LASER surgery ,CARCINOMA in situ ,ONCOLOGIC surgery ,MICROARRAY technology ,GENE expression ,FROZEN tissue sections ,GERMPLASM ,ALKALINE phosphatase ,EQUIPMENT & supplies - Abstract
Microarray and RT-PCR based methods are important tools for analysis of gene expression; however, in tissues containing many different cells types, such as the testis, characterization of gene expression in specific cell types can be severely hampered by noise from other cells. The laser microdissection technology allows for enrichment of specific cell types. However, when the cells are not morphologically distinguishable, it is necessary to use a specific staining method for the target cells. In this study we have tested different fixatives, storage conditions for frozen sections and staining protocols, and present two staining protocols for frozen sections, one for fast and specific staining of fetal germ cells, testicular carcinoma in situ cells, and other cells with embryonic stem cell-like properties that express the alkaline phosphatase, and one for specific staining of lipid droplet-containing cells, which is useful for isolation of the androgen-producing Leydig cells. Both protocols retain a morphology that is compatible with laser microdissection and yield RNA of a quality suitable for PCR and microarray analysis. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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37. Application of stem cell markers in search for neoplastic germ cells in dysgenetic gonads, extragonadal tumours, and in semen of infertile men.
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Hoei-Hansen, Christina E.
- Abstract
Summary: Germ cell tumours (GCTs) are a complex entity. Current areas of attention include early detection and avoidance of unnecessary over-treatment. Novel findings regarding diagnosis of GCTs located in various anatomical sites are described, particularly testicular GCTs and their common progenitor, carcinoma in situ (CIS). Recognition of CIS enables intervention before tumour development, but nevertheless, testicular GCTs are sporadically diagnosed at the pre-invasive stage where minimal treatment is necessary. As presence of CIS is asymptomatic, a simple screening method is needed when CIS is suspected (i.e. in males investigated for infertility). To develop approaches for early detection CIS gene expression studies have been performed showing many similarities with embryonic stem cells with confirmation of established markers (i.e. PLAP, OCT-3/4, KIT) and identification of novel markers (i.e. AP-2γ, NANOG). We have reported a very promising new approach of AP-2γ (or OCT3/4) based immunocytological semen analysis (specificity 93.6%, sensitivity 54.5%). Comparative studies of gonadal/extragonadal GCTs have revealed resemblance pointing towards similar, but not identical, origins. Moreover, infertility and testicular cancer are connected in the ‘Testicular Dysgenesis Syndrome’ and 25% of contralateral testes from testicular GCT patients harbour dysgenetic features, including impaired spermatogenesis. Thus, recent data have provided potential diagnostic tools including CIS detection in semen, microarray-based tumour classification, additional serological GCT markers, and novel stem cell markers for immunohistochemical diagnosis of gonadal and extragonadal GCTs. Many CIS candidate genes are yet uninvestigated, and information from these could increase knowledge about CIS tumour initiation/progression and be used for optimisation of a non-invasive detection method. [Copyright &y& Elsevier]
- Published
- 2008
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38. Environment, testicular dysgenesis and carcinoma in situ testis.
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Olesen, Inge A., Sonne, Si Brask, Hoei-Hansen, Christina E., Rajpert-DeMeyts, Ewa, and Skakkebaek, Niels E.
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GENITAL diseases ,HYPOSPADIAS ,URETHRA ,CRYPTORCHISM ,HUMAN abnormalities - Abstract
The testicular dysgenesis syndrome (TDS) hypothesis proposes that a proportion of the male reproductive disorders–cryptorchidism, hypospadias, infertility and testicular cancer–may be symptoms of one underlying developmental disease, TDS, which is most likely a result of disturbed gonadal development in the embryo. TDS may be caused by genetic factors, environmental/life-style factors, or a combination of both. Some rare disorders of sex development of genetic origin are among the best-known examples of severe TDS. Among the environmental and life-style factors that are suspected to influence the hormonal milieu of the developing gonad are the endocrine disrupters. A prenatal exposure to commonly used chemicals, e.g. phthalates, may result in a TDS-like phenotype in rats. Currently, this animal model is the best model for TDS. In humans the situation is much more complex, and TDS exists in a wide range of phenotypes: from the mildest and most common form, in which impaired spermatogenesis is the only symptom, to the most severe cases, in which the patient may develop testicular cancer. It is of great importance that clinicians in different specialties treating patients with TDS are aware of the association between the different symptoms. [Copyright &y& Elsevier]
- Published
- 2007
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39. Re: Niels J. van Casteren, Hans Stoop, Gert R. Dohle, Ronald de Wit, J. Wolter Oosterhuis, Leendert H.J. Looijenga. Noninvasive Detection of Testicular Carcinoma In Situ in Semen Using OCT3/4. Eur Urol 2008;54:153–60
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Hoei-Hansen, Christina E., Almstrup, Kristian, Skakkebaek, Niels Erik, and Rajpert-De Meyts, Ewa
- Published
- 2009
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40. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.
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Mattison KA, Tossing G, Mulroe F, Simmons C, Butler KM, Schreiber A, Alsadah A, Neilson DE, Naess K, Wedell A, Wredenberg A, Sorlin A, McCann E, Burghel GJ, Menendez B, Hoganson GE, Botto LD, Filloux FM, Aledo-Serrano Á, Gil-Nagel A, Tatton-Brown K, Verbeek NE, van der Zwaag B, Aleck KA, Fazenbaker AC, Balciuniene J, Dubbs HA, Marsh ED, Garber K, Ek J, Duno M, Hoei-Hansen CE, Deardorff MA, Raca G, Quindipan C, van Hirtum-Das M, Breckpot J, Hammer TB, Møller RS, Whitney A, Douglas AGL, Kharbanda M, Brunetti-Pierri N, Morleo M, Nigro V, May HJ, Tao JX, Argilli E, Sherr EH, Dobyns WB, Baines RA, Warwicker J, Parker JA, Banka S, Campeau PM, and Escayg A
- Subjects
- Humans, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Adenosine Triphosphate, Vacuolar Proton-Translocating ATPases genetics, Vacuolar Proton-Translocating ATPases metabolism, Epilepsy genetics
- Abstract
The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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41. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.
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Johannesen KM, Liu Y, Koko M, Gjerulfsen CE, Sonnenberg L, Schubert J, Fenger CD, Eltokhi A, Rannap M, Koch NA, Lauxmann S, Krüger J, Kegele J, Canafoglia L, Franceschetti S, Mayer T, Rebstock J, Zacher P, Ruf S, Alber M, Sterbova K, Lassuthová P, Vlckova M, Lemke JR, Platzer K, Krey I, Heine C, Wieczorek D, Kroell-Seger J, Lund C, Klein KM, Au PYB, Rho JM, Ho AW, Masnada S, Veggiotti P, Giordano L, Accorsi P, Hoei-Hansen CE, Striano P, Zara F, Verhelst H, Verhoeven JS, Braakman HMH, van der Zwaag B, Harder AVE, Brilstra E, Pendziwiat M, Lebon S, Vaccarezza M, Le NM, Christensen J, Grønborg S, Scherer SW, Howe J, Fazeli W, Howell KB, Leventer R, Stutterd C, Walsh S, Gerard M, Gerard B, Matricardi S, Bonardi CM, Sartori S, Berger A, Hoffman-Zacharska D, Mastrangelo M, Darra F, Vøllo A, Motazacker MM, Lakeman P, Nizon M, Betzler C, Altuzarra C, Caume R, Roubertie A, Gélisse P, Marini C, Guerrini R, Bilan F, Tibussek D, Koch-Hogrebe M, Perry MS, Ichikawa S, Dadali E, Sharkov A, Mishina I, Abramov M, Kanivets I, Korostelev S, Kutsev S, Wain KE, Eisenhauer N, Wagner M, Savatt JM, Müller-Schlüter K, Bassan H, Borovikov A, Nassogne MC, Destrée A, Schoonjans AS, Meuwissen M, Buzatu M, Jansen A, Scalais E, Srivastava S, Tan WH, Olson HE, Loddenkemper T, Poduri A, Helbig KL, Helbig I, Fitzgerald MP, Goldberg EM, Roser T, Borggraefe I, Brünger T, May P, Lal D, Lederer D, Rubboli G, Heyne HO, Lesca G, Hedrich UBS, Benda J, Gardella E, Lerche H, and Møller RS
- Subjects
- Genetic Association Studies, Humans, Infant, Mutation, Prognosis, Seizures drug therapy, Seizures genetics, Sodium Channel Blockers therapeutic use, Epilepsy, Generalized drug therapy, Epilepsy, Generalized genetics, Epileptic Syndromes drug therapy, Epileptic Syndromes genetics, Intellectual Disability genetics, NAV1.6 Voltage-Gated Sodium Channel genetics
- Abstract
We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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42. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability.
- Author
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Liu Y, Schubert J, Sonnenberg L, Helbig KL, Hoei-Hansen CE, Koko M, Rannap M, Lauxmann S, Huq M, Schneider MC, Johannesen KM, Kurlemann G, Gardella E, Becker F, Weber YG, Benda J, Møller RS, and Lerche H
- Subjects
- Animals, Cells, Cultured, Humans, Membrane Potentials physiology, Mice, Mice, Inbred C57BL, Rats, Epilepsy genetics, Intellectual Disability genetics, Mutation, Missense genetics, NAV1.6 Voltage-Gated Sodium Channel genetics, Neurons physiology
- Abstract
Ion channel mutations can cause distinct neuropsychiatric diseases. We first studied the biophysical and neurophysiological consequences of four mutations in the human Na+ channel gene SCN8A causing either mild (E1483K) or severe epilepsy (R1872W), or intellectual disability and autism without epilepsy (R1620L, A1622D). Only combined electrophysiological recordings of transfected wild-type or mutant channels in both neuroblastoma cells and primary cultured neurons revealed clear genotype-phenotype correlations. The E1483K mutation causing mild epilepsy showed no significant biophysical changes, whereas the R1872W mutation causing severe epilepsy induced clear gain-of-function biophysical changes in neuroblastoma cells. However, both mutations increased neuronal firing in primary neuronal cultures. In contrast, the R1620L mutation associated with intellectual disability and autism-but not epilepsy-reduced Na+ current density in neuroblastoma cells and expectedly decreased neuronal firing. Interestingly, for the fourth mutation, A1622D, causing severe intellectual disability and autism without epilepsy, we observed a dramatic slowing of fast inactivation in neuroblastoma cells, which induced a depolarization block in neurons with a reduction of neuronal firing. This latter finding was corroborated by computational modelling. In a second series of experiments, we recorded three more mutations (G1475R, M1760I, G964R, causing intermediate or severe epilepsy, or intellectual disability without epilepsy, respectively) that revealed similar results confirming clear genotype-phenotype relationships. We found intermediate or severe gain-of-function biophysical changes and increases in neuronal firing for the two epilepsy-causing mutations and decreased firing for the loss-of-function mutation causing intellectual disability. We conclude that studies in neurons are crucial to understand disease mechanisms, which here indicate that increased or decreased neuronal firing is responsible for distinct clinical phenotypes.
- Published
- 2019
- Full Text
- View/download PDF
43. Danish experience with paediatric epilepsy surgery.
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von Celsing Underbjerg E, Hoei-Hansen CE, Madsen FF, Madsen CG, Høgenhaven H, and Uldall P
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- Adolescent, Brain Neoplasms etiology, Brain Neoplasms surgery, Child, Child, Preschool, Denmark, Drug Resistant Epilepsy complications, Drug Resistant Epilepsy pathology, Female, Follow-Up Studies, Frontal Lobe surgery, Gyrus Cinguli pathology, Humans, Infant, Magnetic Resonance Imaging, Male, Malformations of Cortical Development etiology, Reoperation statistics & numerical data, Retrospective Studies, Sclerosis etiology, Seizures etiology, Temporal Lobe surgery, Treatment Outcome, Brain surgery, Drug Resistant Epilepsy surgery, Seizures surgery
- Abstract
Introduction: Epilepsy surgery is increasingly used to treat children with medically intractable epilepsy. This study investigates the aetiology and seizure outcome in Danish children operated between 1996 and 2010., Methods: Retrospectively collected data on structural magnetic resonance imaging (MRI) diagnoses, surgical procedures and seizure outcomes classified according to the Engel Classification were used. Changes over time grouped as 1996-2000, 2001-2005 and 2006-2010 were analysed., Results: A total of 95 children underwent epilepsy surgery. Sixty-three operations were performed in Denmark and 50 abroad. In all, 14 children needed reoperation. The median follow-up period was four years. At the latest follow-up, Engel class I (indicating no disabling seizures) was found in 67% of the patients. Cortical dysplasia, mesial temporal sclerosis and tumour were the most common MRI findings. The percentage of tumours operated decreased over time, and frontal lobe resections increased. In the 2006-2010 period, resections with normal MRI were performed, resulting in a less favourable Engel outcome. Persistent, unexpected complications were seen in three of 113 operations., Conclusions: The majority of children who undergo epilepsy surgery have a good, worthwhile seizure outcome. The seizure outcome for Danish children corresponds to that of other epilepsy surgery centres. The clinical criteria for selection of patients changed over time., Funding: none., Trial Registration: The Danish Data Protection Agency approved the project with record number: 2013-41-2459.
- Published
- 2015
44. Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors.
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Hoei-Hansen CE, Nielsen JE, Almstrup K, Sonne SB, Graem N, Skakkebaek NE, Leffers H, and Rajpert-De Meyts E
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- Adolescent, Adult, Carcinoma in Situ genetics, Cell Differentiation, Child, Child, Preschool, DNA-Binding Proteins genetics, Female, Gene Expression Regulation, Neoplastic, Germinoma etiology, Germinoma metabolism, Gonadal Dysgenesis complications, Gonadal Dysgenesis pathology, Humans, Infant, Infant, Newborn, Male, Middle Aged, Ovarian Neoplasms genetics, Pregnancy, Steroids pharmacology, Testicular Neoplasms genetics, Transcription Factor AP-2, Transcription Factors genetics, Tretinoin pharmacology, Biomarkers, Tumor, Carcinoma in Situ metabolism, DNA-Binding Proteins metabolism, Gene Expression Regulation, Developmental, Ovarian Neoplasms metabolism, Testicular Neoplasms metabolism, Transcription Factors metabolism
- Abstract
Purpose: Transcription factor activator protein-2gamma (TFAP2C, AP-2gamma) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2gamma in carcinoma in situ testis (CIS, or intratubular germ cell neoplasia), precursor of testicular germ cell tumors. In this study we aimed to investigate the expression pattern of AP-2gamma and to shed light on this factor in germ cell differentiation and the pathogenesis of germ cell neoplasia., Experimental Design: We analyzed expression pattern of AP-2gamma at the RNA and protein level in normal human tissues and a panel of tumors and tumor-derived cell lines. In the gonads, we established the ontogeny of expression of AP-2gamma in normal and dysgenetic samples. We also investigated the regulation of AP-2gamma by steroids and retinoic acid., Results: We detected abundant AP-2gamma in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2gamma in somatic tumors. We found that AP-2gamma expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2gamma protein expression in fetal gonads revealed that it was confined to oogonia/gonocytes and was down-regulated with germ cell differentiation. In some prepubertal intersex cases, AP-2gamma was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells., Conclusions: AP-2gamma is developmentally regulated and associated with the undifferentiated phenotype in germ cells. This transcription factor may be involved in self-renewal and survival of immature germ cells and tissue-specific stem cells. AP-2gamma is a novel marker of testicular CIS and CIS-derived tumors.
- Published
- 2004
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45. Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling.
- Author
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Almstrup K, Hoei-Hansen CE, Wirkner U, Blake J, Schwager C, Ansorge W, Nielsen JE, Skakkebaek NE, Rajpert-De Meyts E, and Leffers H
- Subjects
- Carcinoma in Situ metabolism, Chromosomes, Human genetics, Gene Amplification, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Testicular Neoplasms metabolism, Carcinoma in Situ genetics, Carcinoma in Situ pathology, Stem Cells pathology, Testicular Neoplasms genetics, Testicular Neoplasms pathology
- Abstract
Carcinoma in situ (CIS) is the common precursor of histologically heterogeneous testicular germ cell tumors (TGCTs), which in recent decades have markedly increased and now are the most common malignancy of young men. Using genome-wide gene expression profiling, we identified >200 genes highly expressed in testicular CIS, including many never reported in testicular neoplasms. Expression was further verified by semiquantitative reverse transcription-PCR and in situ hybridization. Among the highest expressed genes were NANOG and POU5F1, and reverse transcription-PCR revealed possible changes in their stoichiometry on progression into embryonic carcinoma. We compared the CIS expression profile with patterns reported in embryonic stem cells (ESCs), which revealed a substantial overlap that may be as high as 50%. We also demonstrated an over-representation of expressed genes in regions of 17q and 12, reported as unstable in cultured ESCs. The close similarity between CIS and ESCs explains the pluripotency of CIS. Moreover, the findings are consistent with an early prenatal origin of TGCTs and thus suggest that etiologic factors operating in utero are of primary importance for the incidence trends of TGCTs. Finally, some of the highly expressed genes identified in this study are promising candidates for new diagnostic markers for CIS and/or TGCTs.
- Published
- 2004
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46. Histological evidence of testicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer.
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Hoei-Hansen CE, Holm M, Rajpert-De Meyts E, and Skakkebaek NE
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- Adolescent, Adult, Aged, Biopsy methods, Carcinoma in Situ pathology, Carcinoma in Situ physiopathology, Cell Transformation, Neoplastic pathology, Germinoma pathology, Germinoma physiopathology, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal physiopathology, Seminoma pathology, Seminoma physiopathology, Sertoli-Leydig Cell Tumor pathology, Sertoli-Leydig Cell Tumor physiopathology, Spermatogenesis physiology, Testis pathology, Testis physiopathology, Neoplasms, Germ Cell and Embryonal pathology, Testicular Neoplasms pathology, Testis abnormalities
- Abstract
This study was prompted by a hypothesis that testicular germ cell cancer may be aetiologically linked to other male reproductive abnormalities as a part of the so-called 'testicular dysgenesis syndrome' (TDS). To corroborate the hypothesis of a common association of germ cell cancer with testicular dysgenesis, microscopic dysgenetic features were quantified in contralateral testicular biopsies in patients with a testicular germ cell tumour. Two hundred and eighty consecutive contralateral testicular biopsies from Danish patients with testicular cancer diagnosed in 1998-2001 were evaluated retrospectively. Two hundred and eighteen specimens were subsequently included in this study, after 63 patients who did not meet inclusion criteria had to be excluded. The presence of carcinoma in situ (which is believed to originate from transformed gonocytes) was detected in 8.7% of biopsies. The incidence of other dysgenetic features was immature tubules with undifferentiated Sertoli cells, 4.6%; microcalcifications (microliths), 6.0%; and the presence of a Sertoli-cell-only pattern in at least a few tubules, 13.8%. The cumulative incidence of one or more signs of testicular dysgenesis was 25.2%. In a few patients, areas with immature and morphologically distorted tubules were also noted. Spermatogenesis was qualitatively normal in 51.4%, whereas 11.5% had very poor or absent spermatogenesis. It is concluded that microscopic testicular dysgenesis is a frequent feature in contralateral biopsies from patients presenting with testicular germ cell neoplasms of the adolescent and young type. The findings therefore support the hypothesis that this cancer is part of a testicular dysgenesis syndrome. The presence of contralateral carcinoma in situ was higher in the present study than previously reported., (Copyright 2003 John Wiley & Sons, Ltd.)
- Published
- 2003
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