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4. Gonadal function and pathology in 17beta-HSD 3 and 5alpha-reductase deficiency.

Author

Boogers, Lidewij S, Brüggenwirth, Hennie T, Wolffenbuttel, Katja P, Hersmus, Remko, Bryce, Jillian, Ahmed, S Faisal, Lucas-Herald, Angela K, Baronio, Federico, Cools, Martine, Ellaithi, Mona, Globa, Evgenia, Güran, Tülay, Hiort, Olaf, Holterhus, Paul-Martin, MсElreavey, Kenneth, Niedziela, Marek, Stancampiano, Marianna Rita, Tosun, Buşra G, Bever, Yolande van, and Oosterhuis, J Wolter

Subjects
*SEX differentiation disorders, *GERM cells, *CASTRATION, *TESTIS, *CANCER cells
Abstract

Objective 17β-Hydroxysteroid dehydrogenase 3 deficiency (17β-HSDD) and 5α-reductase type 2 deficiency (5α-RD) are rare 46,XY differences of sex development (DSD). This study aims to enlarge the limited knowledge on long-term gonadal function and gonadal pathology in these conditions. Design Retrospective multicentre cohort study. Methods Data on phenotype, laboratory results, and hormone treatment were collected from patients aged ≥16 years at time of data collection with genetically confirmed 17β-HSDD and 5α-RD from 10 centres via the I-DSD Registry. If gonadectomy or gonadal biopsy had been performed, pathology reports and/or gonadal tissue or images were collected. Results All 16 patients with 17β-HSDD were raised female; 1 (6%) changed to male gender at age 14. Three females were treated with gonadotrophin-releasing hormone agonists (GnRHa) to prevent virilisation. Thirteen underwent gonadectomy at median age 8 (range 0-17). None had germ cell (pre)malignancies. Of 14 patients with 5α-RD, 10 (71%) were raised female. Five changed gender at age 7-23, of whom 4 to male gender. One was treated with GnRHa. Six underwent gonadectomy at median age 10 (range 0-31). None had germ cell (pre)malignancies. With gonads in situ, puberty spontaneously progressed. Three were treated with dihydrotestosterone. Conclusions A significant percentage of individuals with 17β-HSDD and 5α-RD changed gender, and some were treated with GnRHa to prevent virilisation before making a definitive decision about gonadectomy. When left in situ, spontaneous puberty occurs and germ cell (pre)malignancies seem uncommon at least until early adulthood. Together, these data support delaying a decision about gonadectomy until late adolescence in these conditions. [ABSTRACT FROM AUTHOR]

Published
2025
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5. The proprotein convertase FURIN is a novel aneurysm predisposition gene impairing TGF-β signalling.

Author

He, Zongsheng, IJpma, Arne S, Vreeken, Dianne, Heijsman, Daphne, Rosier, Karen, Verhagen, Hence J M, Bruin, Jorg L de, Brüggenwirth, Hennie T, Roos-Hesselink, Jolien W, Bekkers, Jos A, Huylebroeck, Danny F E, Beusekom, Heleen M M van, Creemers, John W M, and Majoor-Krakauer, Danielle

Subjects
AORTIC aneurysms, TRANSFORMING growth factors, GENETIC variation, DISSECTING aneurysms, OLDER patients
Abstract

Aims Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor β (TGF-β)-signalling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-β maturation. Methods and results Rare FURIN variants were detected by whole-exome sequencing of 781 unrelated aortic aneurysm patients and affected relatives. Thirteen rare heterozygous FURIN variants occurred in 3.7% (29) unrelated index AA patients, of which 72% had multiple aneurysms or a dissection. FURIN maturation and activity of these variants were decreased in vitro. Patient-derived fibroblasts showed decreased pro-TGF-β processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-β-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibres were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-β signalling variably, indicating effect modification by individual genetic backgrounds. Conclusion FURIN is a novel, frequent genetic predisposition for abdominal-, thoracic-, and multiple aortic or middle sized artery aneurysms in older patients, by affecting intracellular TGF-β signalling, depending on individual genetic backgrounds. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Genome-wide methylation analysis in patients with proximal hypospadias – a pilot study and review of the literature.

Author

van Bever, Yolande, Boers, Ruben G, Brüggenwirth, Hennie T, van IJcken, Wilfred Fj, Magielsen, Frank J, de Klein, Annelies, Boers, Joachim B, Looijenga, Leendert Hj, Brosens, Erwin, Gribnau, Joost, and Hannema, Sabine E

Subjects
SMALL for gestational age, SEX differentiation disorders, GENETIC testing, DNA methylation, HYPOSPADIAS, LEUKOCYTES
Abstract

In patients with proximal hypospadias, often no genetic cause is identified despite extensive genetic testing. Many genes involved in sex development encode transcription factors with strict timing and dosing of the gene products. We hypothesised that there might be recurrent differences in DNA methylation in boys with hypospadias and that these might differ between patients born small versus appropriate for gestational age. Genome-wide Methylated DNA sequencing (MeD-seq) was performed on 32bp LpnPI restriction enzyme fragments after RE-digestion in leucocytes from 16 XY boys with unexplained proximal hypospadias, one with an unexplained XX testicular disorder/difference of sex development (DSD) and twelve, healthy, sex- and age-matched controls. Five of seven differentially methylated regions (DMRs) between patients and XY controls were in the Long Intergenic Non-Protein Coding RNA 665 (LINC00665; CpG24525). Three patients showed hypermethylation of MAP3K1. Finally, no DMRs in XX testicular DSD associated genes were identified in the XX boy versus XX controls. In conclusion, we observed no recognizable epigenetic signature in 16 boys with XY proximal hypospadias and no difference between children born small versus appropriate for gestational age. Comparison to previous methylation studies in individuals with hypospadias did not show consistent findings, possibly due to the use of different inclusion criteria, tissues and methods. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients

Author

Demirdas, Serwet, primary, van den Bersselaar, Lisa M., additional, Lechner, Rosan, additional, Bos, Jessica, additional, Alsters, Suzanne I.M., additional, Baars, Marieke J.H., additional, Baas, Annette F., additional, Baysal, Özlem, additional, van der Crabben, Saskia N., additional, Dulfer, Eelco, additional, Giesbertz, Noor A.A., additional, Helderman-van den Enden, Apollonia T.J.M., additional, Hilhorst-Hofstee, Yvonne, additional, Kempers, Marlies J.E., additional, Komdeur, Fenne L., additional, Loeys, Bart, additional, Majoor-Krakauer, Daniëlle, additional, Ockeloen, Charlotte W., additional, Overwater, Eline, additional, van Tintelen, Peter J., additional, Voorendt, Marsha, additional, de Waard, Vivian, additional, Maugeri, Alessandra, additional, Brüggenwirth, Hennie T., additional, van de Laar, Ingrid M.B.H., additional, and Houweling, Arjan C., additional

Published
2024
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8. Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation

Author

de Wagenaar, Nathalie P, primary, van den Bersselaar, Lisa M, additional, Odijk, Hanny J H M, additional, Stefens, Sanne J M, additional, Reinhardt, Dieter P, additional, Roos-Hesselink, Jolien W, additional, Kanaar, Roland, additional, Verhagen, Judith M A, additional, Brüggenwirth, Hennie T, additional, van de Laar, Ingrid M B H, additional, van der Pluijm, Ingrid, additional, and Essers, Jeroen, additional

Published
2024
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9. Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients

Author

Genetica Klinische Genetica, Circulatory Health, Regenerative Medicine and Stem Cells, Genetica, Genetica Groep Van Tintelen, Cancer, Child Health, Demirdas, Serwet, van den Bersselaar, Lisa M, Lechner, Rosan, Bos, Jessica, Alsters, Suzanne I M, Baars, Marieke J H, Baas, Annette F, Baysal, Özlem, van der Crabben, Saskia N, Dulfer, Eelco, Giesbertz, Noor A A, Helderman-van den Enden, Apollonia T J M, Hilhorst-Hofstee, Yvonne, Kempers, Marlies J E, Komdeur, Fenne L, Loeys, Bart, Majoor-Krakauer, Daniëlle, Ockeloen, Charlotte W, Overwater, Eline, van Tintelen, Peter J, Voorendt, Marsha, de Waard, Vivian, Maugeri, Alessandra, Brüggenwirth, Hennie T, van de Laar, Ingrid M B H, Houweling, Arjan C, Genetica Klinische Genetica, Circulatory Health, Regenerative Medicine and Stem Cells, Genetica, Genetica Groep Van Tintelen, Cancer, Child Health, Demirdas, Serwet, van den Bersselaar, Lisa M, Lechner, Rosan, Bos, Jessica, Alsters, Suzanne I M, Baars, Marieke J H, Baas, Annette F, Baysal, Özlem, van der Crabben, Saskia N, Dulfer, Eelco, Giesbertz, Noor A A, Helderman-van den Enden, Apollonia T J M, Hilhorst-Hofstee, Yvonne, Kempers, Marlies J E, Komdeur, Fenne L, Loeys, Bart, Majoor-Krakauer, Daniëlle, Ockeloen, Charlotte W, Overwater, Eline, van Tintelen, Peter J, Voorendt, Marsha, de Waard, Vivian, Maugeri, Alessandra, Brüggenwirth, Hennie T, van de Laar, Ingrid M B H, and Houweling, Arjan C

Published
2024

10. Genome-wide methylation analysis in patients with proximal hypospadias–a pilot study and review of the literature

Author

Pathologie Groep Van Diest, van Bever, Yolande, Boers, Ruben G., Brüggenwirth, Hennie T., van IJcken, Wilfred Fj, Magielsen, Frank J., de Klein, Annelies, Boers, Joachim B., Looijenga, Leendert Hj, Brosens, Erwin, Gribnau, Joost, Hannema, Sabine E., Pathologie Groep Van Diest, van Bever, Yolande, Boers, Ruben G., Brüggenwirth, Hennie T., van IJcken, Wilfred Fj, Magielsen, Frank J., de Klein, Annelies, Boers, Joachim B., Looijenga, Leendert Hj, Brosens, Erwin, Gribnau, Joost, and Hannema, Sabine E.

Published
2024

11. Vascular Ehlers-Danlos Syndrome:A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients

Author

Demirdas, Serwet, van den Bersselaar, Lisa M., Lechner, Rosan, Bos, Jessica, Alsters, Suzanne I.M., Baars, Marieke J.H., Baas, Annette F., Baysal, Özlem, van der Crabben, Saskia N., Dulfer, Eelco, Giesbertz, Noor A.A., Helderman-Van den Enden, Apollonia T.J.M., Hilhorst-Hofstee, Yvonne, Kempers, Marlies J.E., Komdeur, Fenne L., Loeys, Bart, Majoor-Krakauer, Daniëlle, Ockeloen, Charlotte W., Overwater, Eline, van Tintelen, Peter J., Voorendt, Marsha, de Waard, Vivian, Maugeri, Alessandra, Brüggenwirth, Hennie T., van de Laar, Ingrid M.B.H., Houweling, Arjan C., Demirdas, Serwet, van den Bersselaar, Lisa M., Lechner, Rosan, Bos, Jessica, Alsters, Suzanne I.M., Baars, Marieke J.H., Baas, Annette F., Baysal, Özlem, van der Crabben, Saskia N., Dulfer, Eelco, Giesbertz, Noor A.A., Helderman-Van den Enden, Apollonia T.J.M., Hilhorst-Hofstee, Yvonne, Kempers, Marlies J.E., Komdeur, Fenne L., Loeys, Bart, Majoor-Krakauer, Daniëlle, Ockeloen, Charlotte W., Overwater, Eline, van Tintelen, Peter J., Voorendt, Marsha, de Waard, Vivian, Maugeri, Alessandra, Brüggenwirth, Hennie T., van de Laar, Ingrid M.B.H., and Houweling, Arjan C.

Abstract

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Published
2024

12. Response to the comment on Diderich et al. “The role of a multidisciplinary team in managing variants of uncertain clinical significance in prenatal genetic diagnosis” (EJMG 66(10),104844)

Author

Diderich, Karin E.M., Klapwijk, Jasmijn E., van der Schoot, Vyne, van den Born, Myrthe, Wilke, Martina, Joosten, Marieke, Stuurman, Kyra E., Hoefsloot, Lies H., Van Opstal, Diane, Brüggenwirth, Hennie T., Srebniak, Malgorzata I., Diderich, Karin E.M., Klapwijk, Jasmijn E., van der Schoot, Vyne, van den Born, Myrthe, Wilke, Martina, Joosten, Marieke, Stuurman, Kyra E., Hoefsloot, Lies H., Van Opstal, Diane, Brüggenwirth, Hennie T., and Srebniak, Malgorzata I.

Published
2024

13. Response to the comment on Diderich et al. “The role of a multidisciplinary team in managing variants of uncertain clinical significance in prenatal genetic diagnosis” (EJMG 66(10),104844)

Author

Diderich, Karin E.M., primary, Klapwijk, Jasmijn E., additional, van der Schoot, Vyne, additional, van den Born, Myrthe, additional, Wilke, Martina, additional, Joosten, Marieke, additional, Stuurman, Kyra E., additional, Hoefsloot, Lies H., additional, Van Opstal, Diane, additional, Brüggenwirth, Hennie T., additional, and Srebniak, Malgorzata I., additional

Published
2024
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15. Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Author

van den Bersselaar, Lisa M., primary, Verhagen, Judith M.A., additional, Bekkers, Jos A., additional, Kempers, Marlies, additional, Houweling, Arjan C., additional, Baars, Marieke, additional, Overwater, Eline, additional, Hilhorst-Hofstee, Yvonne, additional, Barge-Schaapveld, Daniela Q.C.M., additional, Rompen, Eline, additional, Krapels, Ingrid P.C., additional, Dulfer, Eelco, additional, Wessels, Marja W., additional, Loeys, Bart L., additional, Verhagen, Hence J.M., additional, Maugeri, Alessandra, additional, Roos-Hesselink, Jolien W., additional, Brüggenwirth, Hennie T., additional, and van de Laar, Ingrid M.B.H., additional

Published
2023
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16. Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Author

van den Bersselaar, Lisa M., Verhagen, Judith M.A., Bekkers, Jos A., Kempers, Marlies, Houweling, Arjan C., Baars, Marieke, Overwater, Eline, Hilhorst-Hofstee, Yvonne, Barge-Schaapveld, Daniela Q.C.M., Rompen, Eline, Krapels, Ingrid P.C., Dulfer, Eelco, Wessels, Marja W., Loeys, Bart L., Verhagen, Hence J.M., Maugeri, Alessandra, Roos-Hesselink, Jolien W., Brüggenwirth, Hennie T., and van de Laar, Ingrid M.B.H.

Published
2024
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17. Challenges and Pragmatic Solutions in Pre-Test and Post-Test Genetic Counseling for Prenatal Exome Sequencing

Author

Diderich, Karin E.M., Klapwijk, Jasmijn E., van der Schoot, Vyne, Brüggenwirth, Hennie T., Joosten, Marieke, Srebniak, Malgorzata I., Diderich, Karin E.M., Klapwijk, Jasmijn E., van der Schoot, Vyne, Brüggenwirth, Hennie T., Joosten, Marieke, and Srebniak, Malgorzata I.

Abstract

The yield of genetic prenatal diagnosis has been notably improved by introducing whole genome chromosomal microarray (CMA) and prenatal exome sequencing (pES). However, together with increased numbers of diagnoses made, the need to manage challenging findings such as variants of unknown significance (VUS) and incidental findings (IF) also increased. We have summarized the current guidelines and recommendations and we have shown current solutions used in our tertiary center in the Netherlands. We discuss four of the most common clinical situations: fetus with normal pES results, fetus with a pathogenic finding explaining the fetal phenotype, fetus with a variant of uncertain clinical significance fitting the phenotype and fetus with a variant leading to an incidental diagnosis. Additionally, we reflect on solutions in order to facilitate genetic counseling in an NGS-era.

Published
2023

18. Undetectable anti-Mullerian hormone and inhibin B do not preclude the presence of germ cell tumours in 45,X/46,XY or 46,XY gonadal dysgenesis

Author

Hannema, Sabine E., Wolffenbuttel, Katja P., van Bever, Yolande, Brüggenwirth, Hennie T., van den Berg, Sjoerd A.A., Hersmus, Remko, Oosterhuis, J. Wolter, Looijenga, Leendert H.J., Hannema, Sabine E., Wolffenbuttel, Katja P., van Bever, Yolande, Brüggenwirth, Hennie T., van den Berg, Sjoerd A.A., Hersmus, Remko, Oosterhuis, J. Wolter, and Looijenga, Leendert H.J.

Abstract

Objective: Individuals with 45,X/46,XY or 46,XY gonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone (AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. Design, Patients and Measurements: Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999–2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. Results: Thirteen males and 16 females were included, 20 with 46,XY and 9 with 45,X/46,XY DSD. Three females had dysgerminoma alongside gonadoblastoma; two gonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. Conclusions: Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XY or 46,XY gonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

Published
2023

21. Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Author

van den Bersselaar, Lisa M., primary, Verhagen, Judith M.A., additional, Bekkers, Jos A., additional, Kempers, Marlies, additional, Houweling, Arjan C., additional, Baars, Marieke, additional, Overwater, Eline, additional, Hilhorst-Hofstee, Yvonne, additional, Barge-Schaapveld, Daniela Q.C.M., additional, Rompen, Eline, additional, Krapels, Ingrid P.C., additional, Dulfer, Eelco, additional, Wessels, Marja W., additional, Loeys, Bart L., additional, Verhagen, Hence J.M., additional, Maugeri, Alessandra, additional, Roos-Hesselink, Jolien W., additional, Brüggenwirth, Hennie T., additional, and van de Laar, Ingrid M.B.H., additional

Published
2022
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22. Dual molecular diagnosis contributes to atypical Prader–Willi phenotype in monozygotic twins

Author

Jehee, Fernanda S., de Oliveira, Valdirene T., Gurgel‐Giannetti, Juliana, Pietra, Rafaella X., Rubatino, Fernando V. M., Carobin, Natália V., Vianna, Gabrielle S., de Freitas, Mariana L., Fernandes, Karla S., Ribeiro, Beatriz S. V., Brüggenwirth, Hennie T., Ali‐Amin, Roza, White, Janson J., Akdemir, Zeynep C., Jhangiani, Shalini N., Gibbs, Richard A., Lupski, James R., Varela, Monica C., Koiffmann, Célia, Rosenberg, Carla, and Carvalho, Cláudia M. B.

Published
2017
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24. Health Problems in Adults with Prader–Willi Syndrome of Different Genetic Subtypes: Cohort Study, Meta-Analysis and Review of the Literature

Author

Rosenberg, Anna G. W., primary, Wellink, Charlotte M., additional, Tellez Garcia, Juan M., additional, Pellikaan, Karlijn, additional, Van Abswoude, Denise H., additional, Davidse, Kirsten, additional, Van Zutven, Laura J. C. M., additional, Brüggenwirth, Hennie T., additional, Resnick, James L., additional, Van der Lely, Aart J., additional, and De Graaff, Laura C. G., additional

Published
2022
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25. Multi-Omics Profiling in Marfan Syndrome: Further Insights into the Molecular Mechanisms Involved in Aortic Disease

Author

Verhagen, Judith M.A., Burger, Joyce, Bekkers, Jos A., Den Dekker, Alexander T., von der Thüsen, Jan H., Zajec, Marina, Brüggenwirth, Hennie T., van der Sterre, Marianne L.T., van den Born, Myrthe, Luider, Theo M., van IJcken, Wilfred F.J., Wessels, Marja W., Essers, Jeroen, Roos-Hesselink, Jolien W., van der Pluijm, Ingrid, van de Laar, Ingrid M.B.H., Brosens, Erwin, Verhagen, Judith M.A., Burger, Joyce, Bekkers, Jos A., Den Dekker, Alexander T., von der Thüsen, Jan H., Zajec, Marina, Brüggenwirth, Hennie T., van der Sterre, Marianne L.T., van den Born, Myrthe, Luider, Theo M., van IJcken, Wilfred F.J., Wessels, Marja W., Essers, Jeroen, Roos-Hesselink, Jolien W., van der Pluijm, Ingrid, van de Laar, Ingrid M.B.H., and Brosens, Erwin

Published
2022

26. Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

Author

van den Bersselaar, Lisa M., Verhagen, Judith M.A., Bekkers, Jos A., Kempers, Marlies, Houweling, Arjan C., Baars, Marieke, Overwater, Eline, Hilhorst-Hofstee, Yvonne, Barge-Schaapveld, Daniela Q.C.M., Rompen, Eline, Krapels, Ingrid P.C., Dulfer, Eelco, Wessels, Marja W., Loeys, Bart L., Verhagen, Hence J.M., Maugeri, Alessandra, Roos-Hesselink, Jolien W., Brüggenwirth, Hennie T., van de Laar, Ingrid M.B.H., van den Bersselaar, Lisa M., Verhagen, Judith M.A., Bekkers, Jos A., Kempers, Marlies, Houweling, Arjan C., Baars, Marieke, Overwater, Eline, Hilhorst-Hofstee, Yvonne, Barge-Schaapveld, Daniela Q.C.M., Rompen, Eline, Krapels, Ingrid P.C., Dulfer, Eelco, Wessels, Marja W., Loeys, Bart L., Verhagen, Hence J.M., Maugeri, Alessandra, Roos-Hesselink, Jolien W., Brüggenwirth, Hennie T., and van de Laar, Ingrid M.B.H.

Abstract

PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively.CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.

Published
2022

29. Multi-Omics Profiling in Marfan Syndrome: Further Insights into the Molecular Mechanisms Involved in Aortic Disease

Author

Verhagen, Judith M. A., primary, Burger, Joyce, additional, Bekkers, Jos A., additional, den Dekker, Alexander T., additional, von der Thüsen, Jan H., additional, Zajec, Marina, additional, Brüggenwirth, Hennie T., additional, van der Sterre, Marianne L. T., additional, van den Born, Myrthe, additional, Luider, Theo M., additional, van IJcken, Wilfred F. J., additional, Wessels, Marja W., additional, Essers, Jeroen, additional, Roos-Hesselink, Jolien W., additional, van der Pluijm, Ingrid, additional, van de Laar, Ingrid M. B. H., additional, and Brosens, Erwin, additional

Published
2021
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30. The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant

Author

Pellikaan, Karlijn, Woerden, Geeske M. van, Kleinendorst, Lotte, Rosenberg, Anna G. W., Horsthemke, Bernhard, Grosser, Christian, Zutven, Laura J. C. M. van, Rossum, Elisabeth F. C. van, Lely, Aart J. van der, Resnick, James L., Brüggenwirth, Hennie T., Haelst, Mieke M. van, and Graaff, Laura C. G. de

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, brain, genetic variation, nutritional and metabolic diseases, genetics, prader–willi syndrome, nervous system diseases, genomic imprinting
Abstract

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C&gt, T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

Published
2021
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31. How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies

Author

Klapwijk, Jasmijn E., primary, Srebniak, Malgorzata I., additional, Go, Attie T. J. I., additional, Govaerts, Lutgarde C. P., additional, Lewis, Celine, additional, Hammond, Jennifer, additional, Hill, Melissa, additional, Lou, Stina, additional, Vogel, Ida, additional, Ormond, Kelly E., additional, Diderich, Karin E. M., additional, Brüggenwirth, Hennie T., additional, and Riedijk, Sam R., additional

Published
2021
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32. How to deal with uncertainty in prenatal genomics:A systematic review of guidelines and policies

Author

Klapwijk, Jasmijn E., Srebniak, Malgorzata I., Go, Attie T.J.I., Govaerts, Lutgarde C.P., Lewis, Celine, Hammond, Jennifer, Hill, Melissa, Lou, Stina, Vogel, Ida, Ormond, Kelly E., Diderich, Karin E.M., Brüggenwirth, Hennie T., Riedijk, Sam R., Klapwijk, Jasmijn E., Srebniak, Malgorzata I., Go, Attie T.J.I., Govaerts, Lutgarde C.P., Lewis, Celine, Hammond, Jennifer, Hill, Melissa, Lou, Stina, Vogel, Ida, Ormond, Kelly E., Diderich, Karin E.M., Brüggenwirth, Hennie T., and Riedijk, Sam R.

Abstract

Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.

Published
2021

33. The diagnostic journey of a patient with prader–willi-like syndrome and a unique homozygous snurf-snrpn variant; bio-molecular analysis and review of the literature

Author

Pellikaan, Karlijn, van Woerden, Geeske M., Kleinendorst, Lotte, Rosenberg, Anna G.W., Horsthemke, Bernhard, Grosser, Christian, van Zutven, Laura J.C.M., van Rossum, Elisabeth F.C., van der Lely, Aart J., Resnick, James L., Brüggenwirth, Hennie T., van Haelst, Mieke M., de Graaff, Laura C.G., Pellikaan, Karlijn, van Woerden, Geeske M., Kleinendorst, Lotte, Rosenberg, Anna G.W., Horsthemke, Bernhard, Grosser, Christian, van Zutven, Laura J.C.M., van Rossum, Elisabeth F.C., van der Lely, Aart J., Resnick, James L., Brüggenwirth, Hennie T., van Haelst, Mieke M., and de Graaff, Laura C.G.

Abstract

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

Published
2021

34. Best Practice Guidelines for the Use of Next-Generation Sequencing Applications in Genome Diagnostics: A National Collaborative Study of Dutch Genome Diagnostic Laboratories

Author

Weiss, Marjan M., van der Zwaag, Bert, Jongbloed, Jan D. H., Vogel, Maartje J., Brüggenwirth, Hennie T., Lekanne Deprez, Ronald H., Mook, Olaf, Ruivenkamp, Claudia A. L., van Slegtenhorst, Marjon A., van den Wijngaard, Arthur, Waisfisz, Quinten, Nelen, Marcel R., and van der Stoep, Nienke

Published
2013
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35. Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development

Author

Bever, Yolande van, primary, Brüggenwirth, Hennie T, additional, Wolffenbuttel, Katja P, additional, Dessens, Arianne B, additional, Groenenberg, Irene A L, additional, Knapen, Maarten F C M, additional, De Baere, Elfride, additional, Cools, Martine, additional, van Ravenswaaij-Arts, Conny M A, additional, Sikkema-Raddatz, Birgit, additional, Claahsen-van der Grinten, Hedi, additional, Kempers, Marlies, additional, Rinne, Tuula, additional, Hersmus, Remko, additional, Looijenga, Leendert, additional, and Hannema, Sabine E, additional

Published
2020
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36. Familial Gigantism Caused by an NSD1 Mutation

Author

van Haelst, Mieke M., Hoogeboom, Jeannette J.M., Baujat, Genevieve, Brüggenwirth, Hennie T., Van de Laar, Ingrid, Coleman, Kim, Rahman, Nazneen, Niermeijer, Martinus F., Drop, Sten L.S., and Scambler, Peter J.

Published
2005
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38. Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development.

Author

van Beve, Yolande, Brüggenwirth, Hennie T., Wolffenbutte, Katja P., Dessens, Arianne B., Groenenberg, Irene A. L., Knapen, Maarten F. C. M., De Baere, Elfride, Cools, Martine, van Ravenswaaij-Arts, Conny M. A., Sikkema-Raddatz, Birgit, Claahsen-van der Grinten, Hedi, Kempers, Marlies, Rinne, Tuula, Hersmus, Remko, Looijenga, Leendert, and Hannema, Sabine E.

Abstract

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of- the- art diagnostics. [ABSTRACT FROM AUTHOR]

Published
2020
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39. Multiparameter Investigation of a 46,XX/46,XY Tetragametic Chimeric Phenotypical Male Patient with Bilateral Scrotal Ovotestes and Ovulatory Activity

Author

van Bever, Yolande, primary, Wolffenbuttel, Katja P., additional, Brüggenwirth, Hennie T., additional, Blom, Eric, additional, de Klein, Annelies, additional, Eussen, Bert H.J., additional, van der Windt, Florijn, additional, Hannema, Sabine E., additional, Dessens, Arianne B., additional, Dorssers, Lambert C.J., additional, Biermann, Katharina, additional, Hersmus, Remko, additional, de Rijke, Yolanda B., additional, and Looijenga, Leendert H.J., additional

Published
2017
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40. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E

Published
2017

41. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E

Published
2017

42. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, Claire, primary, Brand, Harrison, additional, Collins, Ryan L, additional, Kammin, Tammy, additional, Mitchell, Elyse, additional, Hodge, Jennelle C, additional, Hanscom, Carrie, additional, Pillalamarri, Vamsee, additional, Seabra, Catarina M, additional, Abbott, Mary-Alice, additional, Abdul-Rahman, Omar A, additional, Aberg, Erika, additional, Adley, Rhett, additional, Alcaraz-Estrada, Sofia L, additional, Alkuraya, Fowzan S, additional, An, Yu, additional, Anderson, Mary-Anne, additional, Antolik, Caroline, additional, Anyane-Yeboa, Kwame, additional, Atkin, Joan F, additional, Bartell, Tina, additional, Bernstein, Jonathan A, additional, Beyer, Elizabeth, additional, Blumenthal, Ian, additional, Bongers, Ernie M H F, additional, Brilstra, Eva H, additional, Brown, Chester W, additional, Brüggenwirth, Hennie T, additional, Callewaert, Bert, additional, Chiang, Colby, additional, Corning, Ken, additional, Cox, Helen, additional, Cuppen, Edwin, additional, Currall, Benjamin B, additional, Cushing, Tom, additional, David, Dezso, additional, Deardorff, Matthew A, additional, Dheedene, Annelies, additional, D'Hooghe, Marc, additional, de Vries, Bert B A, additional, Earl, Dawn L, additional, Ferguson, Heather L, additional, Fisher, Heather, additional, FitzPatrick, David R, additional, Gerrol, Pamela, additional, Giachino, Daniela, additional, Glessner, Joseph T, additional, Gliem, Troy, additional, Grady, Margo, additional, Graham, Brett H, additional, Griffis, Cristin, additional, Gripp, Karen W, additional, Gropman, Andrea L, additional, Hanson-Kahn, Andrea, additional, Harris, David J, additional, Hayden, Mark A, additional, Hill, Rosamund, additional, Hochstenbach, Ron, additional, Hoffman, Jodi D, additional, Hopkin, Robert J, additional, Hubshman, Monika W, additional, Innes, A Micheil, additional, Irons, Mira, additional, Irving, Melita, additional, Jacobsen, Jessie C, additional, Janssens, Sandra, additional, Jewett, Tamison, additional, Johnson, John P, additional, Jongmans, Marjolijn C, additional, Kahler, Stephen G, additional, Koolen, David A, additional, Korzelius, Jerome, additional, Kroisel, Peter M, additional, Lacassie, Yves, additional, Lawless, William, additional, Lemyre, Emmanuelle, additional, Leppig, Kathleen, additional, Levin, Alex V, additional, Li, Haibo, additional, Li, Hong, additional, Liao, Eric C, additional, Lim, Cynthia, additional, Lose, Edward J, additional, Lucente, Diane, additional, Macera, Michael J, additional, Manavalan, Poornima, additional, Mandrile, Giorgia, additional, Marcelis, Carlo L, additional, Margolin, Lauren, additional, Mason, Tamara, additional, Masser-Frye, Diane, additional, McClellan, Michael W, additional, Mendoza, Cinthya J Zepeda, additional, Menten, Björn, additional, Middelkamp, Sjors, additional, Mikami, Liya R, additional, Moe, Emily, additional, Mohammed, Shehla, additional, Mononen, Tarja, additional, Mortenson, Megan E, additional, Moya, Graciela, additional, Nieuwint, Aggie W, additional, Ordulu, Zehra, additional, Parkash, Sandhya, additional, Pauker, Susan P, additional, Pereira, Shahrin, additional, Perrin, Danielle, additional, Phelan, Katy, additional, Aguilar, Raul E Piña, additional, Poddighe, Pino J, additional, Pregno, Giulia, additional, Raskin, Salmo, additional, Reis, Linda, additional, Rhead, William, additional, Rita, Debra, additional, Renkens, Ivo, additional, Roelens, Filip, additional, Ruliera, Jayla, additional, Rump, Patrick, additional, Schilit, Samantha L P, additional, Shaheen, Ranad, additional, Sparkes, Rebecca, additional, Spiegel, Erica, additional, Stevens, Blair, additional, Stone, Matthew R, additional, Tagoe, Julia, additional, Thakuria, Joseph V, additional, van Bon, Bregje W, additional, van de Kamp, Jiddeke, additional, van Der Burgt, Ineke, additional, van Essen, Ton, additional, van Ravenswaaij-Arts, Conny M, additional, van Roosmalen, Markus J, additional, Vergult, Sarah, additional, Volker-Touw, Catharina M L, additional, Warburton, Dorothy P, additional, Waterman, Matthew J, additional, Wiley, Susan, additional, Wilson, Anna, additional, Yerena-de Vega, Maria de la Concepcion A, additional, Zori, Roberto T, additional, Levy, Brynn, additional, Brunner, Han G, additional, de Leeuw, Nicole, additional, Kloosterman, Wigard P, additional, Thorland, Erik C, additional, Morton, Cynthia C, additional, Gusella, James F, additional, and Talkowski, Michael E, additional

Published
2016
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43. Metastatic Disease in Polyploid Uveal Melanoma Patients Is Associated WithBAP1Mutations

Author

Yavuzyigitoglu, Serdar, primary, Mensink, Hanneke W., additional, Smit, Kyra N., additional, Vaarwater, Jolanda, additional, Verdijk, Robert M., additional, Beverloo, Berna, additional, Brüggenwirth, Hennie T., additional, van Marion, Ronald, additional, Dubbink, Hendrikus J., additional, Paridaens, Dion, additional, Naus, Nicole C., additional, de Klein, Annelies, additional, and Kiliç, Emine, additional

Published
2016
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44. List of contributors

Author

Bijma, Hilmar H., Brüggenwirth, Hennie T., Dekkers, Frederike, Diderich, Karin E.M., El Bouazzaoui, Fadua, Emons, Iris, Fisher, Jane, Jansen-Bakkeren, Iris, Joosten, Marieke, Klapwijk, Jasmijn E., Knapen, Maarten F.C.M., Lewis, Celine, Lou, Stina, Ormond, Kelly E., Pajkrt, Eva, Peters, Ingrid A., Petersen, Olav B., Ras, Lara, Riedijk, Sam, Srebniak, Malgorzata I., van Leeuwen, Liesbeth, Vogel, Ida, Wildschut, Hajo I.J., and Zavyalova, Diana

Published
2022
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45. Multiparameter Investigation of a 46,XX/46,XY Tetragametic Chimeric Phenotypical Male Patient with Bilateral Scrotal Ovotestes and Ovulatory Activity.

Author

van Bever, Yolande, Wolffenbuttel, Katja P., Brüggenwirth, Hennie T., Blom, Eric, de Klein, Annelies, Eussen, Bert H.J., van der Windt, Florijn, Hannema, Sabine E., Dessens, Arianne B., Dorssers, Lambert C.J., Biermann, Katharina, Hersmus, Remko, de Rijke, Yolanda B., and Looijenga, Leendert H.J.

Subjects
DISEASES, SCROTUM, GYNECOMASTIA, HYPERPIGMENTATION, CASTRATION, IMMUNOHISTOCHEMISTRY, KARYOTYPES
Abstract

We report on an adult male initially presenting with gynecomastia and a painless scrotal mass without additional genital anomalies. Hyperpigmentation of the skin following the Blaschko's lines was identified. He underwent gonadectomy because of suspected cancer. Histological analyses revealed an ovotestis with ovulatory activity confirmed by immunohistochemistry with multiple markers. Karyotyping of cultured peripheral blood lymphocytes and a buccal smear revealed a 46,XX/46,XY chimeric constitution with different percentages. Multiple molecular analyses as well as blood typing implied a tetragametic origin. After the unilateral gonadectomy, the patient developed recurrent painful cystic swellings of the remaining gonad. Because of the wish to preserve hormonal activity as well as future fertility, the patient underwent surgical resection of a cystic gonadal area. The removed tissue showed ovulation-related features in addition to both testicular and ovarian tissue, diagnosed as an ovotestis. Testosterone therapy was initiated to suppress the persistently elevated gonadotropins and thereby suppress ovarian activity. During treatment, the recurrent pain complaints and cystic swellings ceased, although gonadotropin levels were not fully suppressed. Based on these observations, the importance of a detailed genetic and pathological diagnosis and the clinical dilemmas including the pros and cons of personalized treatment with gonadal preservative surgery are discussed. [ABSTRACT FROM AUTHOR]

Published
2018
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46. A 46,XY Female DSD Patient with Bilateral Gonadoblastoma, a Novel SRY Missense Mutation Combined with a WT1 KTS Splice-Site Mutation

Author

Hersmus, Remko, primary, van der Zwan, Yvonne G., additional, Stoop, Hans, additional, Bernard, Pascal, additional, Sreenivasan, Rajini, additional, Oosterhuis, J. Wolter, additional, Brüggenwirth, Hennie T., additional, de Boer, Suzan, additional, White, Stefan, additional, Wolffenbuttel, Katja P., additional, Alders, Marielle, additional, McElreavy, Kenneth, additional, Drop, Stenvert L. S., additional, Harley, Vincent R., additional, and Looijenga, Leendert H. J., additional

Published
2012
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47. Multiplex ligation-dependent probe amplification equals fluorescence in-situ hybridization for the identification of patients at risk for metastatic disease in uveal melanoma

Author

Vaarwater, Jolanda, primary, van den Bosch, Thomas, additional, Mensink, Hanneke W., additional, van Kempen, Chantal, additional, Verdijk, Rob M., additional, Naus, Nicole C., additional, Paridaens, Dion, additional, Brüggenwirth, Hennie T., additional, Kiliç, Emine, additional, and de Klein, Annelies, additional

Published
2012
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50. Deletion of Exons 1a–2 of BRCA1: A Rather Frequent Pathogenic Abnormality

Author

van den Ouweland, Ans M.W., primary, Dinjens, Winand N.M., additional, Dorssers, Lambert C.J., additional, van Veghel–Plandsoen, Monique M., additional, Brüggenwirth, Hennie T., additional, Withagen–Hermans, Caroline J., additional, Collée, Johanna Margriet, additional, Joosse, Simon A., additional, Terlouw–Kromosoeto, Joan N.R., additional, and Nederlof, Petra M., additional

Published
2009
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