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1. X-linked acrogigantism syndrome: clinical profile and therapeutic responses

Author

Beckers, Albert, Lodish, Maya Beth, Trivellin, Giampaolo, Rostomyan, Liliya, Lee, Misu, Faucz, Fabio R, Yuan, Bo, Choong, Catherine S, Caberg, Jean-Hubert, Verrua, Elisa, Naves, Luciana Ansaneli, Cheetham, Tim D, Young, Jacques, Lysy, Philippe A, Petrossians, Patrick, Cotterill, Andrew, Shah, Nalini Samir, Metzger, Daniel, Castermans, Emilie, Ambrosio, Maria Rosaria, Villa, Chiara, Strebkova, Natalia, Mazerkina, Nadia, Gaillard, Stéphan, Barra, Gustavo Barcelos, Casulari, Luis Augusto, Neggers, Sebastian J, Salvatori, Roberto, Jaffrain-Rea, Marie-Lise, Zacharin, Margaret, Santamaria, Beatriz Lecumberri, Zacharieva, Sabina, Lim, Ee Mun, Mantovani, Giovanna, Zatelli, Maria Chaira, Collins, Michael T, Bonneville, Jean-François, Quezado, Martha, Chittiboina, Prashant, Oldfield, Edward H, Bours, Vincent, Liu, Pengfei, W de Herder, Wouter, Pellegata, Natalia, Lupski, James R, Daly, Adrian F, and Stratakis, Constantine A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Rare Diseases, Pediatric, Clinical Research, Cancer, Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Chromosomes, Human, X, Female, Gigantism, Humans, Infant, Male, Pituitary Neoplasms, Young Adult, gigantism, X chromosome, pituitary adenoma, pediatric, X-LAG syndrome, GPR101, FIPA, duplication, Biological Sciences, Medical and Health Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

Published
2015

2. Germ-line and somatic DICER1 mutations in pineoblastoma

Author

de Kock, Leanne, Sabbaghian, Nelly, Druker, Harriet, Weber, Evan, Hamel, Nancy, Miller, Suzanne, Choong, Catherine S, Gottardo, Nicholas G, Kees, Ursula R, Rednam, Surya P, van Hest, Liselotte P, Jongmans, Marjolijn C, Jhangiani, Shalini, Lupski, James R, Zacharin, Margaret, Bouron-Dal Soglio, Dorothée, Huang, Annie, Priest, John R, Perry, Arie, Mueller, Sabine, Albrecht, Steffen, Malkin, David, Grundy, Richard G, and Foulkes, William D

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetic Testing, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cancer, Adolescent, Brain Neoplasms, Child, Child, Preschool, DEAD-box RNA Helicases, DNA Mutational Analysis, Family Health, Female, Germ-Line Mutation, Humans, Infant, Male, Pineal Gland, Pinealoma, Ribonuclease III, Young Adult, DICER1, miRNA processing, Paediatric brain tumours, Pineal gland, Childhood cancer, Mutation, Pineoblastoma, OMIM #601200, Clinical Sciences, Neurology & Neurosurgery
Abstract

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.

Published
2014

6. Sleep-disordered breathing in Australian children with Prader-Willi syndrome following initiation of growth hormone therapy

Author

Caudri, Daan, Nixon, Gillian M., Nielsen, Aleisha, Mai, Linda, Hafekost, Claire R., Kapur, Nitin, Seton, Chris, Tai, Andrew, Blecher, Greg, Ambler, Geoff, Bergman, Philip B., Vora, Komal A., Crock, Patricia, Verge, Charles F., Tham, Elaine, Musthaffa, Yassmin, Lafferty, Antony R., Jacoby, Peter, Wilson, Andrew C., Downs, Jenny, Choong, Catherine S., Caudri, Daan, Nixon, Gillian M., Nielsen, Aleisha, Mai, Linda, Hafekost, Claire R., Kapur, Nitin, Seton, Chris, Tai, Andrew, Blecher, Greg, Ambler, Geoff, Bergman, Philip B., Vora, Komal A., Crock, Patricia, Verge, Charles F., Tham, Elaine, Musthaffa, Yassmin, Lafferty, Antony R., Jacoby, Peter, Wilson, Andrew C., Downs, Jenny, and Choong, Catherine S.

Abstract

Aim: In children with Prader-Willi syndrome (PWS), growth hormone (GH) improves height and body composition; however, may be associated with worsening sleep-disordered breathing (SDB). Some studies have reported less SDB after GH initiation, but follow-up with polysomnography is still advised in most clinical guidelines. Methods: This retrospective, multicentre study, included children with PWS treated with GH at seven PWS treatment centres in Australia over the last 18 years. A paired analysis comparing polysomnographic measures of central and obstructive SDB in the same child, before and after GH initiation was performed with Wilcoxon signed-rank test. The proportion of children who developed moderate/severe obstructive sleep apnoea (OSA) was calculated with their binomial confidence intervals. Results: We included 112 patients with available paired data. The median age at start of GH was 1.9 years (range 0.1–13.5 years). Median obstructive apnoea hypopnoea index (AHI) at baseline was 0.43/h (range 0–32.9); 35% had an obstructive AHI above 1.0/h. Follow-up polysomnography within 2 years after the start of GH was available in 94 children who did not receive OSA treatment. After GH initiation, there was no change in central AHI. The median obstructive AHI did not increase significantly (P = 0.13), but 12 children (13%, CI95% 7–21%) developed moderate/severe OSA, with clinical management implications. Conclusions: Our findings of a worsening of OSA severity in 13% of children with PWS support current advice to perform polysomnography after GH initiation. Early identification of worsening OSA may prevent severe sequelae in a subgroup of children.

Published
2022

7. Safety of growth hormone replacement in survivors of cancer and intra-cranial and pituitary tumours - A consensus statement

Author

Endocrinologie patientenzorg, Brain, Child Health, Cancer, Boguszewski, Margaret C S, Boguszewski, Cesar L, Chemaitilly, Wassim, Cohen, Laurie E, Gebauer, Judith, Higham, Claire, Hoffman, Andrew R, Polak, Michel, Yuen, Kevin C J, Alos, Nathalie, Antal, Zoltan, Bidlingmaier, Martin, Biller, Beverly M K, Brabant, Georg, Choong, Catherine S Y, Cianfarani, Stefano, Clayton, Peter E, Coutant, Regis, Cardoso-Demartini, Adriane A, Fernandez, Alberto, Grimberg, Adda, Gudmundsson, Kolbeinn, Guevara-Aquirre, Jamie, Ho, Ken K Y, Horikawa, Reiko, Isidori, Andrea M, Jorgensen, Jens Otto Lunde, Kamenicky, Peter, Karavitaki, Niki, Kopchick, John J, Lodish, Maya, Luo, Xiao-Ping, McCormack, Ann I, Meacham, Lillian, Melmed, Shlomo, Sogol Mostoufi-Moab, Sogol, Müller, Hermann L, Neggers, Sebastian J C M M, Aguiar-Oliveira, Manuel H, Ozono, Keiichi, Pennisi, Patricia A, Popovic, Vera, Radovick, Sally, Savendahl, Lars, Touraine, Philippe, van Santen, Hanneke M, Johannsson, Gudmundur, Endocrinologie patientenzorg, Brain, Child Health, Cancer, Boguszewski, Margaret C S, Boguszewski, Cesar L, Chemaitilly, Wassim, Cohen, Laurie E, Gebauer, Judith, Higham, Claire, Hoffman, Andrew R, Polak, Michel, Yuen, Kevin C J, Alos, Nathalie, Antal, Zoltan, Bidlingmaier, Martin, Biller, Beverly M K, Brabant, Georg, Choong, Catherine S Y, Cianfarani, Stefano, Clayton, Peter E, Coutant, Regis, Cardoso-Demartini, Adriane A, Fernandez, Alberto, Grimberg, Adda, Gudmundsson, Kolbeinn, Guevara-Aquirre, Jamie, Ho, Ken K Y, Horikawa, Reiko, Isidori, Andrea M, Jorgensen, Jens Otto Lunde, Kamenicky, Peter, Karavitaki, Niki, Kopchick, John J, Lodish, Maya, Luo, Xiao-Ping, McCormack, Ann I, Meacham, Lillian, Melmed, Shlomo, Sogol Mostoufi-Moab, Sogol, Müller, Hermann L, Neggers, Sebastian J C M M, Aguiar-Oliveira, Manuel H, Ozono, Keiichi, Pennisi, Patricia A, Popovic, Vera, Radovick, Sally, Savendahl, Lars, Touraine, Philippe, van Santen, Hanneke M, and Johannsson, Gudmundur

Published
2022

8. Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance

Author

Sanderson, Elaine E, Shah, Mark, Hooper, Amanda J, Bell, Damon A, and Choong, Catherine S

Subjects
endocrine system, Endocrinology, Diabetes and Metabolism, Diabetes, Australia, nutritional and metabolic diseases, White, January, Paediatric, Internal Medicine, Female, New Disease or Syndrome: Presentations/Diagnosis/Management, Pancreas, hormones, hormone substitutes, and hormone antagonists
Abstract

Summary We report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants. Learning points Insulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents. Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history. Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

Published
2022

19. Exercise training improves vascular function and secondary health measures in survivors of pediatric oncology related cerebral insult

Author

Long, Treya M., primary, Rath, Shoshana R., additional, Wallman, Karen E., additional, Howie, Erin K., additional, Straker, Leon M., additional, Bullock, Andrew, additional, Walwyn, Thomas S., additional, Gottardo, Nicholas G., additional, Cole, Catherine H., additional, Choong, Catherine S., additional, and Naylor, Louise H., additional

Published
2018
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20. Growth Hormone Research Society perspective on biomarkers of GH action in children and adults

Author

Johannsson, Gudmundur, primary, Bidlingmaier, Martin, additional, Biller, Beverly M K, additional, Boguszewski, Margaret, additional, Casanueva, Felipe F, additional, Chanson, Philippe, additional, Clayton, Peter E, additional, Choong, Catherine S, additional, Clemmons, David, additional, Dattani, Mehul, additional, Frystyk, Jan, additional, Ho, Ken, additional, Hoffman, Andrew R, additional, Horikawa, Reiko, additional, Juul, Anders, additional, Kopchick, John J, additional, Luo, Xiaoping, additional, Neggers, Sebastian, additional, Netchine, Irene, additional, Olsson, Daniel S, additional, Radovick, Sally, additional, Rosenfeld, Ron, additional, Ross, Richard J, additional, Schilbach, Katharina, additional, Solberg, Paulo, additional, Strasburger, Christian, additional, Trainer, Peter, additional, Yuen, Kevin C J, additional, Wickstrom, Kerstin, additional, Jorgensen, Jens O L, additional, and _, _, additional

Published
2018
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21. Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Author

de Kock, Leanne, Rivera, Barbara, Revil, Timothée, Thorner, Paul, Goudie, Catherine, Bouron-Dal Soglio, Dorothée, Choong, Catherine S., Priest, John R., Van Diest, Paul J., Tanboon, Jantima, Wagner, Anja, Ragoussis, Jiannis, Choong, Peter F.M., Foulkes, William D, de Kock, Leanne, Rivera, Barbara, Revil, Timothée, Thorner, Paul, Goudie, Catherine, Bouron-Dal Soglio, Dorothée, Choong, Catherine S., Priest, John R., Van Diest, Paul J., Tanboon, Jantima, Wagner, Anja, Ragoussis, Jiannis, Choong, Peter F.M., and Foulkes, William D

Published
2017

22. Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Author

Pathologie patiënten zorg, UMC Utrecht, Cancer, de Kock, Leanne, Rivera, Barbara, Revil, Timothée, Thorner, Paul, Goudie, Catherine, Bouron-Dal Soglio, Dorothée, Choong, Catherine S., Priest, John R., Van Diest, Paul J., Tanboon, Jantima, Wagner, Anja, Ragoussis, Jiannis, Choong, Peter F.M., Foulkes, William D, Pathologie patiënten zorg, UMC Utrecht, Cancer, de Kock, Leanne, Rivera, Barbara, Revil, Timothée, Thorner, Paul, Goudie, Catherine, Bouron-Dal Soglio, Dorothée, Choong, Catherine S., Priest, John R., Van Diest, Paul J., Tanboon, Jantima, Wagner, Anja, Ragoussis, Jiannis, Choong, Peter F.M., and Foulkes, William D

Published
2017

23. Germline Or Somatic Gpr101 Duplication Leads To X-Linked Acrogigantism: A Clinico-Pathological And Genetic Study

Author

Iacovazzo, Donato, Caswell, Richard, Bunce, Benjamin, Jose, Sian, Yuan, Bo, Hernández-Ramírez, Laura C., Kapur, Sonal, Caimari, Francisca, Evanson, Jane, Ferraù, Francesco, Dang, Mary N., Gabrovska, Plamena, Larkin, Sarah J., Ansorge, Olaf, Rodd, Celia, Vance, Mary L., Ramírez-Renteria, Claudia, Mercado, Moisés, Goldstone, Anthony P., Buchfelder, Michael, Burren, Christine P., Gurlek, Alper, Dutta, Pinaki, Choong, Catherine S., Cheetham, Timothy, Trivellin, Giampaolo, Stratakis, Constantine A., Lopes, Maria-Beatriz, Grossman, Ashley B., Trouillas, Jacqueline, Lupski, James R., Ellard, Sian, Sampson, Julian R., Roncaroli, Federico, Korbonits, Márta, and İç Hastalıkları

Subjects
Adenoma, Male, Adolescent, Medizin, Gigantism, Receptors, G-Protein-Coupled, Young Adult, Gene Duplication, Genetics, Humans, XLAG, Pituitary Neoplasms, Child, Germ-Line Mutation, GPR101, Research, Intracellular Signaling Peptides and Proteins, Infant, Pituitary adenoma, R1, CNV mutation, Pituitary, Acromegaly, Child, Preschool, Female, Treatment Outcome, 2734, Neurology (clinical), Cellular and Molecular Neuroscience
Abstract

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly. We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants. We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases. In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0328-1) contains supplementary material, which is available to authorized users.

Published
2016

24. A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes

Author

Bouron-Dal Soglio, Dorothée, primary, de Kock, Leanne, additional, Gauci, Richard, additional, Sabbaghian, Nelly, additional, Thomas, Elizabeth, additional, Atkinson, Helen C., additional, Pachter, Nicholas, additional, Ryan, Simon, additional, Walsh, John P., additional, Kumarasinghe, M. Priyanthi, additional, Carpenter, Karen, additional, Aydoğan, Ayça, additional, Stewart, Colin J.R., additional, Foulkes, William D., additional, and Choong, Catherine S., additional

Published
2017
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25. Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Author

de Kock, Leanne, primary, Rivera, Barbara, additional, Revil, Timothée, additional, Thorner, Paul, additional, Goudie, Catherine, additional, Bouron-Dal Soglio, Dorothée, additional, Choong, Catherine S, additional, Priest, John R, additional, van Diest, Paul J, additional, Tanboon, Jantima, additional, Wagner, Anja, additional, Ragoussis, Jiannis, additional, Choong, Peter FM, additional, and Foulkes, William D, additional

Published
2017
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27. Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations

Author

Christiansen, Jens Sandahl, Backeljauw, Philippe F, Bidlingmaier, Martin, Biller, Beverly M K, Boguszewski, Margaret C S, Casanueva, Felipe F, Chanson, Philippe, Chatelain, Pierre, Choong, Catherine S, Clemmons, David R, Cohen, Laurie E, Cohen, Pinchas, Frystyk, Jan, Grimberg, Adda, Hasegawa, Yukihiro, Haymond, Morey W, Ho, Ken, Hoffman, Andrew R, Holly, Jeff M P, Horikawa, Reiko, Höybye, Charlotte, Jorgensen, Jens Otto Lunde, Johannsson, Gudmundur, Juul, Anders, Katznelson, Laurence, Kopchick, John J., Lee, K O, Lee, Kuk-Wha, Luo, Xiaoping, Melmed, Shlomo, Miller, Bradley S, Misra, Madhusmita, Popovic, Vera, Rosenfeld, Ron G, Ross, Judith, Ross, Richard J, Saenger, Paul, Strasburger, Christian J, Thorner, Michael O, Werner, Haim, Yuen, Kevin C J, Christiansen, Jens Sandahl, Backeljauw, Philippe F, Bidlingmaier, Martin, Biller, Beverly M K, Boguszewski, Margaret C S, Casanueva, Felipe F, Chanson, Philippe, Chatelain, Pierre, Choong, Catherine S, Clemmons, David R, Cohen, Laurie E, Cohen, Pinchas, Frystyk, Jan, Grimberg, Adda, Hasegawa, Yukihiro, Haymond, Morey W, Ho, Ken, Hoffman, Andrew R, Holly, Jeff M P, Horikawa, Reiko, Höybye, Charlotte, Jorgensen, Jens Otto Lunde, Johannsson, Gudmundur, Juul, Anders, Katznelson, Laurence, Kopchick, John J., Lee, K O, Lee, Kuk-Wha, Luo, Xiaoping, Melmed, Shlomo, Miller, Bradley S, Misra, Madhusmita, Popovic, Vera, Rosenfeld, Ron G, Ross, Judith, Ross, Richard J, Saenger, Paul, Strasburger, Christian J, Thorner, Michael O, Werner, Haim, and Yuen, Kevin C J

Abstract

OBJECTIVE: The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH).PARTICIPANTS: A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.EVIDENCE: Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues.CONSENSUS PROCESS: Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.CONCLUSIONS: LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.

Published
2016

28. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Author

Eggers, Stefanie, primary, Sadedin, Simon, additional, van den Bergen, Jocelyn A., additional, Robevska, Gorjana, additional, Ohnesorg, Thomas, additional, Hewitt, Jacqueline, additional, Lambeth, Luke, additional, Bouty, Aurore, additional, Knarston, Ingrid M., additional, Tan, Tiong Yang, additional, Cameron, Fergus, additional, Werther, George, additional, Hutson, John, additional, O’Connell, Michele, additional, Grover, Sonia R., additional, Heloury, Yves, additional, Zacharin, Margaret, additional, Bergman, Philip, additional, Kimber, Chris, additional, Brown, Justin, additional, Webb, Nathalie, additional, Hunter, Matthew F., additional, Srinivasan, Shubha, additional, Titmuss, Angela, additional, Verge, Charles F., additional, Mowat, David, additional, Smith, Grahame, additional, Smith, Janine, additional, Ewans, Lisa, additional, Shalhoub, Carolyn, additional, Crock, Patricia, additional, Cowell, Chris, additional, Leong, Gary M., additional, Ono, Makato, additional, Lafferty, Antony R., additional, Huynh, Tony, additional, Visser, Uma, additional, Choong, Catherine S., additional, McKenzie, Fiona, additional, Pachter, Nicholas, additional, Thompson, Elizabeth M., additional, Couper, Jennifer, additional, Baxendale, Anne, additional, Gecz, Jozef, additional, Wheeler, Benjamin J., additional, Jefferies, Craig, additional, MacKenzie, Karen, additional, Hofman, Paul, additional, Carter, Philippa, additional, King, Richard I., additional, Krausz, Csilla, additional, van Ravenswaaij-Arts, Conny M. A., additional, Looijenga, Leendert, additional, Drop, Sten, additional, Riedl, Stefan, additional, Cools, Martine, additional, Dawson, Angelika, additional, Juniarto, Achmad Zulfa, additional, Khadilkar, Vaman, additional, Khadilkar, Anuradha, additional, Bhatia, Vijayalakshmi, additional, Dũng, Vũ Chí, additional, Atta, Irum, additional, Raza, Jamal, additional, thi Diem Chi, Nguyen, additional, Hao, Tran Kiem, additional, Harley, Vincent, additional, Koopman, Peter, additional, Warne, Garry, additional, Faradz, Sultana, additional, Oshlack, Alicia, additional, Ayers, Katie L., additional, and Sinclair, Andrew H., additional

Published
2016
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29. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients.

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, Rostomyan, Liliya, Daly, Adrian F, Petrossians, Patrick, Nachev, Emil, Lila, Anurag R, Lecoq, Anne-Lise, Lecumberri, Beatriz, Trivellin, Giampaolo, Salvatori, Roberto, Moraitis, Andreas G, Holdaway, Ian, Kranenburg-van Klaveren, Dianne J, Chiara Zatelli, Maria, Palacios, Nuria, Nozieres, Cecile, Zacharin, Margaret, Ebeling, Tapani, Ojaniemi, Marja, Rozhinskaya, Liudmila, Verrua, Elisa, Jaffrain-Rea, Marie-Lise, Filipponi, Silvia, Gusakova, Daria, Pronin, Vyacheslav, Bertherat, Jerome, Belaya, Zhanna, Ilovayskaya, Irena, Sahnoun-Fathallah, Mona, Sievers, Caroline, Stalla, Gunter K, Castermans, Emilie, Caberg, Jean-Hubert, Sorkina, Ekaterina, Auriemma, Renata Simona, Mittal, Sachin, Kareva, Maria, Lysy, Philippe, Emy, Philippe, De Menis, Ernesto, Choong, Catherine S, Mantovani, Giovanna, Bours, Vincent, De Herder, Wouter, Brue, Thierry, Barlier, Anne, Neggers, Sebastian J C M M, Zacharieva, Sabina, Chanson, Philippe, Shah, Nalini Samir, Stratakis, Constantine A, Naves, Luciana A, Beckers, Albert, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, Rostomyan, Liliya, Daly, Adrian F, Petrossians, Patrick, Nachev, Emil, Lila, Anurag R, Lecoq, Anne-Lise, Lecumberri, Beatriz, Trivellin, Giampaolo, Salvatori, Roberto, Moraitis, Andreas G, Holdaway, Ian, Kranenburg-van Klaveren, Dianne J, Chiara Zatelli, Maria, Palacios, Nuria, Nozieres, Cecile, Zacharin, Margaret, Ebeling, Tapani, Ojaniemi, Marja, Rozhinskaya, Liudmila, Verrua, Elisa, Jaffrain-Rea, Marie-Lise, Filipponi, Silvia, Gusakova, Daria, Pronin, Vyacheslav, Bertherat, Jerome, Belaya, Zhanna, Ilovayskaya, Irena, Sahnoun-Fathallah, Mona, Sievers, Caroline, Stalla, Gunter K, Castermans, Emilie, Caberg, Jean-Hubert, Sorkina, Ekaterina, Auriemma, Renata Simona, Mittal, Sachin, Kareva, Maria, Lysy, Philippe, Emy, Philippe, De Menis, Ernesto, Choong, Catherine S, Mantovani, Giovanna, Bours, Vincent, De Herder, Wouter, Brue, Thierry, Barlier, Anne, Neggers, Sebastian J C M M, Zacharieva, Sabina, Chanson, Philippe, Shah, Nalini Samir, Stratakis, Constantine A, Naves, Luciana A, and Beckers, Albert

Abstract

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Published
2015

30. X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, Beckers, Albert, Lodish, Maya Beth, Trivellin, Giampaolo, Rostomyan, Liliya, Lee, Misu, Faucz, Fabio R., Yuan, Bo, Choong, Catherine S., Caberg, Jean-Hubert, Verrua, Elisa, Naves, Luciana Ansaneli, Cheetham, Tim D., Young, Jacques, Lysy, Philippe, Petrossians, Patrick, Cotterill, Andrew, Shah, Nalini Samir, Metzger, Daniel, Castermans, Emilie, Ambrosio, Maria Rosaria, Villa, Chiara, Strebkova, Natalia, Mazerkina, Nadia, Gaillard, Stéphan, Barra, Gustavo Barcelos, Casulari, Luis Augusto, Neggers, Sebastian J., Salvatori, Roberto, Jaffrain-Rea, Marie-Lise, Zacharin, Margaret, Santamaria, Beatriz Lecumberri, Zacharieva, Sabina, Lim, Ee Mun, Mantovani, Giovanna, Zatelli, Maria Chaira, Collins, Michael T, Bonneville, Jean-François, Quezado, Martha, Chittiboina, Prashant, Oldfield, Edward H., Bours, Vincent, Liu, Pengfei, W de Herder, Wouter, Pellegata, Natalia, Lupski, James R., Daly, Adrian F., Stratakis, Constantine A., UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, Beckers, Albert, Lodish, Maya Beth, Trivellin, Giampaolo, Rostomyan, Liliya, Lee, Misu, Faucz, Fabio R., Yuan, Bo, Choong, Catherine S., Caberg, Jean-Hubert, Verrua, Elisa, Naves, Luciana Ansaneli, Cheetham, Tim D., Young, Jacques, Lysy, Philippe, Petrossians, Patrick, Cotterill, Andrew, Shah, Nalini Samir, Metzger, Daniel, Castermans, Emilie, Ambrosio, Maria Rosaria, Villa, Chiara, Strebkova, Natalia, Mazerkina, Nadia, Gaillard, Stéphan, Barra, Gustavo Barcelos, Casulari, Luis Augusto, Neggers, Sebastian J., Salvatori, Roberto, Jaffrain-Rea, Marie-Lise, Zacharin, Margaret, Santamaria, Beatriz Lecumberri, Zacharieva, Sabina, Lim, Ee Mun, Mantovani, Giovanna, Zatelli, Maria Chaira, Collins, Michael T, Bonneville, Jean-François, Quezado, Martha, Chittiboina, Prashant, Oldfield, Edward H., Bours, Vincent, Liu, Pengfei, W de Herder, Wouter, Pellegata, Natalia, Lupski, James R., Daly, Adrian F., and Stratakis, Constantine A.

Abstract

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

Published
2015

31. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients

Author

Rostomyan, Liliya, primary, Daly, Adrian F, additional, Petrossians, Patrick, additional, Nachev, Emil, additional, Lila, Anurag R, additional, Lecoq, Anne-Lise, additional, Lecumberri, Beatriz, additional, Trivellin, Giampaolo, additional, Salvatori, Roberto, additional, Moraitis, Andreas G, additional, Holdaway, Ian, additional, Kranenburg - van Klaveren, Dianne J, additional, Chiara Zatelli, Maria, additional, Palacios, Nuria, additional, Nozieres, Cecile, additional, Zacharin, Margaret, additional, Ebeling, Tapani, additional, Ojaniemi, Marja, additional, Rozhinskaya, Liudmila, additional, Verrua, Elisa, additional, Jaffrain-Rea, Marie-Lise, additional, Filipponi, Silvia, additional, Gusakova, Daria, additional, Pronin, Vyacheslav, additional, Bertherat, Jerome, additional, Belaya, Zhanna, additional, Ilovayskaya, Irena, additional, Sahnoun-Fathallah, Mona, additional, Sievers, Caroline, additional, Stalla, Gunter K, additional, Castermans, Emilie, additional, Caberg, Jean-Hubert, additional, Sorkina, Ekaterina, additional, Auriemma, Renata Simona, additional, Mittal, Sachin, additional, Kareva, Maria, additional, Lysy, Philippe A, additional, Emy, Philippe, additional, De Menis, Ernesto, additional, Choong, Catherine S, additional, Mantovani, Giovanna, additional, Bours, Vincent, additional, De Herder, Wouter, additional, Brue, Thierry, additional, Barlier, Anne, additional, Neggers, Sebastian J C M M, additional, Zacharieva, Sabina, additional, Chanson, Philippe, additional, Shah, Nalini Samir, additional, Stratakis, Constantine A, additional, Naves, Luciana A, additional, and Beckers, Albert, additional

Published
2015
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32. X-linked acrogigantism syndrome: clinical profile and therapeutic responses

Author

Beckers, Albert, primary, Lodish, Maya Beth, additional, Trivellin, Giampaolo, additional, Rostomyan, Liliya, additional, Lee, Misu, additional, Faucz, Fabio R, additional, Yuan, Bo, additional, Choong, Catherine S, additional, Caberg, Jean-Hubert, additional, Verrua, Elisa, additional, Naves, Luciana Ansaneli, additional, Cheetham, Tim D, additional, Young, Jacques, additional, Lysy, Philippe A, additional, Petrossians, Patrick, additional, Cotterill, Andrew, additional, Shah, Nalini Samir, additional, Metzger, Daniel, additional, Castermans, Emilie, additional, Ambrosio, Maria Rosaria, additional, Villa, Chiara, additional, Strebkova, Natalia, additional, Mazerkina, Nadia, additional, Gaillard, Stéphan, additional, Barra, Gustavo Barcelos, additional, Casulari, Luis Augusto, additional, Neggers, Sebastian J, additional, Salvatori, Roberto, additional, Jaffrain-Rea, Marie-Lise, additional, Zacharin, Margaret, additional, Santamaria, Beatriz Lecumberri, additional, Zacharieva, Sabina, additional, Lim, Ee Mun, additional, Mantovani, Giovanna, additional, Zatelli, Maria Chaira, additional, Collins, Michael T, additional, Bonneville, Jean-François, additional, Quezado, Martha, additional, Chittiboina, Prashant, additional, Oldfield, Edward H, additional, Bours, Vincent, additional, Liu, Pengfei, additional, de Herder, Wouter W, additional, Pellegata, Natalia, additional, Lupski, James R, additional, Daly, Adrian F, additional, and Stratakis, Constantine A, additional

Published
2015
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37. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, Trivellin, Giampaolo, Daly, Adrian F., Faucz, Fabio R., Yuan, Bo, Rostomyan, Liliya, Larco, Darwin O., Schernthaner-Reiter, Marie Helene, Szarek, Eva, Leal, Letícia F., Caberg, Jean-Hubert, Castermans, Emilie, Villa, Chiara, Dimopoulos, Aggeliki, Chittiboina, Prashant, Xekouki, Paraskevi, Shah, Nalini, Metzger, Daniel, Lysy, Philippe, Ferrante, Emanuele, Strebkova, Natalia, Mazerkina, Nadia, Zatelli, Maria Chiara, Lodish, Maya, Horvath, Anelia, de Alexandre, Rodrigo Bertollo, Manning, Allison D., Levy, Isaac, Keil, Margaret F., Sierra, Maria de la Luz, Palmeira, Leonor, Coppieters, Wouter, Georges, Michel, Naves, Luciana A., Jamar, Mauricette, Bours, Vincent, Wu, T. John, Choong, Catherine S., Bertherat, Jerome, Chanson, Philippe, Kamenický, Peter, Farrell, William E., Barlier, Anne, Quezado, Martha, Bjelobaba, Ivana, Stojilkovic, Stanko S., Wess, Jurgen, Costanzi, Stefano, Liu, Pengfei, Lupski, James R., Beckers, Albert, Stratakis, Constantine A., UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, Trivellin, Giampaolo, Daly, Adrian F., Faucz, Fabio R., Yuan, Bo, Rostomyan, Liliya, Larco, Darwin O., Schernthaner-Reiter, Marie Helene, Szarek, Eva, Leal, Letícia F., Caberg, Jean-Hubert, Castermans, Emilie, Villa, Chiara, Dimopoulos, Aggeliki, Chittiboina, Prashant, Xekouki, Paraskevi, Shah, Nalini, Metzger, Daniel, Lysy, Philippe, Ferrante, Emanuele, Strebkova, Natalia, Mazerkina, Nadia, Zatelli, Maria Chiara, Lodish, Maya, Horvath, Anelia, de Alexandre, Rodrigo Bertollo, Manning, Allison D., Levy, Isaac, Keil, Margaret F., Sierra, Maria de la Luz, Palmeira, Leonor, Coppieters, Wouter, Georges, Michel, Naves, Luciana A., Jamar, Mauricette, Bours, Vincent, Wu, T. John, Choong, Catherine S., Bertherat, Jerome, Chanson, Philippe, Kamenický, Peter, Farrell, William E., Barlier, Anne, Quezado, Martha, Bjelobaba, Ivana, Stojilkovic, Stanko S., Wess, Jurgen, Costanzi, Stefano, Liu, Pengfei, Lupski, James R., Beckers, Albert, and Stratakis, Constantine A.

Abstract

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Published
2014

39. A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes

Author

Bouron-Dal Soglio, Dorothée, de Kock, Leanne, Gauci, Richard, Sabbaghian, Nelly, Thomas, Elizabeth, Atkinson, Helen C., Pachter, Nicholas, Ryan, Simon, Walsh, John P., Kumarasinghe, M. Priyanthi, Carpenter, Karen, Aydogan, Ayça, Stewart, Colin J.R., Foulkes, William D., and Choong, Catherine S.

Abstract

Background:Hereditary tumour predisposition syndromes may increase the risk for development of thyroid nodules at a young age. We present the case of an adolescent female with Cowden syndrome who had some atypical phenotypic features which overlapped with the DICER1 syndrome. Material and Methods:A 17-year-old female presented with a 3-month history of progressive right neck swelling. Fine needle cytology of the thyroid revealed a follicular neoplasm with features suggestive of follicular variant of papillary thyroid carcinoma and she underwent a hemithyroidectomy. Enlarging nodules in the remaining thyroid led to a completion thyroidectomy at 19 years of age. The patient’s past medical history included an ovarian mixed malignant germ cell tumour, pulmonary nodules and cysts, renal cysts, mucocutaneous lesions, an arachnoid cyst, and a fibrous breast lesion. Macrocephaly was noted on physical examination. Results:Based on the patient’s complex phenotype and young age, a hereditary predisposition syndrome was suspected and genetic testing of PTENand DICER1was undertaken. A heterozygous truncating germ-line PTENmutation was identified, which combined with clinical findings, met criteria for the diagnosis of Cowden syndrome. Additional loss of heterozygosity of the wild-type PTENallele was detected in the right thyroid lesion and ovarian tumour. No DICER1mutations were identified. Conclusions:Genetic testing was crucial in elucidating this patient’s predisposition to the early development of neoplastic and non-neoplastic conditions. Our report also highlights the phenotypic overlap between the Cowden and DICER1 syndromes and illustrates the importance of recognising the variable phenotypic features of hereditary syndromes in order to enable timely implementation of appropriate care.

Published
2018
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42. Androgen Receptor Signaling

Author

Jia, Li, primary, Choong, Catherine S-Y., additional, Ricciardelli, Carmela, additional, Kim, Joshua, additional, Tilley, Wayne D., additional, and Coetzee, Gerhard A, additional

Published
2004
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43. A novel, homozygous mutation in <italic>desert hedgehog</italic> (<italic>DHH</italic>) in a 46, XY patient with dysgenetic testes presenting with primary amenorrhoea: a case report.

Author

Rothacker, Karen M., Ayers, Katie L., Tang, Dave, Joshi, Kiranjit, van den Bergen, Jocelyn A., Robevska, Gorjana, Samnakay, Naeem, Nagarajan, Lakshmi, Francis, Kate, Sinclair, Andrew H., and Choong, Catherine S.

Subjects
PRIMARY amenorrhea, HOMOZYGOSITY, GENETIC mutation
Abstract

Background: Desert hedgehog (DHH) mutations have been described in only a limited number of individuals with 46, XY disorders of sex development (DSD) presenting as either partial or complete gonadal dysgenesis. Gonadal tumours and peripheral neuropathy have been associated with DHH mutations. Herein we report a novel, homozygous mutation of DHH identified through a targeted, massively parallel sequencing (MPS) DSD panel, in a patient presenting with partial gonadal dysgenesis. This novel mutation is two amino acids away from a previously described mutation in a patient who presented with complete gonadal dysgenesis. Adding to the complexity of work-up, our patient also expressed gender identity concern. Case presentation: A 14-year-old, phenotypic female presented with primary amenorrhoea and absent secondary sex characteristics. Investigations revealed elevated gonadotrophins with low oestradiol, testosterone of 0.6 nmol/L and a 46, XY karyotype. Müllerian structures were not seen on pelvic ultrasound or laparoscopically and gonadal biopsies demonstrated dysgenetic testes without neoplasia (partial gonadal dysgenesis). The patient expressed gender identity confusion upon initial notification of investigation findings. Formal psychiatric evaluation excluded gender dysphoria. Genetic analysis was performed using a targeted, MPS DSD panel of 64 diagnostic and 927 research candidate genes. This identified a novel, homozygous mutation in exon 2 of DHH (DHH:NM_021044:exon2:c.G491C:p.R164P). With this finding our patient was screened for the possibility of peripheral neuropathy which was not evident clinically nor on investigation. She was commenced on oestrogen for pubertal induction. Conclusion: The evaluation of patients with DSD is associated with considerable psychological distress. Targeted MPS enables an affordable and efficient method for diagnosis of 46, XY DSD cases. Identifying a genetic diagnosis may inform clinical management and in this case directed screening for peripheral neuropathy. In addition to the structural location of the mutation other interacting factors may influence phenotypic expression in homozygous DHH mutations. [ABSTRACT FROM AUTHOR]

Published
2018
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44. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.

Author

Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernández-Ramírez LC, Kapur S, Caimari F, Evanson J, Ferraù F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramírez-Renteria C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, and Korbonits M

Subjects
Acromegaly complications, Acromegaly genetics, Acromegaly pathology, Adenoma complications, Adenoma genetics, Adenoma pathology, Adolescent, Child, Child, Preschool, Female, Germ-Line Mutation, Gigantism complications, Gigantism pathology, Gigantism therapy, Humans, Infant, Intracellular Signaling Peptides and Proteins genetics, Male, Pituitary Neoplasms complications, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, Treatment Outcome, Young Adult, Gene Duplication, Gigantism genetics, Receptors, G-Protein-Coupled genetics
Abstract

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

Published
2016
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45. Androgen receptor signaling: mechanism of interleukin-6 inhibition.

Author

Jia L, Choong CS, Ricciardelli C, Kim J, Tilley WD, and Coetzee GA

Subjects
Cell Line, Tumor, Cell Nucleus metabolism, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Dihydrotestosterone antagonists & inhibitors, Gene Expression drug effects, Histone Deacetylase 1, Histone Deacetylases metabolism, Humans, Male, Nuclear Proteins metabolism, Nuclear Receptor Co-Repressor 2, Prostate-Specific Antigen biosynthesis, Prostate-Specific Antigen genetics, Prostatic Neoplasms, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-akt, Repressor Proteins metabolism, STAT3 Transcription Factor, Signal Transduction physiology, Trans-Activators antagonists & inhibitors, Trans-Activators metabolism, Transcriptional Activation, Interleukin-6 pharmacology, Prostate-Specific Antigen antagonists & inhibitors, Protein Serine-Threonine Kinases, Receptors, Androgen metabolism, Signal Transduction drug effects
Abstract

Nonsteroidal signaling via the androgen receptor (AR) plays an im-portant role in hormone-refractory prostate cancer. Previously, we have reported that the pleiotropic cytokine, interleukin (IL)-6, inhibited dihydrotestosterone-mediated expression of prostate-specific antigen in LNCaP cells (Jia et al., Mol Can Res 2003;1:385-92). In the present study, we explored the mechanisms involved in this inhibition and considered possible effects on AR nuclear translocation, recruitment of transcription cofactors, and the signaling pathways that may mediate this inhibitory effect. IL-6 neither induced nuclear localization of the AR nor inhibited dihydrotestosterone-induced nuclear translocation of the receptor. IL-6 did not affect AR or p160 coactivator recruitment to the transcription initiation complex on the prostate-specific antigen enhancer and promoter. Moreover, it did not lead to the recruitment of the corepressor silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) or histone deacetylase 1 (HDAC1) at the same sites. IL-6 did, however, prevent the recruitment of the secondary coactivator, p300, to the complex and partially inhibited histone H3 acetylation at the same loci. Furthermore, inhibition by IL-6 was not mediated by the mitogen-activated protein kinase or the Akt pathways and was partially abrogated by signal transducers and activators of transcription-3 knock-down using small interfering RNA. Our results show that IL-6 modulates androgen action through the differential recruitment of cofactors to target genes. These findings may account for the pleiotropic actions of IL-6 in malignant prostate cells.

Published
2004
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