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2. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

Author

Daly, Adrian, Yuan, Bo, Fina, Frederic, Caberg, Jean-Hubert, Trivellin, Giampaolo, Rostomyan, Liliya, de Herder, Wouter, Naves, Luciana, Metzger, Daniel, Cuny, Thomas, Rabl, Wolfgang, Shah, Nalini, Jaffrain-Rea, Marie-Lise, Zatelli, Maria, Faucz, Fabio, Castermans, Emilie, Nanni-Metellus, Isabelle, Lodish, Maya, Muhammad, Ammar, Palmeira, Leonor, Potorac, Iulia, Mantovani, Giovanna, Neggers, Sebastian, Klein, Marc, Barlier, Anne, Liu, Pengfei, Ouafik, LHoucine, Bours, Vincent, Lupski, James, Stratakis, Constantine, and Beckers, Albert

Subjects
X-LAG syndrome, gigantism, molecular genetics, mosaicism, pituitary, Adult, Female, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Middle Aged, Mosaicism, Polymerase Chain Reaction, Syndrome, Young Adult
Abstract

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

Published
2016

3. 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

5. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

Author

Trivellin, Giampaolo, Daly, Adrian, Faucz, Fabio, Yuan, Bo, Rostomyan, Liliya, Larco, Darwin, Schernthaner-Reiter, Marie, Szarek, Eva, Leal, Letícia, 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, Lodish, Maya, Horvath, Anelia, de Alexandre, Rodrigo, Manning, Allison, Levy, Isaac, Keil, Margaret, Sierra, Maria, Palmeira, Leonor, Coppieters, Wouter, Georges, Michel, Naves, Luciana, Jamar, Mauricette, Bours, Vincent, Wu, T, Choong, Catherine, Bertherat, Jerome, Chanson, Philippe, Kamenický, Peter, Farrell, William, Barlier, Anne, Quezado, Martha, Bjelobaba, Ivana, Stojilkovic, Stanko, Wess, Jurgen, Costanzi, Stefano, Liu, Pengfei, Lupski, James, Beckers, Albert, and Stratakis, Constantine

Subjects
Acromegaly, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Chromosome Duplication, Chromosomes, Human, X, Female, Gigantism, Human Growth Hormone, Humans, Infant, Male, Mutation, Phenotype, Protein Conformation, Receptors, G-Protein-Coupled
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

7. List of contributors

Author

Asa, Sylvia L., primary, Beckers, Albert, additional, Betsi, Grigoria, additional, Catalano, Rosa, additional, Chittiboina, Prashant, additional, Chrysoulaki, Maria, additional, Daly, Adrian F., additional, Daraki, Vasiliki, additional, Ezzat, Shereen, additional, Gulde, Sebastian, additional, Hannah-Shmouni, Fady, additional, Hernández-Ramírez, Laura C., additional, Hodgson, Anjelica, additional, Hogan, Elizabeth, additional, Mangili, Federica, additional, Mantovani, Giovanna, additional, Mete, Ozgur, additional, Mytilinaiou, Maria, additional, Pakbaz, Sara, additional, Pellegata, Natalia S., additional, Petrossians, Patrick, additional, Peverelli, Erika, additional, Pieterman, Carolina R.C., additional, Potorac, Iulia, additional, Rostomyan, Liliya, additional, Sfakiotaki, Maria, additional, Stratakis, Constantine A., additional, Tatsi, Christina, additional, Treppiedi, Donatella, additional, Waguespack, Steven G., additional, Xekouki, Paraskevi, additional, and Yuen, Kevin C.J., additional

Published
2021
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18. Dutch founder SDHB exon 3 deletion in patients with pheochromocytoma-paraganglioma in South Africa

Author

Gordon, Debra M., Beckers, Pablo, Castermans, Emilie, Neggers, Sebastian J.C.M.M., Rostomyan, Liliya, Bours, Vincent, Petrossians, Patrick, Dideberg, Vinciane, Beckers, Albert, Daly, Adrian F., Gordon, Debra M., Beckers, Pablo, Castermans, Emilie, Neggers, Sebastian J.C.M.M., Rostomyan, Liliya, Bours, Vincent, Petrossians, Patrick, Dideberg, Vinciane, Beckers, Albert, and Daly, Adrian F.

Abstract

Objective: Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma–paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL. Design: We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors. Methods: Next-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes. Results: From a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHB exon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHD and three MEN1 variants were identified among MEN1 and young-onset pituitary adenoma patients. Conclusions: This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.

Published
2022

22. List of Contributors

Author

Abusag, Milad, primary, Arboleda, Valerie, additional, Arnold, Andrew, additional, Assié, Guillaume, additional, Beckers, Albert, additional, Bell, Graeme I., additional, Bertagna, Xavier, additional, Bertherat, Jérôme, additional, Brierley, Gemma V., additional, Cantara, Silvia, additional, Carmody, David, additional, Christensen, Jane Hvarregaard, additional, Clément, Karine, additional, Cummings, Shelly, additional, Daly, Adrian F., additional, Deladoëy, Johnny, additional, Dreijerink, Koen M., additional, Dubern, Béatrice, additional, Dumitrescu, Alexandra M., additional, Ehrmann, David A., additional, Evans, Douglas B., additional, Favus, Murray J., additional, Garg, Abhimanyu, additional, Geurts, Jennifer L., additional, Grasberger, Helmut, additional, Greeley, Siri Atma W., additional, Groussin, Lionel, additional, Höppener, Jo W., additional, Hoffman, Leslie, additional, Holick, Michael F., additional, Huang, Elbert S., additional, Huvenne, Hélène, additional, Hwa, Vivian, additional, Jones, Andrea L., additional, Joseph, Loren J., additional, Kahaly, George J., additional, Koren, Dorit, additional, Lauter, Kelly, additional, Libé, Rossella, additional, Links, Thera P., additional, Lips, Cornelis J., additional, McPhaul, Michael J., additional, Naylor, Rochelle N., additional, New, Maria I., additional, Nielsen, Sarah M., additional, Nimkarn, Saroj, additional, O'Rahilly, Stephen, additional, Pacini, Furio, additional, Palladino, Andrew, additional, Philipson, Louis H., additional, Pohlenz, Joachim, additional, Radovick, Sally, additional, Raygada, Margarita, additional, Refetoff, Samuel, additional, Rich, Thereasa A., additional, Rinkes, Inne Borel, additional, Rittig, Søren, additional, Romero, Christopher J., additional, Rosenfeld, Ron G., additional, Rostomyan, Liliya, additional, Savage, David B., additional, Semple, Robert K., additional, Støy, Julie, additional, Stratakis, Constantine A., additional, Strauss, Bernard S., additional, Timmers, Marc, additional, Tounian, Patrick, additional, Valk, Gerlof D., additional, van der Horst-Schrivers, Anouk N.A., additional, van der Luijt, Rob B., additional, van Nesselrooij, Bernadette P.M., additional, Van Vliet, Guy, additional, Vilain, Eric, additional, Vriens, Menno, additional, Wang, Tracy S., additional, Weiss, Roy E., additional, Yau, Mabel, additional, and Zuchner, Stephan, additional

Published
2016
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28. Cardiovascular complications in pituitary gigantism (results of an international study)

Author

Rostomyan Liliya, Daly Adrian, Shah Nalini, A Naves Luciana, Barlier Anne, Jaffrain-Rea Marie-Lise, Emy Philippe, Neggers Sebastian, Santamaria Beatriz Lecumberri, Holdaway Ian, Brue Thierry, Stalla Gunter, Salvatori Roberto, Bertherat Jerome Yves, Maiter Dominique, Zacharin Margaret, Lila Anurag, Filipponi Silvia, Mukhopadhyay Satinath, Ebeling Tapani, Ojaniemi Marja, McCormack Ann I, Kuismin Outi, Lecoq Anne-Lise, Sahnoun-Fathallah Mona, Jung-Sievers Caroline, Malchiodi Elena, Rozhinskaya Liudmila, Nazzari Elena, Mittal Sachin, Verrua Elisa, Sorkina Ekaterina, Dreval Alexander, Devuyst France, Bilbao Ismene, Auriemma Renata Simona, Garcia Nuria Palacios, Ilovaiskaya Irena, Pronin Vyacheslav, Colao Annamaria, Ferone Diego, Spada Anna, Petrossians Patrick, Beck-Peccoz Paolo, Stratakis Constantine A, Chanson Philippe, and Beckers Albert

Subjects
Pituitary Gigantism, business.industry, Physiology, Medicine, business, Gigantism
Published
2018

29. Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells

Author

Polidoro, Michela Anna, Rotondi, Sandra, Morace, Roberta, Rostomyan, Liliya, Colapietro, Alessandro, Arcella, Antonietta, Ventura, Luca, Angelucci, Adriano, Giangaspero, Felice, Esposito, Vincenzo, Beckers, Albert, and Jaffrain-Rea, Marie-Lise

Subjects
aryl hydrocarbon receptor interacting protein (AIP), fenofibrate, non-functioning pituitary adenomas, nuclear receptors, prolactinomas, WY 14 643, Adolescent, Adult, Aged, Cell Proliferation, Female, Fenofibrate, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, PPAR alpha, Pituitary Neoplasms, Prolactinoma, Pyrimidines, Somatotrophs, Young Adult, Endocrinology, Diabetes and Metabolism, Biochemistry, Endocrinology, Clinical Biochemistry, Biochemistry (medical)
Published
2018

30. AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients

Author

Daly, Adrian F, primary, Rostomyan, Liliya, additional, Betea, Daniela, additional, Bonneville, Jean-François, additional, Villa, Chiara, additional, Pellegata, Natalia S, additional, Waser, Beatrice, additional, Reubi, Jean-Claude, additional, Waeber Stephan, Catherine, additional, Christ, Emanuel, additional, and Beckers, Albert, additional

Published
2019
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32. Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells

Author

Polidoro, Michela, primary, Rotondi, Sandra, additional, Morace, Roberta, additional, Rostomyan, Liliya, additional, Colapietro, Alessandro, additional, Arcella, Antonietta, additional, Ventura, Luca, additional, Angelucci, Adriano, additional, Giangaspero, Felice, additional, Esposito, Vincenzo, additional, Beckers, Albert, additional, and Jaffrain-Rea, Marie-Lise, additional

Published
2018
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33. Growth Hormone Releasing Hormone Excess and Blockade in X-LAG Syndrome

Author

Daly, Adrian F., Lysy, Philippe A., Desfilles, Céline, Rostomyan, Liliya, Mohamed, Amira, Caberg, Jean-Hubert, Raverot, Veronique, Castermans, Emilie, Marbaix, Etienne, Maiter, Dominique, Brunelle, Chloe, Trivellin, Giampaolo, Stratakis, Constantine A., Bours, Vincent, Raftopoulos, Christian, Beauloye, Veronique, Barlier, Anne, and Beckers, Albert

Subjects
endocrine system, Antineoplastic Agents, Hormonal, Genetic Diseases, X-Linked, Syndrome, Growth Hormone-Releasing Hormone, Octreotide, Article, Gigantism, Prolactin, Child, Preschool, Growth Hormone, Tumor Cells, Cultured, Humans, Female, Pituitary Neoplasms, Receptors, Ghrelin, Somatostatin, hormones, hormone substitutes, and hormone antagonists
Abstract

X-linked acrogigantism (X-LAG) syndrome is a newly-described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated growth hormone (GH) and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GH-releasing hormone (GHRH) levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(D-Arg2)-GHRH (1–29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.

Published
2015

34. Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism

Author

Beckers, Albert, primary, Fernandes, Daniel, additional, Fina, Frederic, additional, Novak, Mario, additional, Abati, Angelo, additional, Rostomyan, Liliya, additional, Thiry, Albert, additional, Ouafik, L’Housine, additional, Pasture, Bertrand, additional, Pinhasi, Ron, additional, and Daly, Adrian F, additional

Published
2017
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35. GHRH excess and blockade in X-LAG syndrome

Author

UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, UCL - (SLuc) Service de neurochirurgie, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - (SLuc) Service d'anatomie pathologique, Daly, Adrian F, Lysy, Philippe, Defilles, Céline, Rostomyan, Liliya, Mohamed, Amira, Caberg, Jean-Hubert, Raverot, Veronique, Castermans, Emily, Marbaix, Etienne, Maiter, Dominique, Brunelle, Chloe, Trivellin, Giampaolo, Stratakis, Constantine A, Bours, Vincent, Raftopoulos, Christian, Beauloye, Véronique, Barlier, Anne, Beckers, Albert, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Unité d'endocrinologie pédiatrique, UCL - (SLuc) Service de neurochirurgie, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - (SLuc) Service d'anatomie pathologique, Daly, Adrian F, Lysy, Philippe, Defilles, Céline, Rostomyan, Liliya, Mohamed, Amira, Caberg, Jean-Hubert, Raverot, Veronique, Castermans, Emily, Marbaix, Etienne, Maiter, Dominique, Brunelle, Chloe, Trivellin, Giampaolo, Stratakis, Constantine A, Bours, Vincent, Raftopoulos, Christian, Beauloye, Véronique, Barlier, Anne, and Beckers, Albert

Abstract

X-linked acrogigantism (X-LAG) syndrome is a newly-described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated growth hormone (GH) and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GH-releasing hormone (GHRH) levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(D-Arg²)-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.

Published
2016

38. Characterization of GPR101 transcript structure and expression patterns

Author

Trivellin, Giampaolo, primary, Bjelobaba, Ivana, additional, Daly, Adrian F, additional, Larco, Darwin O, additional, Palmeira, Leonor, additional, Faucz, Fabio R, additional, Thiry, Albert, additional, Leal, Letícia F, additional, Rostomyan, Liliya, additional, Quezado, Martha, additional, Schernthaner-Reiter, Marie Helene, additional, Janjic, Marija M, additional, Villa, Chiara, additional, Wu, T John, additional, Stojilkovic, Stanko S, additional, Beckers, Albert, additional, Feldman, Benjamin, additional, and Stratakis, Constantine A, additional

Published
2016
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40. Expression of Peroxisome Proliferator-Activated Receptor alpha (PPARα) in somatotropinomas: Relationship with Aryl hydrocarbon receptor Interacting Protein (AIP) and in vitro effects of fenofibrate in GH3 cells

Author

Rotondi, Sandra, primary, Modarelli, Alessio, additional, Oliva, Maria-Antonietta, additional, Rostomyan, Liliya, additional, Sanita, Patrizia, additional, Ventura, Luca, additional, Daly, Adrian F., additional, Esposito, Vincenzo, additional, Angelucci, Adriano, additional, Arcella, Antonietta, additional, Giangaspero, Felice, additional, Beckers, Albert, additional, and Jaffrain-Rea, Marie-Lise, additional

Published
2016
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42. 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

43. 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

44. GHRH excess and blockade in X-LAG syndrome

Author

Daly, Adrian F, primary, Lysy, Philippe A, additional, Desfilles, Céline, additional, Rostomyan, Liliya, additional, Mohamed, Amira, additional, Caberg, Jean-Hubert, additional, Raverot, Veronique, additional, Castermans, Emilie, additional, Marbaix, Etienne, additional, Maiter, Dominique, additional, Brunelle, Chloe, additional, Trivellin, Giampaolo, additional, Stratakis, Constantine A, additional, Bours, Vincent, additional, Raftopoulos, Christian, additional, Beauloye, Veronique, additional, Barlier, Anne, additional, and Beckers, Albert, additional

Published
2015
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45. 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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46. 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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47. The clinical characteristics of X-linked acro-gigantism syndrome

Author

Daly, Adrian, primary, Trivellin, Giampaolo, additional, Rostomyan, Liliya, additional, Yuan, Bo, additional, Choong, Catherine, additional, Young, Jacques, additional, Mantovani, Giovanna, additional, Naves, Luciana, additional, Lysy, Philippe, additional, Cheetham, Tim, additional, Shah, Nalini, additional, Metzger, Daniel, additional, Zatelli, Maria Chiara, additional, Strebkova, Natalia, additional, Mazerkina, Nadia, additional, Collins, Michael, additional, Lodish, Maya Beth, additional, Lupski, James, additional, Stratakis, Constantine, additional, and Beckers, Albert, additional

Published
2015
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48. The genetic causes of pituitary gigantism

Author

Rostomyan, Liliya, primary, Daly, Adrian, additional, Petrossians, Patrick, additional, Trivellin, Giampaolo, additional, Shah, Nalini, additional, Mantovani, Giovanna, additional, Neggers, Sebastian, additional, Castermans, Emilie, additional, Caberg, Jean-Hubert, additional, Chanson, Philippe, additional, Zacharieva, Sabina, additional, Naves, Luciana, additional, and Beckers, Albert, additional

Published
2015
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50. X-linked acro-gigantism (X-LAG): a new form of infant-onset pituitary gigantism

Author

Trivellin, Giampaolo, primary, Daly, Adrian F., additional, Faucz, Fabio R., additional, Yuan, Bo, additional, Rostomyan, Liliya, additional, Larco, Darwin O., additional, Bjelobaba, Ivana, additional, Leal, Leticia F., additional, Schernthaner-Reiter, Marie Helene, additional, Dimopoulos, Aggeliki, additional, Chittiboina, Prashant, additional, Choong, Catherine S., additional, Kamenicky, Peter, additional, Wu, T. John, additional, Costanzi, Stefano, additional, Feldman, Benjamin, additional, Stojilkovic, Stanko S., additional, Lupski, James R., additional, Beckers, Albert, additional, and Stratakis, Constantine A., additional

Published
2015
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