Ericka B Trarbach1,2, Giampaolo Trivellin3,4, Isabella P P Grande1, Felipe H G Duarte2, Alexander A L Jorge1, Felipe Barjud Pereira do Nascimento5,6, Heraldo M Garmes7, Marcia Nery8, Berenice B Mendonca9, Constantine A Stratakis3, Marcello D Bronstein2, Raquel S Jallad10,11. 1. Laboratorio de Endocrinologia Celular E Molecular/LIM25, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. 2. Unidade de Neuroendocrinologia, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Eneas de Carvalho Aguiar, 155, PAMB, 8 andar, São Paulo, SP, CEP 05403-010, Brazil. 3. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA. 4. Endocrinology Unit and Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy. 5. Faculdade de Medicina, Instituto de Radiologia, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. 6. Departamento de Radiologia E Diagnóstico Por Imagem, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil. 7. Divisao de Endocrinologia, Departamento de Clinica Medica, Faculdade de Ciencias Medicas da Universidade Estadual de Campinas (FCM-Unicamp), Campinas, SP, Brazil. 8. Unidade de Diabetes, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. 9. Unidade de Endocrinologia Do Desenvolvimento, Laboratorio de Hormonios E Genetica Molecular/LIM42, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. 10. Laboratorio de Endocrinologia Celular E Molecular/LIM25, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. raquel.jallad@hc.fm.usp.br. 11. Unidade de Neuroendocrinologia, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Eneas de Carvalho Aguiar, 155, PAMB, 8 andar, São Paulo, SP, CEP 05403-010, Brazil. raquel.jallad@hc.fm.usp.br.
Abstract
PURPOSE: Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil. METHODS: Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH). RESULTS: Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9 years old and diagnosis at 5 and 15 years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background. CONCLUSION: We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.
PURPOSE:Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil. METHODS: Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH). RESULTS: Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9 years old and diagnosis at 5 and 15 years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background. CONCLUSION: We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.
Authors: Liliya Rostomyan; Adrian F Daly; Patrick Petrossians; Emil Nachev; Anurag R Lila; Anne-Lise Lecoq; Beatriz Lecumberri; Giampaolo Trivellin; Roberto Salvatori; Andreas G Moraitis; Ian Holdaway; Dianne J Kranenburg-van Klaveren; Maria Chiara Zatelli; Nuria Palacios; Cecile Nozieres; Margaret Zacharin; Tapani Ebeling; Marja Ojaniemi; Liudmila Rozhinskaya; Elisa Verrua; Marie-Lise Jaffrain-Rea; Silvia Filipponi; Daria Gusakova; Vyacheslav Pronin; Jerome Bertherat; Zhanna Belaya; Irena Ilovayskaya; Mona Sahnoun-Fathallah; Caroline Sievers; Gunter K Stalla; Emilie Castermans; Jean-Hubert Caberg; Ekaterina Sorkina; Renata Simona Auriemma; Sachin Mittal; Maria Kareva; Philippe A Lysy; Philippe Emy; Ernesto De Menis; Catherine S Choong; Giovanna Mantovani; Vincent Bours; Wouter De Herder; Thierry Brue; Anne Barlier; Sebastian J C M M Neggers; Sabina Zacharieva; Philippe Chanson; Nalini Samir Shah; Constantine A Stratakis; Luciana A Naves; Albert Beckers Journal: Endocr Relat Cancer Date: 2015-07-17 Impact factor: 5.678
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Authors: Paraskevi Xekouki; Eva Szarek; Petra Bullova; Alessio Giubellino; Martha Quezado; Spyridon A Mastroyannis; Panagiotis Mastorakos; Christopher A Wassif; Margarita Raygada; Nadia Rentia; Louis Dye; Antony Cougnoux; Deloris Koziol; Maria de La Luz Sierra; Charalampos Lyssikatos; Elena Belyavskaya; Carl Malchoff; Jessica Moline; Charis Eng; Louis James Maher; Karel Pacak; Maya Lodish; Constantine A Stratakis Journal: J Clin Endocrinol Metab Date: 2015-02-19 Impact factor: 5.958
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