The CABLES1 cell cycle regulator participates in the adrenal–pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing’s disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.
Laura C Hernández-Ramírez, Ryhem Gam, Nuria Valdés, Maya B Lodish, Nathan Pankratz, Aurelio Balsalobre, Yves Gauthier, Fabio R Faucz, Giampaolo Trivellin, Prashant Chittiboina, John Lane, Denise M Kay, Aggeliki Dimopoulos, Stephan Gaillard, Mario Neou, Jérôme Bertherat, Guillaume Assié, Chiara Villa, James L Mills, Jacques Drouin and Constantine A Stratakis
Iulia Potorac, Patrick Petrossians, Adrian F Daly, Franck Schillo, Claude Ben Slama, Sonia Nagi, Mouna Sahnoun, Thierry Brue, Nadine Girard, Philippe Chanson, Ghaidaa Nasser, Philippe Caron, Fabrice Bonneville, Gérald Raverot, Véronique Lapras, François Cotton, Brigitte Delemer, Brigitte Higel, Anne Boulin, Stéphan Gaillard, Florina Luca, Bernard Goichot, Jean-Louis Dietemann, Albert Beckers and Jean-François Bonneville
Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (P<0.0001), were associated with higher IGF1 levels (P=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (P<0.0001). Acromegalic men tended to be younger at diagnosis than women (P=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (P<0.0001), whereas in women optic chiasm compression of macroadenomas occurred more often (P=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.
Albert Beckers, Maya Beth Lodish, Giampaolo Trivellin, Liliya Rostomyan, Misu Lee, Fabio R Faucz, Bo Yuan, Catherine S Choong, Jean-Hubert Caberg, Elisa Verrua, Luciana Ansaneli Naves, Tim D Cheetham, Jacques Young, Philippe A Lysy, Patrick Petrossians, Andrew Cotterill, Nalini Samir Shah, Daniel Metzger, Emilie Castermans, Maria Rosaria Ambrosio, Chiara Villa, Natalia Strebkova, Nadia Mazerkina, Stéphan Gaillard, Gustavo Barcelos Barra, Luis Augusto Casulari, Sebastian J Neggers, Roberto Salvatori, Marie-Lise Jaffrain-Rea, Margaret Zacharin, Beatriz Lecumberri Santamaria, Sabina Zacharieva, Ee Mun Lim, Giovanna Mantovani, Maria Chaira Zatelli, Michael T Collins, Jean-François Bonneville, Martha Quezado, Prashant Chittiboina, Edward H Oldfield, Vincent Bours, Pengfei Liu, Wouter W de Herder, Natalia Pellegata, James R Lupski, Adrian F Daly and Constantine A Stratakis
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.