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Giampaolo Trivellin, Ricardo R Correa, Maria Batsis, Fabio R Faucz, Prashant Chittiboina, Ivana Bjelobaba, Darwin O Larco, Martha Quezado, Adrian F Daly, Stanko S Stojilkovic, T John Wu, Albert Beckers, Maya B Lodish and Constantine A Stratakis

Cushing’s disease (CD) in children is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Germline or somatic mutations in genes such as MEN1, CDKIs, AIP, and USP8 have been identified in pediatric CD, but the genetic defects in a significant percentage of cases are still unknown. In this study, we investigated the orphan G-protein-coupled receptor GPR101, a gene known to be involved in somatotropinomas, for its possible involvement in corticotropinomas. We performed GPR101 sequencing, expression analyses by RT-qPCR and immunostaining, and functional studies (cell proliferation, pituitary hormone secretion, and cAMP measurement) in a series of patients with sporadic CD secondary to ACTH-secreting adenomas in whom we extracted DNA from peripheral blood and pituitary tumor samples (n=36). No increased GPR101 expression was observed in tumors compared with normal pituitary (NP) tissues, nor did we find a correlation between GPR101 and ACTH expression levels. Sequence analysis revealed a very rare germline heterozygous GPR101 variant (p.G31S) in one patient with CD. Overexpression of the p.G31S variant did not lead to increased growth and proliferation, although modest effects on cAMP signaling were observed. GPR101 is not overexpressed in ACTH-secreting tumors compared with NPs. In conclusion, rare germline GPR101 variant was found in one patient with CD, but in vitro studies did not support a consistent pathogenic effect. GPR101 is unlikely to be involved in the pathogenesis of CD.

Free access

Fabio R Faucz, Anelia D Horvath, Monalisa F Azevedo, Isaac Levy, Beata Bak, Ying Wang, Paraskevi Xekouki, Eva Szarek, Evgenia Gourgari, Allison D Manning, Rodrigo Bertollo de Alexandre, Emmanouil Saloustros, Giampaolo Trivellin, Maya Lodish, Paul Hofman, Yvonne C Anderson, Ian Holdaway, Edward Oldfield, Prashant Chittiboina, Maria Nesterova, Nienke R Biermasz, Jan M Wit, Daniel J Bernard and Constantine A Stratakis

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

Open access

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

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.

Free access

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.