Publications of Albert BECKERS
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See detailGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

in Nature Communications (2020), 11(1), 4752

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over ... [more ▼]

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function. [less ▲]

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See detailmiR-34a is upregulated in AIP-mutated somatotropinomas and promotes octreotide resistance.
Bogner, Eva-Maria; Daly, Adrian ULiege; Gulde, Sebastian et al

in International journal of cancer (2020)

Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs ... [more ▼]

Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation in AIPmut + vs AIPmut- PA samples by array analysis. miR-34a and miR-145 were highly expressed in AIPmut + vs AIPmut- somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip(-/-) mouse embryonic fibroblasts upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and anti-proliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut + vs AIPmut- PA. Taken together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut + acromegaly. This article is protected by copyright. All rights reserved. [less ▲]

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See detailPituitary Disease in AIP Mutation-Positive Familial Isolated Pituitary Adenoma (FIPA): A Kindred-Based Overview
Bilbao Garay, Ismene; Daly, Adrian ULiege; Egaña Zunzunegi, Nerea et al

in Journal of Clinical Medicine (2020), 9(6), 2003

rClinically-relevant pituitary adenomas occur in about 1:1000 of the general population, but only about 5% occur in a known genetic or familial setting. Familial isolated pituitary adenomas (FIPA) are one ... [more ▼]

rClinically-relevant pituitary adenomas occur in about 1:1000 of the general population, but only about 5% occur in a known genetic or familial setting. Familial isolated pituitary adenomas (FIPA) are one of the most important inherited settings for pituitary adenomas and the most frequent genetic cause is a germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene. AIP mutations lead to young-onset macroadenomas that are difficult to treat. Most are growth hormone secreting tumors, but all other secretory types can exist and the clinical profile of affected patients is variable. We present an overview of the current understanding of AIP mutation-related pituitary disease and illustrate various key clinical factors using examples from one of the largest AIP mutation-positive FIPA families identified to date, in which six mutation-affected members with pituitary disease have been diagnosed. We highlight various clinically significant features of FIPA and AIP mutations, including issues related to patients with acromegaly, prolactinoma, apoplexy and non-functioning pituitary adenomas. The challenges faced by these AIP mutation-positive patients due to their disease and the long-term outcomes in older patients are discussed. Similarly, the pitfalls encountered due to incomplete penetrance of pituitary adenomas in AIP-mutated kindreds are discussed. [less ▲]

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See detailPancreatic neuroendocrine neoplasm associated with a familial MAX deletion
PETIGNOT, Sandrine ULiege; Daly, Adrian ULiege; CASTERMANS, Emilie ULiege et al

in Hormone and Metabolic Research (2020)

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See detailClinical and Molecular Update on Genetic Causes of Pituitary Adenomas.
Vasilev, Vladimir; Daly, Adrian ULiege; Zacharieva, Sabina et al

in Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme (2020)

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See detailThe roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA).
Vasilev, Vladimir ULiege; Daly, Adrian ULiege; Trivellin, Giampaolo et al

in Endocrine-Related Cancer (2020)

Familial isolated pituitary adenomas (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory ... [more ▼]

Familial isolated pituitary adenomas (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy. [less ▲]

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See detailThe Epidemiology of Pituitary Adenomas.
Daly, Adrian ULiege; Beckers, Albert ULiege

in Endocrinology and metabolism clinics of North America (2020), 49(3), 347-355

Pituitary adenomas are usually nonmalignant, but have a heavy burden on patients and health care systems. Increased availability of MRI has led to an increase in incidentally found pituitary lesions and ... [more ▼]

Pituitary adenomas are usually nonmalignant, but have a heavy burden on patients and health care systems. Increased availability of MRI has led to an increase in incidentally found pituitary lesions and clinically relevant pituitary adenomas. Epidemiologic studies show that pituitary adenomas are increasing in incidence (between 3.9 and 7.4 cases per 100,000 per year) and prevalence (76 to 116 cases per 100,000 population) in the general population (approximately 1 case per 1000 of the general population). Most new cases diagnosed are prolactinomas and nonsecreting pituitary adenomas. Most clinically relevant pituitary adenomas occur in females, but pituitary adenomas are clinically heterogeneous. [less ▲]

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See detailNeuroimaging of aggressive pituitary tumors
BONNEVILLE, Jean-François ULiege; NECHIFOR - POTORAC, Iulia ULiege; Beckers, Albert ULiege

in Reviews in Endocrine and Metabolic Disorders (2020)

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See detailEstudios clinicos y geneticos en tres miembros de una familia afectados con adenomas hipofisarios aislados con prolactinomas homogeneos.
Vacchiano, Vanina; Seleme, Silvia; Daly, Adrian ULiege et al

in Medicina (2020), 80(2), 181-184

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated ... [more ▼]

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology. [less ▲]

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See detailHEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis.
Trivellin, Giampaolo; Faucz, Fabio R.; Daly, Adrian ULiege et al

in Endocrine-Related Cancer (2020), 27(8), 87-97

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated ... [more ▼]

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands. [less ▲]

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See detailImagerie par résonance magnétique de la région hypothalamohypophysaire
BONNEVILLE, Jean-François ULiege; NECHIFOR - POTORAC, Iulia ULiege; BONNEVILLE, F et al

in EMC - Endocrinologie (2020)

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See detailMultivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.
Coopmans, Eva C.; Korevaar, Tim I. M.; van Meyel, Sebastiaan W. F. et al

in The Journal of clinical endocrinology and metabolism (2020), 105(9),

CONTEXT: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients ... [more ▼]

CONTEXT: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. OBJECTIVE: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. DESIGN: Retrospective multicenter study. SETTING: Eight participating European centers. METHODS: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. RESULTS: Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β  = 0.002, SE = 0.001, P = .014, respectively). CONCLUSION: Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse. [less ▲]

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See detailMutlidisciplinary management of acromegaly : a consensus
Giustina, A; Barkhoudarian, G; Beckers, Albert ULiege et al

in Reviews in Endocrine and Metabolic Disorders (2020)

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See detailSomatostatin Analogue Resistance in McCune-Albright Syndrome
Vandevoorde, Stéphanie ULiege; Daly, Adrian ULiege; Hanson, Julien ULiege et al

Poster (2019, December)

McCune-Albright Syndrome (MAS) is a disorder characterized by involvement of multiple tissues, including skin, bone and endocrine glands. MAS is caused by post-zygotic mosaicism for GNAS gene mutations ... [more ▼]

McCune-Albright Syndrome (MAS) is a disorder characterized by involvement of multiple tissues, including skin, bone and endocrine glands. MAS is caused by post-zygotic mosaicism for GNAS gene mutations, which lead to a constitutively active form of the Gαs protein and increased cAMP levels. In the somatotropes of the pituitary, this increased cAMP leads to excessive growth hormone (GH) secretion. Somatostatin analogues (SSA), such as octreotide, that binds to somatostatin receptor SSTR2 are used in MAS patients to reduce GH secretion. However, MAS patients generally do not respond well to SSA, and GH control can rarely be achieved with SSA alone. In an in vitro model of MAS, five of the most common activating GNAS mutations lead to an increased level of cAMP, and a resistance to the treatment with SSA due to hyperactivated phosphokinase A. To further determine the underlying molecular causes of the SSA resistance, we studied the phosphorylation status of Filamin A (FLNA), a protein that couples somatostatin receptors to their cytoplasmic partners and to the cytoskeleton. Preliminary results suggest that three mutations of the GNAS gene may increase the phosphorylation status of FLNA. [less ▲]

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See detailA series of 9 pregnancies with hyperthyroidism and Graves disease : fetal and maternal follow up
DELANNOY, Pauline ULiege; GRANDFILS, Sébastien ULiege; LEBRETHON, Marie-Christine ULiege et al

in Abstract book : Annual congress of the Belgian Society of Internal Medicine (2019, December)

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See detailWhat is new from the Liege register of acromegaly ?
Beckers, Albert ULiege

Scientific conference (2019, November 16)

Detailed reference viewed: 32 (3 ULiège)
See detailWhy do they grow so tall ?
Beckers, Albert ULiege

Scientific conference (2019, November 15)

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See detailWhy do they grow so tall ? Genetics of pituitary gigantism and clinical implications
Beckers, Albert ULiege

Scientific conference (2019, November 08)

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