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 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 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 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 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 detailCompound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development.
NECHIFOR - POTORAC, Iulia ULiege; Trehan, Ashutosh; Szymanska, Kamila et al

in European journal of endocrinology (2019)

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand ... [more ▼]

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically-female patient with pubertal delay, had a 46,XY karyotype and was diagnosed with 46X,Y disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower molecular weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46X,Y DSD illustrates how three different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations. [less ▲]

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See detailExcellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma.
Coopmans, Eva C.; van Meyel, Sebastiaan W. F.; Pieterman, Kay J. et al

in European journal of endocrinology (2019)

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very ... [more ▼]

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy , a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis, or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis, or both in prolactinomas. [less ▲]

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See detailAIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center.
Daly, Adrian ULiege; Cano, David A.; Venegas, Eva et al

in Endocrine Connections (2019)

BACKGROUND: Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset ... [more ▼]

BACKGROUND: Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy. AIMS: We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary-referral center. METHODS: Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring </=30 years of age, familial isolated pituitary adenoma (FIPA) kindreds, and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response. RESULTS: Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (p=0.002) and were more frequently sparsely-granulated (p=0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen. CONCLUSIONS: Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of published risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely-granulated subtype but no relationship with SSA-responsiveness was seen. The genetics of aggressive, treatment-resistant and familial pituitary adenomas remain largely unexplained and screening criteria could be significantly refined. [less ▲]

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See detailEpidemiology and Management Challenges in Prolactinomas.
VROONEN, Laurent ULiege; Daly, Adrian ULiege; Beckers, Albert ULiege

in Neuroendocrinology (2019)

Clinically relevant pituitary adenomas are present in about 1 per 1000 of the general population and prolactinomas are by far the most common clinical subtype of pituitary adenomas. Usually prolactinomas ... [more ▼]

Clinically relevant pituitary adenomas are present in about 1 per 1000 of the general population and prolactinomas are by far the most common clinical subtype of pituitary adenomas. Usually prolactinomas affect pre-menopausal women and present with typical symptoms of menstrual disturbance and/or galactorrhea. They are generally managed with dopamine agonists to restore fertility and to control symptoms and tumour size. In a subset of prolactinomas, however, management remains challenging. Studies in recent years have identified the factors related to dopamine agonist resistance, such as, male sex, genetic features, and aggressive tumor behaviour. Certain other patient groups represent particular challenges for management, such as pediatric patients and pregnant women. Treatment with dopamine agonists is usually safe and effective, and adverse effects such as clinically relevant cardiac valvular complications and impulse control disorders may occur in isolated instances. A number of important disease characteristics of prolactinomas remain to be explained, such as the difference in sex prevalence before and after menopause, the higher prevalence of macroadenomas in older males and the biochemical mechanisms of resistance to dopaminergic agonists. [less ▲]

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See detailGenetic Testing in Pituitary Adenomas: What, How, and In Whom?
Daly, Adrian ULiege; Beckers, Albert ULiege

in Endocrinología, Diabetes y Nutrición (2019), 66(2), 71-73

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See detailShrinkage of pituitary adenomas with pasireotide
Daly, Adrian ULiege; NECHIFOR - POTORAC, Iulia ULiege; PETROSSIANS, Patrick ULiege et al

in The lancet. Diabetes & endocrinology (2019), 7(7), 509

Detailed reference viewed: 93 (20 ULiège)