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Albert Beckers and Adrian F Daly

Pituitary adenomas occur in a familial setting in multiple endocrine neoplasia type 1 (MEN1) and Carney’s complex (CNC), which occur due to mutations in the genes MEN1 and PRKAR1A respectively. Isolated familial somatotropinoma (IFS) is also a well-described clinical syndrome related only to patients with acrogigantism. Pituitary adenomas of all types – not limited to IFS – can occur in a familial setting in the absence of MEN1 and CNC; this phenotype is termed familial isolated pituitary adenomas (FIPA). Over the past 7 years, we have described over 90 FIPA kindreds. In FIPA, both homogeneous and heterogeneous pituitary adenoma phenotypes can occur within families; virtually all FIPA kindreds contain at least one prolactinoma or somatotropinoma. FIPA differs from MEN1 in terms of a lower proportion of prolactinomas and more frequent somatotropinomas in the FIPA cohort. Patients with FIPA are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. A minority of FIPA families overall (15%) exhibit mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene; AIP mutations are present in only half of IFS kindreds occurring as part of the FIPA cohort. In families with AIP mutations, pituitary adenomas have a penetrance of over 50%. AIP mutations are extremely rare in patients with sporadic pituitary adenomas. This review deals with pituitary adenomas that occur in a familial setting, describes in detail the clinical, pathological, and genetic features of FIPA, and addresses aspects of the clinical approach to FIPA families with and without AIP mutations.

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Roger Abs, Achilles Stevenaert and Albert Beckers

Abs R, Stevenaert A, Beckers A. Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause–effect relationship. Eur J Endocrinol 1994;131:355–8. ISSN 0804–4643

A 51-year-old female patient with long-standing hyperthyroidism due to a thyrotropin-secreting pituitary adenoma is reported, who became thyrotoxic again shortly after successful pituitary surgery. Functional testing and scintigraphy suggested the diagnosis of autonomous functioning thyroid nodules, which was confirmed by pathological examination of the resected thyroid tissue. This is the first report revealing the transition from a pituitary-dependent to a thyroid-dependent hyperthyroidism. Autonomous functioning thyroid nodules are, however, considered an intrinsic thyroid defect. In similarity with other disorders, in which trophic hormones may induce an autonomous secretion by the target gland, this report opens the possibility that a humoral factor may play a role in the development of autonomous functioning thyroid nodules.

A Beckers, CHU-B35, Department of Endocrinology, Sart-Tilman, B-4000 Liège, Belgium

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Roger Abs, Frank Nobels, Johan Verhelst, Philippe Chanson, Charles Mahler, Bob Corthouts, Pierre Blockx and Albert Beckers

We aimed to investigate the dynamics of adrenocorticotropin (ACTH) and cortisol secretion in pituitary-dependent Cushing's syndrome with bilateral macronodular adrenal hyperplasia presenting as a single adrenal macronodule, and to determine the imaging characteristics of this syndrome. Three female patients were studied. Plasma ACTH and serum cortisol secretion were studied by determining their rhythmicity and pulsatility and their responses to the administration of ovine corticotropin-releasing factor, thyrotropin-releasing hormone, metyrapone, tetracosactrin, insulin and dexamethasone. Techniques used to localize the anatomical lesion were bilateral simultaneous inferior petrosal sinus sampling, magnetic resonance examination of the pituitary, computed tomography (CT) scanning and [75Se]cholesterol scintigraphy of the adrenal glands. Plasma ACTH and serum cortisol levels were measured using a commercial radioimmunoassay and an immunoradiometric assay. The ACTH and cortisol pulse number and amplitude were calculated using established computer software. In all three patients ACTH and cortisol secretory dynamics fulfilled the requirements for diagnosis of pituitary-dependent Cushing's syndrome. A close relationship between ACTH and cortisol pulses also favored a pituitary dependency. Study of the amplitude of cortisol pulses classified two patients in the group of hypopulsatile Cushing's disease. Adrenal CT scanning demonstrated the presence of a large single nodule. [75Se]Cholesterol scintigraphy showed bilateral radionuclide uptake, although mostly localized over the adrenal nodule. All patients underwent successful trans-sphenoidal hypophysectomy. Over a period of 1 year, a slow shrinkage of the adrenal nodule was observed in two patients, while no change in volume was observed in one patient. Demonstration of an adrenal macronodule on CT scanning in patients with Cushing's syndrome is in itself insufficient to allow the diagnosis of hypercorticism due to a unilateral adrenal adenoma. Additional dynamic endocrine testing, inferior petrosal sinus sampling and imaging techniques such as [75Se]cholesterol scintigraphy remain necessary to reach a correct diagnosis.

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Vladimir Vasilev, Liliya Rostomyan, Adrian F Daly, Iulia Potorac, Sabina Zacharieva, Jean-François Bonneville and Albert Beckers

Pituitary incidentalomas are a by-product of modern imaging technology. The term ‘incidentaloma’ is neither a distinct diagnosis nor a pathological entity. Rather, it is a collective designation for different entities that are discovered fortuitously, requiring a working diagnosis based on the input of the radiologist, endocrinologist and often a neurosurgeon. In addition to pathological conditions affecting the pituitary gland, a thorough knowledge of the radiological characteristics of normal variants and technical artifacts is required to arrive at an accurate differential diagnosis. After careful radiological and hormonal evaluation, the vast majority of pituitary incidentalomas turn out to be non-functioning pituitary microadenomas and Rathke’s cleft cysts (RCCs). Based on the low growth potential of non-functioning pituitary microadenomas and RCCs, periodic MRI surveillance is currently considered the optimal management strategy. Stricter follow-up is required for macroadenomas, as increases in size occur more frequently.

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Silvia Vandeva, Adrian F Daly, Patrick Petrossians, Sabina Zacharieva and Albert Beckers

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

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Adolfo Rivero-Müller, Iulia Potorac, Axelle Pintiaux, Adrian F Daly, Albert Thiry, Catherine Rydlewski, Michelle Nisolle, Anne-Simone Parent, Ilpo Huhtaniemi and Albert Beckers

Objective

The LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation.

Methods

Five affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed.

Results

The five affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain. In vitro studies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin.

Conclusions

This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.

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Patrizio Lancellotti, Elena Livadariu, Muriel Markov, Adrian F Daly, Maria-Cristina Burlacu, Daniela Betea, Luc Pierard and Albert Beckers

Aims

The cardiac valvular risk associated with lower exposure to cabergoline in common endocrine conditions such as hyperprolactinemia is unknown.

Methods and results

We performed a cross-sectional, case–control echocardiographic study to assess the valvular status in 102 subjects receiving cabergoline for endocrine disorders and 51 matched control subjects. Cabergoline treatment ranged from 12 to 228 months, with a cumulative dose of 18–1718 mg. Valvular regurgitation was equally prevalent in both groups and was almost exclusively mild. Two cabergoline-treated subjects had moderate mitral regurgitation; there was no relationship between cabergoline dose and the presence or severity of mitral valve regurgitation (P=NS). Mitral valve tenting area was significantly greater in the cabergoline group when compared with the control subjects (P=0.03). Mitral valve leaflet thickening was observed in 5.9% of cabergoline-treated subjects; no relationship with the cumulative cabergoline dose was found. No patient had aortic or tricuspid valvular restriction.

Conclusion

No significantly increased risk of clinically relevant cardiac valve disorders was found in subjects treated with long-term cabergoline therapy at the doses used in endocrine practice. While exposure to cabergoline appears to be safe during low-dose long-term therapy, an association with subclinical changes in mitral valve geometry cannot be completely excluded.

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Patrick Petrossians, Liliane Borges-Martins, Consuelo Espinoza, Adrian Daly, Daniela Betea, Hernan Valdes-Socin, Achille Stevenaert, Philippe Chanson and Albert Beckers

Introduction: Invasive GH-secreting pituitary adenomas are rarely cured by surgery and although long-term therapy with somatostatin analogs (SSAs) may be employed, hormonal control is achieved in only 60% of cases. The impact of tumor debulking on subsequent control of acromegaly with SSAs has not been studied previously.

Methods: We studied retrospectively the response to SSA therapy in acromegalic patients before and after incomplete surgical tumor excision. A case review identified 24 acromegalic patients who had received SSA therapy for ≥1 month before and after gross total resection or debulking of adenomas. No patient received radiotherapy or combination treatment with SSAs and dopamine agonists during the study. GH and IGF-I responses to SSAs were recorded pre- and postoperatively. Postoperative SSA therapy was begun after a washout period of 1–3 months to assess the hormonal effects of the surgery alone.

Results: Before preoperative SSA treatment, 24/24 (100%) patients had elevated GH levels and IGF-I levels were elevated in 19/21 (90.5%) patients with recorded values. During preoperative SSA treatment, GH and IGF-I levels were normalized in 7/24 (29.2%) and 11/24 (45.8%) patients respectively. Following postoperative washout, GH was controlled in only 3/24 (12.5%) patients, while IGF-I was controlled in 8/19 (42.1%) patients with available data. During the second SSA treatment period, normal GH levels were seen in 13/24 (54.2%) patients, while IGF-I control was noted in 18/23 (78.3%).

Conclusion: Gross total tumor resection or debulking increases the likelihood of achieving biochemical disease control with SSAs in acromegalic patients with adenomas that were not amenable to complete surgical resection and in whom primary SSA therapy was unable to achieve good biochemical control.

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Iulia Potorac, Ashutosh Trehan, Kamila Szymańska, Julie Fudvoye, Albert Thiry, Ilpo Huhtaniemi, Adrian F Daly, Albert Beckers, Anne-Simone Parent and Adolfo Rivero-Müller

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin 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 46,XY 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 46,XY DSD illustrates how 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.

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Juliet E Jennings, Marianthi Georgitsi, Ian Holdaway, Adrian F Daly, Maria Tichomirowa, Albert Beckers, Lauri A Aaltonen, Auli Karhu and Fergus J Cameron

Objective

Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA). We report a large Samoan FIPA kindred from Australia/New Zealand with an R271W mutation that was associated with aggressive pituitary tumors.

Design and methods

Case series with germline screening of AIP and haplotype analyses among R271W families.

Results

This previously unreported kindred consisted of three affected individuals that either presented with or had first symptoms of a pituitary macroadenoma in late childhood or adolescence. The index case, a 15-year-old male with incipient gigantism and his maternal aunt, had somatotropinomas, and the maternal uncle of the index case had a prolactinoma. All tumors were large (15, 40, and 60 mm maximum diameter) and two required transcranial surgery and radiotherapy. All three affected subjects and ten other unaffected relatives were found to be positive for a germline R271W AIP mutation. Comparison of the single nucleotide polymorphism patterns among this family and two previously reported European FIPA families with the same R271W mutation demonstrated no common ancestry.

Conclusions

This kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot that should be studied further in functional studies.