Update on the treatment of pituitary adenomas: familial and genetic considerations.

peer reviewedClinically-relevant pituitary adenomas occur with a prevalence of approximately 1 per 1000 population in Belgium. Pituitary adenomas that occur in families are likely to have an important genetic pathophysiological basis. Currently about 5% of all pituitary adenoma cases have a family history of pituitary adenomas, classically due to multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Over the last decade we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes, a condition named 'familial isolated pituitary adenoma' (FIPA). Clinical features of FIPA differ from those of sporadic pituitary adenomas in that patients with FIPA are often younger and have larger tumours at diagnosis. Approximately 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. In this review we examine new findings on the epidemiology of pituitary adenomas and we review familial causes of pituitary adenomas with a particular emphasis on modern clinical testing. In addition, the clinical and genetic features of FIPA are described as FIPA represents a useful framework to study the features of pituitary adenomas that occur in a familial setting

Predictors and rates of treatment-resistant tumor growth in acromegaly

Background: Multimodal therapy for acromegaly affords adequate disease control for many patients; however, there remains a subset of individuals that exhibit treatment-resistant disease. The issue of treatment-resistant pituitary tumor growth remains relatively under-explored. Methods: We assessed the literature for relevant data regarding the surgical, medical and radio-therapeutic treatment of acromegaly in order to identify the factors that were predictive of aggressive or treatment-resistant pituitary tumor behavior in acromegaly and undertook an assessment of the rates of failure to control tumor progression with available treatment modalities. Results: Young age at diagnosis, large tumor size, high growth hormone secretion and certain histological markers are predictors of future aggressive tumor behavior in acromegaly. Significant tumor regrowth occurs in less than 10% of cases thought to be cured surgically, whereas failure to control tumor growth is seen in less than 1% of patients receiving radiotherapy. Somatostatin analogs induce a variable degree of tumor shrinkage in acromegaly but up to 2.2% of somatostatin analog-treated tumors continue to grow. Relative to other therapies, limited data are available for pegvisomant, but these indicate that persistent tumor growth occurs in 1.6-2.9% of cases followed up regularly with serial magnetic resonance imaging scans. Conclusions: Treatment-resistant tumor progression occurs in a small minority of patients with acromegaly, regardless of treatment modality. Young patients with large tumors or those with high pre-treatment levels of growth hormone particularly warrant close monitoring for continued tumor progression during treatment for acromegaly

Management of acromegaly

Acromegaly is caused by hypersecretion of growth hormone and resultant overproduction of insulin-like growth factor-1 and is associated with increased mortality and morbidity. Successful treatment modalities have been developed and are used in a multistep approach allowing normal life expectancy as well as improved quality of life in an increasing number of patients

Medical management of pituitary gigantism and acromegaly

peer reviewedAcromegaly and pituitary gigantism are two related clinical manifestations of chronic growth hormone (GH) and insulin-like growth factor 1 (IGF-1) hypersecretion, usually from a pituitary adenoma. Management of acromegaly is guided by consensus reports based on accumulated clinical trials, in which medical therapies including somatostatin analogs, the GH receptor antagonist pegvisomant, and dopamine agonists play a key role alongside neurosurgery. Pituitary gigantism represents a severe subtype of acromegaly, as it affects children/adolescents whose growth plates have not fused. Apart from the risk of increased final adult height, patients with pituitary gigantism also have relatively aggressive and treatment resistant disease. This phenotype is driven by the presence of genetic mutations in nearly 50% of pituitary gigantism cases, including AIP mutations, X-linked acrogigantism syndrome, and McCune-Albright syndrome. This chapter assesses the consensus medical therapy of acromegaly and highlights specific aims and challenges for the effective management of patients with pituitary gigantism. © 2021 Elsevier Inc. All rights reserved

Clinical and genetic aspects of familial isolated pituitary adenomas

Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2–3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up

The pre-atmospheric hydrogen inventory of CM carbonaceous chondrites

Understanding the quantity and isotopic composition of water that has been delivered to Earth over its history is crucial for models our planet’s evolution, and predicting habitability across the solar system. Here we have used stepwise pyrolysis to measure the hydrogen inventory of CM carbonaceous chondrites, which are likely to have been a major source of volatiles for the early Earth. Stepwise pyrolysis potentially enables the carriers of pre-terrestrial hydrogen to be identified, and distinguished from hydrogen that may have been added during the meteorite’s time on Earth. Twelve CM meteorites were analysed, and from their bulk hydrogen composition, petrologic type and nature of parent body processing, they can be divided into three subsets. The CMs of subset A have been mildly aqueously altered. Their hydrogen is hosted by isotopically light phyllosilicate, isotopically heavy organic matter, and adsorbed terrestrial water that is comparable to or slightly heavier than phyllosilicate. The subset B meteorites have been heavily aqueously altered and their hydrogen is also in phyllosilicate, organic matter and adsorbed terrestrial water. Their pyrolysis profiles differ from subset A in that the phyllosilicates dehydroxylate at higher temperatures owing to differences in mineralogy and chemical composition. The hydrogen that was evolved from organic matter may also have been isotopically lighter owing to loss of deuterium during aqueous alteration. Subset C meteorites were heated on their parent body after aqueous alteration, leading to loss of hydrogen from phyllosilicates and organic matter such that half of the water that they evolve was added after falling to Earth. Taking the 12 CMs together, an average of 0.20 wt. % H (21 % of total H) is terrestrial, and recalculation of bulk compositions without this component can raise bulk δD of individual meteorites by up to 73 ‰. Carbonaceous chondrites in our collections differ in the abundance and isotopic composition of hydrogen relative to their parent asteroid(s). An accurate understanding of the nature of water that was delivered to early Earth can only come from the analysis of materials that have been isolated from the terrestrial atmosphere, such as those returned from Ryugu and Bennu

Bases moléculaires du gigantisme hypophysaire

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Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene.

peer reviewedOBJECTIVE: 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

miR-34a is upregulated inAIP-mutated somatotropinomas and promotes octreotide resistance

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 germlineAIPmutations (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 inAIPmut+ vsAIPmut- PA samples by array analysis. miR-34a and miR-145 were highly expressed inAIPmut+ vsAIPmut- somatotropinomas. Ectopic expression ofAIPmut (p.R271W) inAip(-/-)mouse embryonic fibroblasts (MEFs) upregulated miR-34a and miR-145, establishing a causal link betweenAIPmut 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 antiproliferative effects. miR-34a directly targetsGnai2encoding G alpha i2, a G protein subunit inhibiting cAMP production. Accordingly, G alpha i2 levels were significantly lower inAIPmut+ vsAIPmut- PA. Taken together, somatotropinomas withAIPmutations overexpress miR-34a, which in turn downregulates G alpha i2 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 mutantAIPthat promotes a cellular phenotype mirroring the aggressive clinical features ofAIPmut+ acromegaly.Peer reviewe