scholarly journals The Genetics of Pituitary Adenomas

2019 ◽  
Vol 9 (1) ◽  
pp. 30 ◽  
Author(s):  
Christina Tatsi ◽  
Constantine A. Stratakis
Keyword(s):  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia Type ◽  
Carney Complex ◽  
Copy Number Variations ◽  
Genetic Defects ◽  
Genomic Changes ◽  
Genetic Landscape ◽  
Tumor Level ◽  
Relevant Family History

The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called “3 P association” of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.

scholarly journals The clinical, pathological, and genetic features of familial isolated pituitary adenomas

2007 ◽  
Vol 157 (4) ◽  
pp. 371-382 ◽  
Author(s):  
Albert Beckers ◽  
Adrian F Daly
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia Type ◽  
Clinical Syndrome ◽  
Clinical Approach ◽  
Interacting Protein ◽  
The Past ◽  
Aryl Hydrocarbon ◽  
Genetic Features

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.

scholarly journals Differences in Menin Expression in Pituitary Adenomas in Multiple Endocrine Neoplasia Type 1, Its Phenocopies and Sporadic Acromegaly

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A535-A536
Author(s):  
Diana A Dimitrova ◽  
Elizaveta O Mamedova ◽  
Anastasia M Lapshina ◽  
Vilen N Azizyan ◽  
Andrey Y Grigoriev ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Cytoplasmic Expression ◽  
Men 1 ◽  
Endocrine Neoplasia ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Introduction: Multiple endocrine neoplasia type 1 syndrome (MEN 1) is caused by mutations in MEN1 gene, encoding menin protein. A combination of pituitary adenomas (PA) and primary hyperparathyroidism (PHPT) in patients without MEN1 mutations is defined as MEN 1 phenocopy. The aim of the study is to find if there are any differences in menin expression in PA of patients with genetically confirmed MEN 1, MEN 1 phenocopies and sporadic acromegaly. Materials and Methods: Formalin-fixed paraffin-embedded PA tissues were obtained from 9 genetically confirmed MEN 1 patients (group 1), 12 patients with MEN 1 phenocopies (a combination of PA and PHPT) (group 2) and 14 patients with sporadic acromegaly (group 3). The integrity of the tissues was tested by immunohistochemistry (IHC) using antibodies against the nuclear protein Pit-1. MEN1 mutations were confirmed or excluded by Sanger sequencing or by NGS (NextSeq550, Illumina, USA). Expression of menin was assessed using IHC (Anti-Menin antibody — ChIP Grade, Abcam, UK). Results: The distribution of PA by the type of secretion in group 1 was: 3 — ACTH-secreting, 2 — PRL-secreting, 2 — GH+PRL, 1 — TSH+PRL, 1 — ACTH+PRL, 1 — silent gonadotroph adenoma. All 12 PA from group 2 were GH-secreting. All 14 PA in group 3 were GH-secreting without mixed secretion. The median age at the moment of transsphenoidal surgery in group 1 was 35 years [27; 47], in group 2 — 59 years [56; 65], in group 3 — 56 years [53; 62]. There were 2 men and 7 women in group 1; 2 men and 10 women in group 2; 4 men and 10 women in group 3. In group 1 patients did not receive somatostation analogues (SSA), 7 patients received cabergoline. In group 2 seven patients received SSA, in group 3 — 4 patients received SSA, 2 patients received cabergoline. The results of menin staining were (negative staining/positive cytoplasmic staining/positive nuclear staining): group 1 — 4/4/0; group 2 — 0/11/1; group 3 — 1/7/6. Phenocopy group showed significantly more cytoplasmic expression of menin than in MEN 1 group (p<0.008). MEN 1 group also differed from sporadic acromegaly group by nuclear expression of menin (p<0.015). No statistical significance between sporadic and phenocopy groups was found (p=0.07). Although there were no differences among these groups, the group 2 showed weak nuclear expression only in one case, while in group 3 the menin staining was present both in the nucleus and cytoplasm in equal proportions. Conclusion: Menin expression is generally preserved in PA in MEN 1 phenocopies and sporadic acromegaly, though with different pattern of nuclear and cytoplasmic expression, while its expression varies in PA in MEN 1. These findings suggest that pathogenesis of PA in MEN 1 phenocopies and sporadic acromegaly may have similarities. The mechanisms of co-occurrence of PA and PHPT in MEN 1 phenocopies are poorly understood and epigenetic modifications downstream menin interacting pathways could play a role.

scholarly journals Genetic and Epigenetic Causes of Pituitary Adenomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Mengqi Chang ◽  
Chengxian Yang ◽  
Xinjie Bao ◽  
Renzhi Wang
Keyword(s):  
Pituitary Adenomas ◽  
Neurofibromatosis Type ◽  
Carney Complex ◽  
Hormone Production ◽  
Guanine Nucleotide Binding Protein ◽  
Interacting Protein ◽  
Von Hippel Lindau ◽  
Aryl Hydrocarbon ◽  
Guanine Nucleotide Binding

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

Cytogenetic studies in sporadic and multiple endocrine neoplasia type 1-associated pituitary adenomas

1993 ◽  
Vol 7 (1) ◽  
pp. 63-65 ◽  
Author(s):  
Laura Papi ◽  
Gabriella Baldassarri ◽  
Enrico Montali ◽  
Umberto Bigozzi ◽  
Franco Ammannati ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Cytogenetic Studies

scholarly journals Pituitary adenomas in the setting of multiple endocrine neoplasia type 1: a single-institution experience

2020 ◽  
pp. 1-7
Author(s):  
Salomon Cohen-Cohen ◽  
Desmond A. Brown ◽  
Benjamin T. Himes ◽  
Lydia P. Wheeler ◽  
Michael W. Ruff ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Treatment Strategies ◽  
Pituitary Tumors ◽  
Single Institution ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Nonfunctional Pituitary Adenomas

OBJECTIVEMultiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal-dominant tumor disorder characterized by the development of pituitary tumors and other endocrine neoplasms. Diagnosis is made clinically based on the development of 2 or more canonical lesions (parathyroid gland, anterior pituitary, and enteropancreatic tumors) or in family members of a patient with a clinical diagnosis of MEN1 and the occurrence of one of the MEN1-associated tumors. The goal of this study was to characterize pituitary tumors arising in the setting of MEN1 at a single institution. The probability of tumor progression and the likelihood of surgical intervention in patients with asymptomatic nonfunctional pituitary adenomas were also analyzed.METHODSA retrospective review of a prospectively maintained institutional database was performed for patients with MEN1 diagnosed from 1970 to 2017. Data included patient demographics, tumor characteristics, treatment strategies, and outcomes.RESULTSA review of the database identified 268 patients diagnosed with MEN1, of whom 158 (59%) were female. Among the 268 patients, 139 (51.8%) had pituitary adenomas. There was a higher prevalence in women than in men (65% vs 35%, p < 0.005). Functional adenomas (57%) were more common. Prolactin-secreting adenomas were the most common functional tumors. Macroadenomas were seen in 27% of patients and were more likely to be symptomatic and locally aggressive (p < 0.001). Forty-nine patients (35%) underwent transsphenoidal resection at some point during their disease course. In 52 patients who were initially observed with MEN1 asymptomatic nonfunctional adenomas, only 5 (10%) progressed to need surgery. In MEN1 patients, an initial parathyroid lesion is most likely followed in order by pituitary, pancreatic, adrenal, and, finally, rare carcinoid tumors.CONCLUSIONSAsymptomatic nonfunctional pituitary adenomas in patients with MEN1 may be followed safely with MRI. In this series, parathyroid tumors developed at the lowest median age of all cardinal tumors, and development of additional cardinal MEN1 lesions followed a predictable pattern. This pattern of disease progression could have significant implications for disease surveillance in clinical practice and may help to target clinical resources to the lesions most likely to develop next. This may aid with early detection and treatment and warrants further study.

scholarly journals Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features

2001 ◽  
pp. 227-235 ◽  
Author(s):  
E Ferretti ◽  
ML Jaffrain Rea ◽  
C Asteria ◽  
D Di Stefano ◽  
V Esposito ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Germ Line ◽  
Somatostatin Analogues ◽  
High Serum ◽  
Giant Pituitary Adenoma ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

OBJECTIVE: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. MATERIALS AND METHODS: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. RESULTS: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. CONCLUSION: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.

scholarly journals Somatic MEN1 gene mutation does not contribute significantly to sporadic pituitary tumorigenesis

1999 ◽  
pp. 573-576 ◽  
Author(s):  
J Poncin ◽  
A Stevenaert ◽  
A Beckers
Keyword(s):  
Pituitary Adenomas ◽  
Multiple Endocrine Neoplasia Type ◽  
Gene Mutations ◽  
Men1 Gene ◽  
Pituitary Tumorigenesis ◽  
Genetic Abnormalities ◽  
Parathyroid Tumours ◽  
Allelic Deletion ◽  
Common Manifestation

Pituitary adenomas are a common manifestation of multiple endocrine neoplasia type 1 (MEN1) but most of them occur sporadically. There are only a few well defined genetic abnormalities known to occur in these sporadic tumours. The MEN1 gene located on 11q13 has recently been cloned and allelic deletion and mutation analysis studies have implicated the MEN1 gene in a significant fraction of the sporadic counterparts of typical MEN1 neoplasms (parathyroid tumours, insulinomas and gastrinomas). To determine if MEN1 gene inactivation is also involved in the development of sporadic pituitary adenomas, allelic deletions of chromosome 11q13 and MEN1 gene mutations and polymorphisms were assessed in 35 sporadic tumours of the anterior pituitary (9 prolactin-secreting, 8 GH-secreting, 3 TSH-secreting, 2 TSH/GH-secreting, 4 Cushing, 9 silent). Thirty-one tumours were found to be heterozygous for at least one MEN1 intragenic polymorphism (25 cases) or for a flanking gene polymorphism (6 cases). The remaining tumours were not informative. No mutations were found in any tumour except in one prolactinoma which was homozygous or hemizygous for a mutation (1-117 C-->T) in a region close to the promoter. Unfortunately, blood or normal tissue was not available in this case. Our data show that somatic MEN1 mutations do not contribute significantly to tumorigenesis of sporadic pituitary adenomas and suggest that mutation of other genes are likely to contribute to the pathogenesis of these tumours.

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