scholarly journals Genetic and metabolic characteristics of familial isolated pituitary adenomas

2013 ◽  
Vol 10 (2) ◽  
pp. 3-10 ◽  
Author(s):  
N S Dalantaeva ◽  
I I Dedov
Keyword(s):  
Pituitary Adenomas ◽  
Pituitary Tumors ◽  
Suppressor Gene ◽  
Carney Complex ◽  
Incomplete Penetrance ◽  
Chromosome 11 ◽  
Gene Encoding ◽  
Metabolic Characteristics ◽  
Aryl Hydrocarbon ◽  
Aip Gene

Familial isolated pituitary adenoma (FIPA) – a relatively new term for the disease, which is characterized by an autosomal dominant inheritance with incomplete penetrance, resulting in the development of pituitary tumors with no distinguishing features other endocrine diseases or syndromes, such as, for example, the syndrome multiple endocrine neoplasia type 1 (MEN-1 syndrome) or the Carney complex. FIPA-families account for about 2% of all cases of pituitary adenomas. Among the FIPA-family about 15–20% have mutations in the gene encoding the protein aryl hydrocarbon receptor. This suppressor gene located on the long arm of chromosome 11. Etiological gene for the rest of the greater percentage of FIPA-family is still unknown. Germline mutations in the AIP gene have also been found in patients with early development of pituitary adenomas, mainly secreting growth hormone, much rarely – prolactin and adrenocorticotropic hormone without a clear family history. Such cases are called "simple". Somatic mutations of the AIP gene in pituitary tumors or other sites has not yet been described

scholarly journals Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

2013 ◽  
Vol 34 (2) ◽  
pp. 239-277 ◽  
Author(s):  
Albert Beckers ◽  
Lauri A. Aaltonen ◽  
Adrian F. Daly ◽  
Auli Karhu
Keyword(s):  
Pituitary Adenoma ◽  
Aryl Hydrocarbon Receptor ◽  
Pituitary Adenomas ◽  
Pituitary Tumors ◽  
Carney Complex ◽  
Cushing Disease ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Serious Disease ◽  
Aip Gene

Abstract Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.

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

2009 ◽  
Vol 161 (5) ◽  
pp. 799-804 ◽  
Author(s):  
Juliet E Jennings ◽  
Marianthi Georgitsi ◽  
Ian Holdaway ◽  
Adrian F Daly ◽  
Maria Tichomirowa ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Index Case ◽  
Young Patients ◽  
Case Series ◽  
Pituitary Tumors ◽  
Maximum Diameter ◽  
Interacting Protein ◽  
Functional Studies ◽  
Aryl Hydrocarbon ◽  
Aip Gene

ObjectiveMutations 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 methodsCase series with germline screening of AIP and haplotype analyses among R271W families.ResultsThis 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.ConclusionsThis 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.

scholarly journals Isolated Macroprolactinomas in Four Young Adult Males Harboring a Variant of the Aryl Hydrocarbon Interacting Protein (AIP) Gene: Isn’t It Too Much of a Coincidence?

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A591-A591
Author(s):  
Carolina Marques Chaves ◽  
Mariana M Chaves ◽  
Joao Anselmo
Keyword(s):  
Gene Mutation ◽  
Pituitary Adenomas ◽  
Young Patients ◽  
Visual Field Defects ◽  
Incomplete Penetrance ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Male Patients ◽  
Giant Prolactinomas ◽  
Aip Gene

Abstract Background: Germline mutations in the Aryl hydrocarbon receptor-Interacting Protein (AIP) gene are associated with pituitary adenomas in young patients usually in the setting of Familial Isolated Pituitary Adenomas (FIPA). The majority of these adenomas are somatotropinomas followed by prolactinomas, and rarely non-secreting adenomas. AIP-mutation-related prolactinomas predominantly affect men, as opposed to sporadic prolactinomas, that typically affect women. Clinical Case: We previously described an AIP gene mutation in two patients affected by prolactinomas. During the past years, we continued our study and have identified two more male patients with macroprolactinomas originally from the same small village and harboring the same AIP gene mutation. These male patients aged 19 to 44 years at the time of diagnosis. Two of them had neurological manifestations as the first clinical manifestation of the disease, one was studied because of hypogonadism and two patients had visual field defects. All of them had prolactin levels above 1000 ng/dl (mean 2946.5±948.7 ng/dl, reference range 10-21). In the imaging exams (CT/MRI) they presented pituitary adenomas larger than 20 mm (macroprolactinomas) and in two of the cases, the adenomas were even larger than 40 mm (giant prolactinomas). In order to exclude mutations most often associated with prolactinomas, DNA samples were obtained and analyzed by Next Generation Sequencing (NGS) using TruSightCancer Gene Set (Illumina) methodology. Investigation of significant deletions and/or duplications was performed using the MLPA (Multiplex ligation-dependent probe amplification) technique. None of the patients were positive for mutations of Multiple Endocrine Neoplasia type 1 (MEN1) gene. A variant of the AIP gene c.47G>A, expecting to lead to a substitution of arginine by histidine at position 16 (p.Arg16His) of the AIP was found in these four patients, including a father and his son. Seven asymptomatic carriers were identified among their first-degree relatives. In silico analysis and the information available in the literature, as well as in databases is not in agreement with the pathogenicity of this variant of the AIP gene. However, our findings point to a founder effect transmitted as a dominant trait with incomplete penetrance (4 out of 11 patients, 36%). Conclusion: The variant of the AIP gene identified in our patients behaved as a pathogenic mutation and was only associated with prolactinomas, including two giant prolactinomas.

Familial isolated pituitary adenoma syndrome

2011 ◽  
Vol 152 (18) ◽  
pp. 722-730 ◽  
Author(s):  
Judit Dénes ◽  
Márta Korbonits ◽  
Erika Hubina ◽  
Gábor László Kovács ◽  
László Kovács ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Aryl Hydrocarbon Receptor ◽  
Pituitary Adenomas ◽  
Protein Gene ◽  
Gene Mutations ◽  
Carney Complex ◽  
Incomplete Penetrance ◽  
Causative Gene ◽  
Interacting Protein ◽  
Aryl Hydrocarbon

Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor. Orv. Hetil., 2011, 152, 722–730.

scholarly journals Aryl Hydrocarbon Receptor-Interacting Protein Gene Mutations in Familial Isolated Pituitary Adenomas: Analysis in 73 Families

2007 ◽  
Vol 92 (5) ◽  
pp. 1891-1896 ◽  
Author(s):  
Adrian F. Daly ◽  
Jean-François Vanbellinghen ◽  
Sok Kean Khoo ◽  
Marie-Lise Jaffrain-Rea ◽  
Luciana A. Naves ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Outcome Measures ◽  
Pituitary Adenomas ◽  
Collaborative Study ◽  
Gene Mutations ◽  
Pituitary Tumors ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Aip Gene ◽  
The Impact

Abstract Context: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. Objective: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). Design: This was a multicenter, international, collaborative study. Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries. Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures. Intervention: There was no intervention. Results: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

scholarly journals Pituitary Disease in AIP Mutation-Positive Familial Isolated Pituitary Adenoma (FIPA): A Kindred-Based Overview

2020 ◽  
Vol 9 (6) ◽  
pp. 2003
Author(s):  
Ismene Bilbao Garay ◽  
Adrian F. Daly ◽  
Nerea Egaña Zunzunegi ◽  
Albert Beckers
Keyword(s):  
Pituitary Adenomas ◽  
Incomplete Penetrance ◽  
Long Term Outcomes ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Pituitary Disease ◽  
Clinically Significant ◽  
Aip Gene ◽  
Non Functioning Pituitary Adenomas

Clinically-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.

Aryl hydrocarbon receptor interacting protein(AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas

2008 ◽  
Vol 69 (4) ◽  
pp. 621-627 ◽  
Author(s):  
Marianthi Georgitsi ◽  
Ernesto De Menis ◽  
Salvatore Cannavò ◽  
Markus J. Mäkinen ◽  
Karoliina Tuppurainen ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Children And Adolescents ◽  
Gene Mutation ◽  
Mutation Analysis ◽  
Pituitary Adenomas ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Aip Gene ◽  
Gene Mutation Analysis

scholarly journals Aryl hydrocarbon receptor-interacting protein and pituitary adenomas: a population-based study on subjects exposed to dioxin after the Seveso, Italy, accident

2008 ◽  
Vol 159 (6) ◽  
pp. 699-703 ◽  
Author(s):  
Angela Cecilia Pesatori ◽  
Andrea Baccarelli ◽  
Dario Consonni ◽  
Andrea Lania ◽  
Paolo Beck-Peccoz ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Pituitary Adenomas ◽  
Pituitary Tumors ◽  
Population Based ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Registration System ◽  
Lombardy Region ◽  
Aryl Hydrocarbon ◽  
Incident Cases

ObjectiveThe pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects.DesignWe investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin following an industrial accident in 1976.MethodsThrough the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232 745).ResultsWe identified 42 pituitary adenomas in the reference area, 1 prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9–45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5–7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3–1.8, P=0.48).ConclusionsThe study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high–intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.

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.

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