Genetic and Epigenetic Causes of Pituitary Adenomas

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

Acta Endocrinologica ◽

10.1530/eje-07-0348 ◽

2007 ◽

Vol 157 (4) ◽

pp. 371-382 ◽

Cited By ~ 102

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.

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Familial isolated pituitary adenoma syndrome

Orvosi Hetilap ◽

10.1556/oh.2011.29093 ◽

2011 ◽

Vol 152 (18) ◽

pp. 722-730 ◽

Cited By ~ 1

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.

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

Endocrine Reviews ◽

10.1210/er.2012-1013 ◽

2013 ◽

Vol 34 (2) ◽

pp. 239-277 ◽

Cited By ~ 188

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.

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No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia

Endocrine Related Cancer ◽

10.1677/erc-07-0025 ◽

2007 ◽

Vol 14 (3) ◽

pp. 901-906 ◽

Cited By ~ 39

Author(s):

A Raitila ◽

M Georgitsi ◽

A Karhu ◽

K Tuppurainen ◽

M J Mäkinen ◽

...

Keyword(s):

Growth Hormone ◽

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Direct Sequencing ◽

Endocrine System ◽

Carney Complex ◽

Endocrine Tumors ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Endocrine Neoplasia

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.

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Faculty Opinions recommendation of Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1168265.630419 ◽

2009 ◽

Author(s):

Niki Karavitaki ◽

Theingi Aung

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Clinical Implications ◽

Interacting Protein ◽

Aryl Hydrocarbon

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Faculty Opinions recommendation of Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5418956.5374054 ◽

2010 ◽

Author(s):

Ernesto De Menis ◽

Paola Sartorato

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Complete Penetrance

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miR-107 Is Overexpressed in Pituitary Adenomas and Inhibits the Expression of Aryl Hydrocarbon Receptor-Interacting Protein (AIP)

10.1210/endo-meetings.2011.part2.p2.p1-412 ◽

2011 ◽

pp. P1-412-P1-412

Author(s):

Giampaolo Trivellin ◽

Susana Igreja ◽

Edwin Garcia ◽

Harvinder S Chahal ◽

Henriett Butz ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Interacting Protein ◽

Aryl Hydrocarbon

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Genetic and metabolic characteristics of familial isolated pituitary adenomas

Obesity and metabolism ◽

10.14341/2071-8713-4817 ◽

2013 ◽

Vol 10 (2) ◽

pp. 3-10 ◽

Cited By ~ 2

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

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First Encounters

Instant Neurological Diagnosis ◽

10.1093/med/9780199361953.003.0001 ◽

2016 ◽

pp. 1-22

Author(s):

Christopher H. Hawkes ◽

Kapil D. Sethi ◽

Thomas R. Swift

Keyword(s):

Fragile X ◽

Relapsing Polychondritis ◽

Neurofibromatosis Type ◽

Carney Complex ◽

Ehlers Danlos Syndrome ◽

Type Iv ◽

The Face ◽

Sturge Weber Syndrome ◽

The Voice

This chapter describes disorders that can be diagnosed as the patient enters the consulting room, and how the patient turns to close the door, walks toward the clinician and shakes the clinician’s hand. Much information is gleaned by inspecting the face, clothes, fingernails, and jewelry or listening to the voice and smelling the breath. The clinician works as a bedside Sherlock Holmes. Some of the symptoms addressed in this chapter include hypersalivation, Horner's syndrome, and macroglossia. Individual disorders described include idiopathic intracranial hypertension, neurofibromatosis type 1, Sturge-Weber syndrome, Waardenburg syndrome, Vogt Harada Koyanagi syndrome, Fabry’s disease, fragile X syndrome, relapsing polychondritis, myasthenia gravis, Ehlers Danlos Syndrome type IV, Carney complex, cocaine and meth addiction, and ankylosing spondylitis, among others.

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