Clinical Experience in the Screening and Management of a Large Kindred With Familial Isolated Pituitary Adenoma Due to an Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutation

Williams, Fred E.; Hunter, Steven; Bradley, Lisa; Chahal, Harvinder; Storr, Helen L; Akker, Scott; Kumar, Ajith; Orme, Stephen M.; Evanson, Jane; Abid, Noina; Morrison, Patrick J.; Korbonits, Márta; Atkinson, A. B.

doi:10.1210/jc.2013-2868

Cited by 51 publications

(39 citation statements)

References 38 publications

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“…It would be interesting to know whether this strong pituitary phenotype (Raitila et al 2010) is maintained after several years of backcrosses in the original environment. Similar to our observation, the penetrance of pituitary adenomas in AIP-mutated families is low, but subtle hormonal abnormalities may exist in some AIP mutation carriers who have not yet developed pituitary adenomas (Naves et al 2007, Williams et al 2014.…”

Section: Discussionsupporting

confidence: 89%

“…The initial description of this model mentioned a very strong pituitary phenotype, with adenomas occurring in 100% of mutants by the age of 15 months (Raitila et al 2010). This strong penetrance contrasts with the human situation (Williams et al 2014). To better characterize the endocrine phenotype of these mice, we examined the somatic growth and GH secretion of male mice at different ages.…”

Section: Discussionmentioning

confidence: 99%

“…The AIP-mutated giants are predominantly males (Daly et al 2010, Cazabat et al 2012. Predisposition to pituitary adenoma due to AIP mutation is also characterized by low penetrance (about 20%) (Williams et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice

Lecoq

Zizzari

Hage

et al. 2016

Journal of Endocrinology

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Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip +/− ) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip +/− mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip +/− mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip +/− mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip +/− mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip +/− mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip +/− mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice

Lecoq

Zizzari

Hage

et al. 2016

Journal of Endocrinology

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“…These data are in agreement with the literature that usually reported a penetrance of AIP mutations in the low range (15-30 % approximately), although it may significantly differ between studies [3,4,11].…”

Section: Discussionsupporting

confidence: 92%

“…The most common features that suggest a pathological significance of an AIP variant are: the segregation of the variant with the disease; the small prevalence of the variant in the general population (i.e. the A299 V single nucleotide polymorphism was observed in 1.3 % of European population) [11]; the conservation across species; the evidence of the loss of heterozygosity; the in silico or the functional in vitro evidence of a pathogenic significance [11].…”

Section: Introductionmentioning

confidence: 99%

A novel germline mutation in the aryl hydrocarbon receptor-interacting protein (Aip) gene in an Italian family with gigantism

Urbani

Russo

Raggi

et al. 2014

J Endocrinol Invest

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Molecular Genetics in Acromegaly

Xekouki

Stratakis²

2016

Encyclopedia of Life Sciences

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Pituitary tumours are the most frequent intracranial neoplasms, affecting 1/1000 of the worldwide population. Growth hormone (GH)‐secreting adenomas, also known as somatotropinomas, comprise about 20% of all pituitary tumours. Acromegaly is the clinical syndrome that results from high levels of GH in patients after the end of their growing years, whereas gigantism occurs when high GH acts on a skeleton that is still growing. Most cases of acromegaly/gigantism occur as a result of sporadic GH‐secreting pituitary adenomas. However, in 5% of cases (and significantly more frequently in the young ages), they can occur as a result of a genetic defect, most of the time in association with other endocrine abnormalities or as an isolated disorder. These familial syndromes include multiple endocrine neoplasia (MEN) type 1 (MEN1), Carney complex (CNC), MEN type 4 (MEN4). McCune–Albright syndrome (MAS), familial isolated pituitary adenoma (FIPA), the 3Ps association (pheochromocytoma/paraganglioma and pituitary adenoma syndrome or 3PAs) and X‐linked acrogigantism (X‐LAG). Key Concepts About 5% of acromegaly may be caused by a genetic mutation; this may be significantly higher in the young ages. The frequency of GH‐producing pituitary tumours in MEN1 syndrome is only about 10%, with a mean age at diagnosis comparable to the sporadic GH‐secreting adenomas (40–45 years) but with a more aggressive behaviour. The incidence of GH‐producing pituitary tumours in Carney complex (CNC) has been estimated to be less than 15%; however, insulin‐like growth factor 1 (IGF‐1) elevation may be present in up to 80% of affected patients who have no detectable tumours due to somatomammotrophic hyperplasia, which may precede clinically evident acromegaly. GH excess is found in up to 20% of patients with McCune–Albright syndrome mainly due to GH‐producing cell hyperplasia rather than due to pituitary tumours, which are identified in only a few patients. Somatotropinomas are the most common tumour type in both AIP mutation‐positive and ‐negative familial isolated pituitary adenoma (FIPA) families. AIP mutation‐positive FIPA patients are more likely to have larger tumours, more likely to invade the extrasellar region and more resistant to medication treatment GH‐secreting pituitary adenomas in 3PAs due to SDHx mutations display more aggressive phenotype, are more resistant to somatostatin analogues, and most often require surgery X‐linked acrogigantism (X‐LAG) caused by an Xq26.3 genomic duplication is a paediatric disorder characterised by early onset gigantism resulting from an excess of growth hormone as early as in infancy. The GPR101 gene duplication most likely causes X‐LAG.

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Clinical Experience in the Screening and Management of a Large Kindred With Familial Isolated Pituitary Adenoma Due to an Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutation

Cited by 51 publications

References 38 publications

Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice

Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice

A novel germline mutation in the aryl hydrocarbon receptor-interacting protein (Aip) gene in an Italian family with gigantism

Molecular Genetics in Acromegaly

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