scholarly journals Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis

2013 ◽  
Vol 169 (6) ◽  
pp. 867-884 ◽  
Author(s):  
Feng Cai ◽  
Yi-Dan Zhang ◽  
Xiuli Zhao ◽  
Ya-Kun Yang ◽  
Si-Hai Ma ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Young Patients ◽  
Gene Mutations ◽  
Missense Variant ◽  
Han Chinese ◽  
Nucleotide Polymorphisms ◽  
Intron Insertion ◽  
Interacting Protein ◽  
Sporadic Tumor ◽  
Aip Gene

ObjectiveThe aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort.DesignOur study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls.MethodsAIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis.ResultsWe identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (≤30 years) and pediatric (≥18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families).ConclusionAIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition.

scholarly journals High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas

2011 ◽  
Vol 165 (4) ◽  
pp. 509-515 ◽  
Author(s):  
Maria A Tichomirowa ◽  
Anne Barlier ◽  
Adrian F Daly ◽  
Marie-Lise Jaffrain-Rea ◽  
Cristina Ronchi ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Pediatric Patients ◽  
Young Patients ◽  
Gene Mutations ◽  
Clinical Analysis ◽  
Clinical Genetic ◽  
Interacting Protein ◽  
Aip Gene ◽  
Pituitary Macroadenomas

BackgroundAryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.MethodsWe included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.ResultsOverall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.ConclusionGermline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

scholarly journals Frequency of AIP Gene Mutations in Young Patients With Acromegaly: A Registry-Based Study

2014 ◽  
Vol 99 (12) ◽  
pp. E2789-E2793 ◽  
Author(s):  
Christof Schöfl ◽  
Jürgen Honegger ◽  
Michael Droste ◽  
Martin Grussendorf ◽  
Reinhard Finke ◽  
...  
Keyword(s):  
Family History ◽  
Direct Sequencing ◽  
Positive Family History ◽  
Young Patients ◽  
Gene Mutations ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Number Of Patients ◽  
The Individual ◽  
Aip Gene

Context: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. Objective: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. Design: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. Intervention: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. Results: Five patients had either a mutation (c.490C&gt;T, c.844C&gt;T, and c.911G&gt;A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. Conclusions: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

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&gt;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.

OR01-5 Prevalence of AIP gene mutations in young patients with acromegaly

2012 ◽  
Vol 22 ◽  
pp. S3
Author(s):  
C. Schöfl ◽  
J. Honegger ◽  
M. Droste ◽  
M. Grussendorf ◽  
R. Finke ◽  
...  
Keyword(s):  
Young Patients ◽  
Gene Mutations ◽  
Aip Gene

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 Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort

2014 ◽  
Vol 171 (5) ◽  
pp. 659-666 ◽  
Author(s):  
Veronica Preda ◽  
Márta Korbonits ◽  
Simon Cudlip ◽  
Niki Karavitaki ◽  
Ashley B Grossman
Keyword(s):  
Pituitary Adenomas ◽  
Young Patients ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
University Hospital ◽  
Tertiary Referral Centre ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Genetic Testing Guidelines ◽  
Low Prevalence

AimTo study the prevalence of germline mutations of the aryl-hydrocarbon receptor interacting protein (AIP) gene in a large cohort of patients seen in the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), UK, with apparently sporadic pituitary adenomas, who were either diagnosed or had relevant clinical manifestations by the age of 40 years.PatientsWe prospectively investigated all patients who were seen at Oxford University Hospital, OCDEM, and a tertiary referral centre, between 2012 and 2013, and presented with pituitary tumours under the age of 40 years and with no family history: a total of 127 patients were enrolled in the study.MethodsLeukocyte-origin genomic DNA underwent sequence analysis of exons 1–6 and the flanking intronic regions of theAIPgene (NM_003977.2), with dosage analysis by multiplex ligation-dependent probe amplification.ResultsAIPvariants were detected in 3% of the 127 patients, comprising four of 48 patients with acromegaly (8%), 0 of 43 with prolactinomas, 0 of the 20 patients with non-functioning adenomas, 0 of 15 with corticotroph adenomas and 0 of one with a thyrotroph adenomas. Definite pathogenetic mutations were seen in 2/4 variants, comprising 4.2% of patients with acromegaly.ConclusionsThis prospective cohort study suggests a relatively low prevalence ofAIPgene mutations in young patients with apparently sporadic pituitary adenomas presenting to a tertiary pituitary UK centre. Those with somatotroph macroadenomas have a higher rate ofAIPmutation. These findings should inform discussion of genetic testing guidelines.

scholarly journals Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations

2013 ◽  
Vol 20 (5) ◽  
pp. 753-766 ◽  
Author(s):  
Marie-Lise Jaffrain-Rea ◽  
Sandra Rotondi ◽  
Annarita Turchi ◽  
Gianluca Occhi ◽  
Anne Barlier ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Aryl Hydrocarbon Receptor ◽  
Primary Cultures ◽  
Gene Mutations ◽  
Somatostatin Analogues ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Tumour Shrinkage ◽  
Suprasellar Extension

Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH-PA). As recent data suggest a role for AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence ofGspstatus was studied in a subset of tumours (n=39, 14Gsp+) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%,P=0.016). AHR expression or localisation did not differ between the two groups. Similarly,in vitrooctreotide induced a median twofold increase in AIP expression (range 1.2–13.9,P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 andP=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect ofGspstatus was a significantly lower nuclear AHR score inGsp+vsGsp−tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless ofGspstatus, and AIP up-regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR.

Sign in / Sign up

Export Citation Format

Share Document