Emergence of Pituitary Adenoma in a Child during Surveillance: Clinical Challenges and the Family Members’ View in anAIPMutation-Positive Family

Introduction. Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are responsible for 15–30% of familial isolated pituitary adenomas (FIPAs). We report a FIPA kindred with a heterozygous deletion inAIP, aiming to highlight the indications and benefits of genetic screening, variability in clinical presentations, and management challenges in this setting.Patients. An 18-year-old male was diagnosed with a clinically nonfunctioning pituitary adenoma (NFPA). Two years later, his brother was diagnosed with a somatolactotrophinoma, and a small Rathke’s cleft cyst and a microadenoma were detected on screening in their 17-year-old sister. Following amenorrhoea, their maternal cousin was diagnosed with hyperprolactinaemia and two distinct pituitary microadenomas. A 12-year-old niece developed headache and her MRI showed a microadenoma, not seen on a pituitary MRI scan 3 years earlier.Discussion. Out of the 14 members harbouring germlineAIPmutations in this kindred, 5 have pituitary adenoma. Affected members had different features and courses of disease. Bulky pituitary and not fully suppressed GH on OGTT can be challenging in the evaluation of females in teenage years. Multiple pituitary adenomas with different secretory profiles may arise in the pituitary of these patients. Small, stable NFPAs can be present in mutation carriers, similar to incidentalomas in the general population. Genetic screening and baseline review, with follow-up of younger subjects, are recommended inAIPmutation-positive families.

Download Full-text

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.

Download Full-text

MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00546.2011 ◽

2012 ◽

Vol 303 (6) ◽

pp. E708-E719 ◽

Cited By ~ 44

Author(s):

Giampaolo Trivellin ◽

Henriett Butz ◽

Juliette Delhove ◽

Susana Igreja ◽

Harvinder S. Chahal ◽

...

Keyword(s):

Pituitary Adenoma ◽

Tumor Suppressor ◽

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Expression Profiles ◽

Luciferase Assay ◽

Human Neuroblastoma ◽

Interacting Protein ◽

Aryl Hydrocarbon

Abnormal microRNA (miRNA) expression profiles have recently been associated with sporadic pituitary adenomas, suggesting that miRNAs can contribute to tumor formation; miRNAs are small noncoding RNAs that inhibit posttranscriptional expression of target mRNAs by binding to target sequences usually located in the 3′-UTR. In this study, we investigated the role played by miR-107, a miRNA associated with different human cancers, in sporadic pituitary adenomas and its interaction with the pituitary tumor suppressor gene aryl hydrocarbon receptor-interacting protein ( AIP). miR-107 expression was evaluated in pituitary adenoma and normal pituitary samples using microRNA screen TLDA (TaqMan Low-Density Array) and RT-qPCR assays. We show that miR-107 expression was significantly upregulated in GH-secreting and nonfunctioning pituitary adenomas. We found that human AIP-3′-UTR is a target of miR-107 since miR-107 inhibited in vitro AIP expression to 53.9 ± 2% of the miRNA control in a luciferase assay and reduced endogenous AIP mRNA expression to 53 ± 22% of the miRNA control in human cells. However, we did not observe a negative correlation between AIP and miR-107 expression in the human tumor samples. Furthermore, we show that miR-107 overexpression inhibited cell proliferation in human neuroblastoma and rat pituitary adenoma cells. In conclusion, miR-107 is overexpressed in pituitary adenomas and may act as a tumor suppressor. We have identified and confirmed AIP as a miR-107 target gene. Expression data in human samples suggest that the expression of AIP and miR-107 could be influenced by a combination of tumorigenic factors as well as compensatory mechanisms stimulated by the tumorigenic process.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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

Download Full-text

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

Download Full-text

Pediatric Pituitary Adenoma: Case Series, Review of the Literature, and a Skull Base Treatment Paradigm

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0038-1625984 ◽

2018 ◽

Vol 79 (01) ◽

pp. 091-114 ◽

Cited By ~ 19

Author(s):

Avital Perry ◽

Christopher Graffeo ◽

Christopher Marcellino ◽

Bruce Pollock ◽

Nicholas Wetjen ◽

...

Keyword(s):

Systematic Review ◽

Pituitary Adenoma ◽

Skull Base ◽

Pituitary Adenomas ◽

Pediatric Population ◽

Csf Leak ◽

Persistent Disease ◽

Treatment Paradigm ◽

Surgical Cure

Background Pediatric pituitary adenoma is a rare skull base neoplasm, accounting for 3% of all intracranial neoplasms in children and 5% of pituitary adenomas. Compared with pituitary tumors in adults, secreting tumors predominate and longer disease trajectories are expected due to the patient age resulting in a natural history and treatment paradigm that is complex and controversial. Objectives The aims of this study were to describe a large, single-institution series of pediatric pituitary adenomas with extensive long-term follow-up and to conduct a systematic review examining outcomes after pituitary adenoma surgery in the pediatric population. Methods The study cohort was compiled by searching institutional pathology and operative reports using diagnosis and site codes for pituitary and sellar pathology, from 1956 to 2016. Systematic review of the English language literature since 1970 was conducted using PubMed, MEDLINE, Embase, and Google Scholar. Results Thirty-nine surgically managed pediatric pituitary adenomas were identified, including 15 prolactinomas, 14 corticotrophs, 7 somatotrophs, and 4 non-secreting adenomas. All patients underwent transsphenoidal resection (TSR) as the initial surgical treatment. Surgical cure was achieved in 18 (46%); 21 experienced recurrent/persistent disease, with secondary treatments including repeat surgery in 10, radiation in 14, adjuvant pharmacotherapy in 11, and bilateral adrenalectomy in 3. At the last follow-up (median 87 months, range 3–581), nine remained with recurrent/persistent disease (23%).Thirty-seven publications reporting surgical series of pediatric pituitary adenomas were included, containing 1,284 patients. Adrenocorticotropic hormone (ACTH)-secreting tumors were most prevalent (43%), followed by prolactin (PRL)-secreting (37%), growth hormone (GH)-secreting (12%), and nonsecreting (7%). Surgical cure was reported in 65%. Complications included pituitary insufficiency (23%), permanent visual dysfunction (6%), chronic diabetes insipidus (DI) (3%), and postoperative cerebrospinal fluid (CSF) leak (4%). Mean follow-up was 63 months (range 0–240), with recurrent/persistent disease reported in 18% at the time of last follow-up. Conclusion Pediatric pituitary adenomas are diverse and challenging tumors with complexities far beyond those encountered in the management of routine adult pituitary disease, including nuanced decision-making, a technically demanding operative environment, high propensity for recurrence, and the potentially serious consequences of hypopituitarism with respect to fertility and growth potential in a pediatric population. Optimal treatment requires a high degree of individualization, and patients are most likely to benefit from consolidated, multidisciplinary care in highly experienced centers.

Download Full-text

Ki-67/MIB-1 and Recurrence in Pituitary Adenoma

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0041-1735874 ◽

2021 ◽

Author(s):

Kent Tadokoro ◽

Colten Wolf ◽

Joseph Toth ◽

Cara Joyce ◽

Meharvan Singh ◽

...

Keyword(s):

Systematic Review ◽

Pituitary Adenoma ◽

Recurrence Rate ◽

Pituitary Adenomas ◽

Cellular Proliferation ◽

Published Data ◽

Ki 67 ◽

Institutional Data ◽

Mib 1

Abstract Objectives Ki-67/MIB-1 is a marker of cellular proliferation used as a pathological parameter in the clinical assessment of pituitary adenomas, where its expression has shown utility in predicting the invasiveness of these tumors. However, studies have shown variable results when using Ki-67/MIB-1 association with recurrence. The purpose of this study is to determine if a high Ki-67/MIB-1 labeling index (LI) is predictive of recurrence in pituitary adenomas. Methods A retrospective chart review was performed for patients undergoing pituitary adenoma resection with at least 1 year of follow-up. Additionally, systematic data searches were performed and included studies that correlated recurrence rate to Ki-67/MIB-1 LI. Our institutional data were included in a synthesis with previously published data. Results Our institutional review included 79 patients with a recurrence rate of 26.6%. We found that 8.8% of our patients had a high Ki-67/MIB-1 LI (>3%); however, high Ki-67/MIB-1 was not associated with recurrence. The systematic review identified 244 articles and 49 full-text articles that were assessed for eligibility. Quantitative analysis was performed on 30 articles including our institutional data and 18 studies reported recurrence by level of Ki-67/MIB-1 LI. Among studies that compared Ki-67/MIB-1 ≥3 vs. <3%, 10 studies reported odds ratios (OR) greater than 1 of which 6 were statistically significant. A high Ki-67/MIB-1 had higher odds of recurrence via the pooled odds ratio (OR = 4.15, 95% confidence interval [CI]: 2.31–7.42). Conclusion This systematic review suggests that a high Ki-67/MIB-1 should prompt an increased duration of follow-up due to the higher odds of recurrence of pituitary adenoma.

Download Full-text