Familial pituitary adenomas can occur in MEN1 and Carney complex, as well as in the recently characterized familial isolated pituitary adenoma (FIPA) syndrome. FIPA is an autosomal dominant disease with incomplete penetrance, characterized by early-onset disease, often aggressive tumor growth and a predominance of somatotroph and lactotroph adenomas. In 20% of FIPA families, heterozygous mutations have been described in the aryl hydrocarbon receptor interacting (AIP) gene, whereas in other families the causative gene(s) are unknown. It has been suggested that AIP is a tumor suppressor gene and although experimental data support this hypothesis, the exact molecular mechanism by which its disruption leads to tumorigenesis is unclear. Here we discuss the clinical, genetic and molecular features of patients with FIPA.

Clinical, genetic and molecular characterisation of patients with familial isolated pituitary adenomas (FIPA)

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 RN...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00546.2011

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

Acromegaly is caused by a somatotropinoma in the vast majority of the cases. These are monoclonal tumors that can occur sporadically or rarely in a familial setting. In the last few years, novel familial syndromes have been described and recent studies explored the landscape of somatic mutations in sporadic somatotropinomas. This short review concentrates on the current knowledge of the genetic basis of both familial and sporadic acromegaly.

/pdf/the-genetic-background-of-acromegaly-28s9e2ouat.pdf

The genetic background of acromegaly

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.

The causes and consequences of pituitary gigantism.

Pituitary adenomas are common neoplasms. Their classification is based upon size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment and recurrence. Although they are considered benign tumors, some of them are difficult to treat due to their tendency to recur despite standardized treatment. Functional tumors present other challenges for normalizing their biochemical activity. Novel approaches for early diagnosis, as well as different perspectives on classification, may help to identify subgroups of patients with similar characteristics, creating opportunities to match each patient with the best personalized treatment option. In this paper, we present the progress in the diagnosis and classification of different subgroups of patients with pituitary tumors that may be managed with specific considerations according to their tumor subtype.

/pdf/progress-in-the-diagnosis-and-classification-of-pituitary-t9p5ougwum.pdf

Progress in the Diagnosis and Classification of Pituitary Adenomas.

CONTEXT

The pathogenic effect of AIP mutations (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts.

OBJECTIVE

To analyze the mechanism/speed of protein turnover of wild-type (WT) and missense AIP variants, correlating protein half-life with clinical parameters.

DESIGN

Half-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed.

SETTING

Clinical academic research institution.

PATIENTS

Data was obtained from our cohort of pituitary adenoma patients and literature-reported cases.

INTERVENTIONS

Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. GST pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by co-immunoprecipitation and gene knockdown. Relevant clinical data was collected.

MAIN OUTCOME MEASURES

Half-life of WT and mutant AIP proteins and its correlation with clinical parameters.

RESULTS

Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7h). AIP variants were divided in stable proteins (median 77.7h [IQR 60.7-92.9]), and those with short (27h [21.6-28.7]) or very short (7.7h [5.6-10.5]) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r=0.411, P=0.002). The FBXO3-containing SCF complex was identified as the E3 ubiquitin-ligase recognizing AIP.

CONCLUSIONS

AIP is a stable protein, driven to ubiquitination by the SCF complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype.

Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations

Familial pituitary tumors are increasingly recognized. While some of these cases are related to well-known syndromic conditions such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex, others belong to the familial isolated pituitary adenoma (FIPA) patient group. The discovery of heterozygous, loss-of-function germline mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 2006 has subsequently enabled the identification of a mutation in this gene in 20% of FIPA families and 20% of childhood-onset simplex somatotroph adenomas. The exact mechanism by which the lack of AIP leads to pituitary adenomas is not clear. AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas. This review aims to summarize currently available clinical data on AIP mutation-positive and negative FIPA patients.

Familial isolated pituitary adenomas: an emerging clinical entity.

Can the stability of variant aryl hydrocarbon receptor interacting protein (AIP) be a marker for pathogenicity in FIPA (familial isolated pituitary adenoma)

Are ''in silico'' predictions reliable regarding splice-site mutations? - Studies in the aryl hydrocarbon receptor-interacting protein (AIP)

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Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations

Familial isolated pituitary adenomas: an emerging clinical entity.

Can the stability of variant aryl hydrocarbon receptor interacting protein (AIP) be a marker for pathogenicity in FIPA (familial isolated pituitary adenoma)

Are ''in silico'' predictions reliable regarding splice-site mutations? - Studies in the aryl hydrocarbon receptor-interacting protein (AIP)