Abstract
Clinically-relevant pituitary adenomas occur in about 1:1000 of the general population, but only about 5% occur in a known genetic or familial setting. Familial isolated pituitary adenomas (FIPA) are one of the most important inherited settings for pituitary adenomas and the most frequent genetic cause is a germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene. AIP mutations lead to young-onset macroadenomas that are difficult to treat. Most are growth hormone secreting tumors, but all other secretory types can exist and the clinical profile of affected patients is variable. We present an overview of the current understanding of AIP mutation-related pituitary disease and illustrate various key clinical factors using examples from one of the largest AIP mutation-positive FIPA families identified to date, in which six mutation-affected members with pituitary disease have been diagnosed. We highlight various clinically significant features of FIPA and AIP mutations, including issues related to patients with acromegaly, prolactinoma, apoplexy and non-functioning pituitary adenomas. The challenges faced by these AIP mutation-positive patients due to their disease and the long-term outcomes in older patients are discussed. Similarly, the pitfalls encountered due to incomplete penetrance of pituitary adenomas in AIP-mutated kindreds are discussed.
Highlights
Relevant pituitary adenomas have a prevalence of about one per thousand in the general population and are an important cause of morbidity due to the combined impact of hormonal dysfunction and tumoral mass effects [1,2]
The importance of mixed growth hormone (GH) and prolactin secreting adenomas in aryl hydrocarbon receptor-interacting protein (AIP)-mutated patients is highlighted by the experience of one case in the kindred whose profile suggests that mild IGF-1 excess might have developed over time
It must be borne in mind that not all pituitary adenomas found in AIP-mutated familial isolated pituitary adenomas (FIPA) kindreds are necessarily definitively linked to the genetic mutation
Summary
Relevant pituitary adenomas have a prevalence of about one per thousand in the general population and are an important cause of morbidity due to the combined impact of hormonal dysfunction and tumoral mass effects [1,2]. As somatotropinomas secreting excess growth hormone (GH) are the most frequently encountered pituitary adenoma in the setting of AIP mutations, the young onset and aggressive tumor growth mean that AIP mutations are the main genetic cause of pituitary gigantism (about 30% of cases) [12]. Results from large international studies have identified many hundreds of FIPA kindreds and have characterized a wide variety of AIP mutations and deletions affecting various families and individuals [13,14]. Within these families, the clinical presentations can vary beyond the more typical picture of the young-onset acromegaly patient to include other pituitary tumor types. To illustrate the various ways that AIP mutations can present in the FIPA setting, we describe and discuss the experiences of a large kindred with six affected individuals with AIP mutations and pituitary adenoma-related disease
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