Abstract
ContextGermline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).ObjectiveTo compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.Design12-year prospective, observational study.Participants & SettingWe studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).ResultsProspectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).ConclusionsProspectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.
Highlights
Familial isolated pituitary adenoma (FIPA) is a heterogeneous condition that involves the presence of pituitary neuroendocrine tumor (PitNET) in 2 or more members of the same family without other syndromic manifestations
Up to 20% of all familial isolated pituitary adenoma (FIPA) and 50% of familial acromegaly kindreds carry germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene [1,3,4]. These mutations are seen in sporadically diagnosed PitNETs, in young patients, where the lack of family history is usually due to incomplete penetrance rather than de novo mutations [5,6,7,8]
The typical AIP mutation-positive (AIPmut) phenotype is characterized by a young patient presenting with a large invasive growth hormone (GH)-secreting PitNET that is refractory to conventional treatments [1,3,4,5,9,10,11], with AIPmut somatotropinomas being responsible for 29% of pituitary gigantism cases [12]
Summary
Study population We selected our study population from our cohort (2079 patients with PitNETs and their 1029 unaffected relatives) recruited via the collaborative research network of the International FIPA Consortium (collaborators listed at the end of the manuscript) between February 2007 and April 2019; details of recruitment have been previously described [3]. Indications for AIP genetic testing were [1] patients with FIPA; [2] macroadenomas with disease onset at ≤30 years; and [3] PitNETs with disease onset at ≤18 years. First-degree family members of individuals carrying AIP mutations were offered genetic testing. We included in our analysis all patients with known AIP mutational status matching these criteria (n = 1477). We excluded patients with undetermined affected status (ie, proven AIPmut carriers who did not undergo clinical screening or had pending clinical test results by the time of data analysis). Patients with X-linked acrogigantism or syndromic disease (multiple endocrine neoplasia type 1 (MEN1), MEN4, Carney complex, SDHxrelated, McCune–Albright and DICER1 syndromes, identified on the basis of clinical, biochemical, and genetic testing as appropriate) were excluded
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