Abstract
Pituitary adenomas (PA) are amongst the most prevalent intracranial tumors, causing complications by hormonal overproduction or deficiency and tumor mass effects, with 95% of cases occurring sporadically. Associated germline mutations (AIP, MEN1, CDKN1B, PRKAR1A, SDHx) and Xq26.3 microduplications are increasingly identified, but the clinical consequences in sporadic PA remain unclear. This systematic review evaluates predictors of a genetic cause of sporadic PA and the consequences for treatment outcome. We undertook a sensitive MEDLINE/Pubmed, EMBASE, and Web of Science search with critical appraisal of identified studies. Thirty-seven studies on predictors of mutations and 10 studies on the influence on treatment outcome were included. AIP and MEN1 mutations were associated with young age of PA diagnosis. AIP mutations were also associated with gigantism and macroadenomas at time of diagnosis. Xq26.3 microduplications were associated with PA below the age of five. AIP and MEN1 mutation analysis is therefore recommended in young patients (≤30 years). AIP mutation analysis is specifically recommended for patients with PA induced gigantism and macroadenoma. Screening for Xq26.3 microduplications is advisable in children below the age of five with increased growth velocity due to PA. There is no evidence supporting mutation analysis of other genes in sporadic PA. MEN1 mutation related prolactinoma respond well to dopamine agonists while AIP mutation associated somatotroph and lactotroph adenoma are frequently resistant to medical treatment. In patients harboring an Xq26.3 microduplication treatment is challenging, although outcome is not different from other patients with PA induced gigantism. Effective use of genetic analysis may lead to early disease identification, while knowledge of the impact of germline mutations on susceptibility to various treatment modalities helps to determine therapeutic strategies, possibly lowering disease morbidity.
Highlights
Pituitary adenomas (PAs) are amongst the most frequently encountered intracranial tumors with a reported prevalence for clinically relevant PAs of 68–98 per 100,000 (1–6)
There is some evidence that treatment outcome is better in
no well-founded conclusions can be drawn for this subgroup
Summary
Pituitary adenomas (PAs) are amongst the most frequently encountered intracranial tumors with a reported prevalence for clinically relevant PAs of 68–98 per 100,000 (1–6). Frontiers in Endocrinology | www.frontiersin.org van den Broek et al. Genetic Analysis in Pituitary Adenomas can be seen in the context of an inherited syndromic condition leading to an increased risk of PAs (most frequently Multiple Endocrine Neoplasia Type 1 (MEN1)) or without other (endocrine) manifestations in case of familial isolated pituitary adenoma (FIPA). Clinical implications of identifying germline mutations in patients with PA, in terms of treatment and prognosis, have been reported by different authors (9–12). The amount of publications concerning germline mutations in (sporadic) pituitary adenoma has increased enormously. The mechanisms underlying pituitary tumorigenesis and the role of germline mutations in PAs in a sporadic setting remain poorly understood. The reported yield of genetic screening varies enormously, presumably due to a great variety of study populations, genetic screening methods and methodological quality of studies
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