Abstract
Introduction: Germline mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) are responsible for up to 50% of familial isolated pituitary adenoma (FIPA) kindreds affected only with somatotropinomas. AIP mutation-positive (AIPmut) somatotropinomas present earlier, more aggressively and are often more resistant to therapy. We aimed to further characterise AIPmut somatotropinomas in terms of clinical features and outcomes. Methods: We studied AIPmut somatotropinomas which presented clinically; prospectively-diagnosed AIPmut somatotropinomas (i.e. somatotropinomas diagnosed following genetic and clinical screening) were excluded from the analysis. Indications for AIP genetic testing were: i) FIPA patients, ii) sporadic pituitary GH-secreting macroadenomas with disease onset <30y, or iii) GH-secreting microadenomas with age of onset <18y. Results: Out of 784 patients with somatotropinomas included in our study, 139 had an AIP mutation (17.7%). In comparison to AIP mutation-negative somatotropinomas (AIPneg), patients with AIPmut somatotropinomas had a younger age at first symptoms (18.9±9.0 vs 26.1±11.7y; p<0.001) and at diagnosis (24.1±10.5 vs 30.1±12.4y; p<0.001), higher rates of pituitary apoplexy (9.5 vs 1.9%; p<0.001), suprasellar extension (66.1 vs 45.3%; p=0.003), extrasellar extension (81.2 vs 68.3%; p=0.032) and a higher mean number of pituitary deficiencies at diagnosis (0.4±0.9 vs 0.2±0.6, p=0.020). The clinical diagnosis of most AIPmut patients was gigantism (55.4 vs 18.4%, p<0.001). The mean final height was higher in the AIPmut somatotropinoma subgroup (187.2±18.4 vs 177.2±19.6cm; p<0.001). AIPmut male patients ended up taller than AIPneg males (193.0±17.7 vs 183.0±23.1cm; p=0.002); similarly, AIPmut female patients were taller than AIPneg ones (175.5±13.0 vs 169.2±8.6cm; p=0.007). Both AIPmut and AIPneg groups had more male patients (60.4% in AIPmut and 52.7% in AIPneg groups). The mean number of overall treatments (2.34±1.65 vs 2.32±1.45; p=0.896) or surgical operations (1.05±0.78 vs 1.07±0.63; p=0.745) did not differ significantly between AIPmut and AIPneg somatotropinomas; however, AIPmut patients were more often treated with radiotherapy (41.7 vs 28.0%; p=0.020). Conclusions:AIPmut somatotropinomas present earlier and more often with pituitary apoplexy, suprasellar and extrasellar extensions, and had a higher number of pituitary deficiencies. The remarkably higher final height in the AIPmut setting, both in males and females, likely reflects the earlier onset of disease, but also emphasizes the management challenges as suggested by the increased proportion of patients requiring radiotherapy.