Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors

Abstract

Context Germline 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). Objective To 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. Design 12-year prospective, observational study. Participants & Setting We 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). Results Prospectively 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). Conclusions Prospectively 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.

Pituitary Disease in AIP Mutation-Positive Familial Isolated Pituitary Adenoma (FIPA): A Kindred-Based Overview

“…Therefore, in AIP mutation carriers undergoing MRI screening, caution should be exercised before definitively labeling such tumors as being “ AIP related” pituitary adenomas, as such cases may behave in a manner that is indistinguishable from other incidentalomas on follow-up. In support of this, recent data from screening analyses suggest that nearly half of prospectively diagnosed pituitary adenomas in AIP mutation carriers are non-functioning microadenomas; these non-functioning tumors are usually not associated with hormonal abnormalities and rarely receive any treatment during long-term follow-up [ 34 ]. Screening, therefore, should be focused particularly on identifying undiagnosed tumors in young AIP mutation carriers from childhood to early adulthood.…”

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

“…In the sporadic cohort (n = 777), 53 (6.8%) had an AIP mutation ( Table 1). Within the sporadic tumor subgroup, 10.5% (50 out of 477) of somatotropinomas, 1.5% (3 out of 197) of prolactinomas, and none (0 out of 54) of the NF-PitNET cases were found to harbor a germline AIP mutation (Table 3; all supplementary material and figures are located in a digital research materials repository (17)).…”

“…Forty-four different germline pathogenic/likely pathogenic AIP mutations were identified, including 5 previously not described mutations (exon 1 deletion; c.344delT (p.L115fs*41); c.773T>G (p.L258R); c.779delA (p.K260fs*44); c.863_864del (p.F288Cfs*? )), among the 167 AIPmut patients (17). The most common mutation types were nonsense mutations (27%) and frameshift mutations (25%), followed by missense (18%), splice site (7%), in-frame insertions/deletions (9%), and large genomic deletions (7%), and we had 1 each of promoter, start site, and stop-loss mutations.…”

“…In our study population, we identified 17 different AIP variants classified as benign, likely benign, or variants of uncertain significance according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria (17,18). We note that one of the most common AIP variants identified, p.R304Q, although controversial, is currently classified as variant of uncertain significance (19), patients from these kindreds were allocated to the AIPneg subgroup.…”

“…The mean final height was higher in the AIPmut somatotropinoma subgroup both for males (193 ± 18 vs 185 ± 14 cm; P = .004) and females (175 ± 13 vs 169 ± 9 cm; P = .017) ( Table 3). Patients with AIPmut prolactinomas had higher rates of pituitary apoplexy than AIPneg counterparts, which remained significantly higher when considering only clinically presenting cases (17). AIPmut NF-PitNETs had lower rates of macroadenomas, hypopituitarism at last follow-up, lower tumor diameter, and fewer pituitary deficiencies at diagnosis, as well as requiring fewer treatments and surgery than their nonmutated counterparts; however, when excluding the 10 prospectively diagnosed AIPmut NF-PitNETs patients these significant differences were lost ( 17).…”