Risk category system to identify pituitary adenoma patients with AIP mutations

Abstract

Background: Predictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk category system for aryl hydrocarbon receptor-interacting protein (AIP) mutations in patients with pituitary adenomas.

Methods: An international cohort of 2227 subjects were consecutively recruited between 2007 and 2016, including patients with pituitary adenomas (familial and sporadic) and their relatives. All probands (n=1429) were screened for AIP mutations, and those diagnosed with a pituitary adenoma prospectively, as part of their clinical screening (n=24), were excluded from the analysis. Univariate analysis was performed comparing patients with and without AIP mutations. Based on a multivariate logistic regression model, six potential factors were identified for the development of a risk category system, classifying the individual risk into low-risk, moderate-risk and high-risk categories. An internal cross-validation test was used to validate the system.

Results: 1405 patients had a pituitary tumour, of which 43% had a positive family history, 55.5% had somatotrophinomas and 81.5% presented with macroadenoma. Overall, 134 patients had an AIP mutation (9.5%). We identified four independent predictors for the presence of an AIP mutation: age of onset providing an odds ratio (OR) of 14.34 for age 0-18 years, family history (OR 10.85), growth hormone excess (OR 9.74) and large tumour size (OR 4.49). In our cohort, 71% of patients were identified as low risk (<5% risk of AIP mutation), 9.2% as moderate risk and 20% as high risk (≥20% risk). Excellent discrimination (c-statistic=0.87) and internal validation were achieved.

Conclusion: We propose a user-friendly risk categorisation system that can reliably group patients into high-risk, moderate-risk and low-risk groups for the presence of AIP mutations, thus providing guidance in identifying patients at high risk of carrying an AIP mutation. This risk score is based on a cohort with high prevalence of AIP mutations and should be applied cautiously in other populations.

Keywords: AIP mutations; acromegaly; familial pituitary adenoma; risk category system; screening.

Figure 1

Area under the receiver operating characteristic curve of the AIP mutation risk category system is 0.87 (95% CI 0.84 to 0.90), indicating an excellent discriminating power.

Figure 2

Risk stratification for AIP mutations, classified as low risk (<5%), moderate risk (5%–19%) or high risk (≥20%). Red: risk of AIP mutation ≥20%; orange: risk of AIP mutation between 5% and 19%; green: risk of AIP mutation <5%. GH, growth hormone; macro, macroadenoma; micro, microadenoma; simplex, patients with no known family history.

Figure 3

AIP screening algorithm based on the proposed risk category system. The overall risk category of a kindred should be based on the risk score of the family member with the highest risk. AIP, aryl hydrocarbon receptor-interacting protein. *See figure 2.