Endocrine Abstracts

Background: AIP codes for the aryl hydrocarbon receptor-interacting protein which is a co-chaperone protein with numerous binding partners. AIP acts as a tumour suppressor gene within the pituitary and heterozygous pathogenic germline AIP variants (AIPvar) result in apparently isolated pituitary disease. However, a recently described multi-system syndrome in AIPvar homozygotes raises potential, previously unobserved phenotypic consequences of AIPvar heterozygosity.

Aims: 1) To characterise the phenotype of AIP-related pituitary disease 2) To investigate for possible additional AIP-associated disease.

Methods: Prospective, international observational study of individuals with likely pathogenic and pathogenic germline AIP variants.

Results: Four hundred and eighteen AIPvar heterozygotes were identified. Two hundred and twelve had pituitary disease, with 31 diagnosed prospectively after cascade genetic testing. A slight majority diagnosed prospectively had non-functioning tumours (55%). The majority of non-prospectively diagnosed patients had acromegaly or gigantism (85%), 13% developed prolactinoma and 2% clinically non-functioning tumour. In patients with growth hormone excess, the phenotype varied from radiological pituitary hyperplasia with subtle growth hormone excess to young onset, proliferative tumours with florid growth hormone excess. Prolactinomas showed a similar pattern, ranging from microadenoma to giant, invasive tumours. Six percent of AIPvar heterozygotes had autistic spectrum disorder (6%), showing a range of autistic spectrum phenotypes including attention-deficit/hyperactivity disorder. This phenotype was independent of pituitary lesions, hormone excess/deficiencies and the use of cabergoline therapy. This prevalence is higher than that observed in the general population, where prevalence is about 1%.

Conclusions: AIPvar result in heterogeneous pituitary disease which is not always classically aggressive. AIPvar heterozygotes appear to have a higher prevalence of autistic spectrum disorders. These findings require validation and mechanistic studies to investigate the potential molecular biology of such an association.