A novel pathogenic AIP variant associated with familial isolated pituitary adenoma.

purposeFamilial Isolated Pituitary Adenoma (FIPA) is a rare autosomal dominant condition associated with germline mutations in the Aryl Hydrocarbon Receptor-Interacting Protein (AIP) gene in ~ 20% of the cases. This study aims to characterize a novel AIP variant in a Sardinian family through genetic, clinical and immunohistochemical analyses and evaluate its pathogenicity.

methodsThe proband, a 17-year-old girl with an invasive prolactin (PRL)-secreting Pituitary Neuroedocrine Tumor (Pit-NET), also known as a pituitary adenoma, underwent germline AIP testing, extended to family members. All variant carriers underwent clinical and radiologic evaluation. Immunohistochemistry for AIP expression was performed on Pituitary adenoma/PitNet tissue from an affected relative. Variant pathogenicity was classified according to guidelines.

resultsA novel heterozygous AIP germline variant, c.479del (p.Pro160LeufsTer11 ), was identified in the proband and six relatives. Cabergoline treatment led to PRL levels normalization and tumor shrinkage in the proband. An affected cousin had an aggressive GH-secreting Pituitary adenoma/PitNet requiring multiple treatments. All other carriers had no clinical findings, and their imaging was unremarkable. The variant causes a premature stop codon leading to a truncated protein, lacking the three C-terminal tetratricopeptide repeat domains, essential for AIP protein-protein interactions and tumor suppressor function. Immunohistochemistry showed reduced AIP expression. The variant is classified as pathogenic.

conclusionThis report expands the variants spectrum of AIP-related FIPA, confirming intra-familial phenotypic variability, from asymptomatic carriers to aggressive Pituitary adenoma/PitNet. Early genetic screening and surveillance are essential for timely diagnosis and personalized management.