Clinical Presentation and Targeted Genetic Evaluation of Familial Isolated Pituitary Adenomas: A Single-Center Case Series

Background: Familial isolated pituitary adenomas (FIPA) are characterized by considerable clinical and genetic heterogeneity. Although germline pathogenic variants in AIP account for a subset of cases, most FIPA families remain genetically unexplained. We aimed to describe the clinical characteristics, tumor phenotype, treatment outcomes, and targeted genetic evaluation of FIPA families from a tertiary endocrine referral center. Methods: We retrospectively identified FIPA families among patients with pituitary neuroendocrine tumors (PitNETs) evaluated at a tertiary endocrine referral center between 2019 and 2024. FIPA was defined as PitNETs occurring in at least two related individuals without clinical features suggestive of syndromic endocrine disease. Clinical, radiological, histopathological, and genetic data were analyzed. Results: Among 1068 patients with PitNETs, seven FIPA families were retrospectively identified (0.66% of the source cohort), comprising 20 affected individuals. Index cases included four women and three men, with a mean age at diagnosis of 37.1 ± 17.3 years. Somatotroph PitNETs predominated among index cases (5/7), whereas nonfunctioning PitNETs were more frequent among affected relatives (9/13). Six of seven index tumors were macroadenomas, and cavernous sinus invasion was present in two. No pathogenic or likely pathogenic variants in AIP or MEN1 were identified by Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA) detected no copy number alterations involving AIP, MEN1, or CDKN1B. Conclusions: This series highlights the clinical heterogeneity of FIPA and the differing tumor spectrum between index cases and affected relatives. The absence of pathogenic variants identified by targeted genetic testing further illustrates the genetic heterogeneity of familial pituitary tumor predisposition.