Endocrine Abstracts

JOINT1926

Introduction: Familial Isolated Pituitary Adenomas (FIPA) syndrome is characterized by the presence of Pituitary Neuroendocrine Tumors (PitNET) in at least two family members, without clinical features suggestive of other genetic syndromes. Germline mutations in the Aryl Hydrocarbon Receptor-Interacting Protein gene (AIP) are identified in ~10-20% of FIPA cases, with low penetrance (12.5-30%) and an autosomal dominant inheritance pattern. These mutations are often associated with early-onset PitNET, typically secreting growth hormone, prolactin, or both. The AIP structure contains an alpha-helix and three tetratricopeptide repeat (TPR) domains in the C-terminal region, crucial for protein-protein interactions. This study investigates the impact of a novel AIP variant in a 17-year-old girl with an invasive macroprolactinoma and a family history of PitNET.

Methods: AIP germline mutations were investigated by direct DNA sequencing of the AIP gene exons 2, 4, 5, and 6 using the Sanger method. The impact of genetic variants on protein structure was assessed using the NextProt platform. The proband’s family was investigated for the presence of PitNET and AIP variants.

Results: Genetic analysis identified a novel heterozygous variant in exon 4 of the AIP gene (c.479delC) in the proband: a frameshift mutation causing a premature stop codon (Ter170). This nonsense variation leads to the loss of TPR1-3 and the alpha-helix, key functional C-terminal domains. The mother and five maternal relatives of the proband carried the variant: one had a PitNET and the others did not show any clinical manifestations. The proband presented a grade IV KNOSP macroprolactinoma at age 17, responding to cabergoline with tumor shrinkage and prolactin normalization. The other carrier was diagnosed at age 39 with an invasive GH-secreting PitNET and required medical therapy after surgery and Gamma-Knife radiosurgery due to residual disease.

Discussion and Conclusions: The c.479delC AIP variant identified in this study is associated with FIPA, with a confirmed incomplete penetrance and invasive, aggressive early-onset GH- and PRL-secreting PitNETs in patients displaying the FIPA phenotype. The variant causes the loss of AIP molecular interaction domains, potentially contributing to tumorigenesis. These findings highlight the importance of genetic screening in families with a history of PitNETs, enabling early diagnosis and personalized treatment strategies.