AIP – Familial Isolated Pituitary Adenoma

Familial isolated pituitary adenoma (FIPA) is an autosomal dominant disorder characterized by non-syndromic pituitary tumors in two or more family members. Germline mutations in the AIP gene were first described in FIPA kindreds, accounting for ∼15–25% of families and manifesting with young-onset somatotroph and lactotroph adenomas with incomplete penetrance (PMID:17244780). Clinical screening of mutation carriers identifies subclinical disease and informs early intervention strategies.

In an international cohort of 73 FIPA families (156 affected individuals), 11 unrelated kindreds harbored heterozygous AIP variants, including nonsense, frameshift, splice and large deletion alleles, with segregation of mutation and pituitary adenoma across multiple generations (PMID:17244780). Case reports have detailed pathogenic alleles such as c.241C>T (p.Arg81Ter) in exon 2, which segregates in affected relatives and leads to truncated AIP protein (PMID:22527616). Penetrance estimates range from 20–30% but vary with age and familial context.

The AIP variant spectrum comprises loss-of-function alleles (nonsense: c.943C>T (p.Gln315Ter); frameshift: c.500delC (p.Pro167HisfsTer3)), missense changes (e.g., p.Cys238Tyr), synonymous/splice variants and occasional deep-intronic alterations. Recurrent alleles include R304* and p.Arg304Ter in multiple cohorts, reflecting mutational hotspots at the C-terminal α-7 helix region (PMID:24789813; PMID:19443539; PMID:24423289).

Functional studies support AIP as a tumor suppressor: wild-type AIP overexpression in GH3 and HEK293 cells suppresses proliferation and GH secretion, whereas mutant proteins lose this activity and fail to bind client partners such as PDE4A5 and AhR, leading to aberrant cAMP signaling (PMID:18381572; PMID:23702468; PMID:24662816). In vivo, human AIP rescues Drosophila CG1847 knockout viability, whereas pathogenic missense variants (p.Cys238Tyr, p.Arg325Gln) do not, validating their loss-of-function nature (PMID:29632148).

Conflicting data have arisen for the c.911G>A (p.Arg304Gln) allele, which is observed at appreciable frequency in population databases without clear loss-of-heterozygosity in tumors and displays equivocal functional impact, suggesting it is likely benign for FIPA predisposition (PMID:40070360).

Integration of genetic segregation, robust functional concordance, and recurrent mutational hotspots underpins a Strong clinical validity classification for the AIP–FIPA association. Genetic evidence is Strong, supported by multiple pedigrees with segregation and diverse pathogenic variant types. Functional evidence is Moderate, with consistent in vitro and in vivo assays confirming a loss-of-function mechanism. Key Take-home: AIP genetic testing is recommended in families with early-onset pituitary adenomas to enable predictive surveillance and tailored management.

References

• The Journal of clinical endocrinology and metabolism • 2007 • Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families PMID:17244780
• Pituitary • 2012 • Genetic analysis in a patient presenting with meningioma and familial isolated pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of the AIP gene in the pathogenesis of the pituitary tumor PMID:22527616
• Endocrine pathology • 2014 • A novel C-terminal nonsense mutation, Q315X, of the aryl hydrocarbon receptor-interacting protein gene in a Japanese familial isolated pituitary adenoma family PMID:24789813
• Endocrine-related cancer • 2009 • Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma PMID:19443539
• The Journal of clinical endocrinology and metabolism • 2014 • Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation PMID:24423289
• The Journal of clinical endocrinology and metabolism • 2008 • The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas PMID:18381572
• Endocrine-related cancer • 2013 • Aip regulates cAMP signalling and GH secretion in GH3 cells PMID:23702468
• Oncogene • 2015 • AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling PMID:24662816
• Journal of medical genetics • 2018 • In vivo bioassay to test the pathogenicity of missense human AIP variants PMID:29632148
• European journal of endocrinology • 2025 • Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis PMID:40070360

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