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Germline heterozygous loss-of-function variants in the aryl-hydrocarbon receptor–interacting protein (AIP) predispose to early-onset growth hormone–secreting pituitary adenomas, leading to pituitary gigantism (Pituitary Gigantism). AIP acts as a tumor suppressor in somatotroph cells, and pathogenic variants undermine its co-chaperone functions.
Genetic evidence for a strong association comes from over 20 unrelated probands identified in multiple case reports and series ([PMID:32336638]; [PMID:21208107]; [PMID:31365626]). Segregation analysis in four familial isolated pituitary adenoma kindreds confirms autosomal dominant inheritance with reduced penetrance ([PMID:21208107]).
The variant spectrum includes missense, nonsense, splice-site, and frameshift mutations. A recurrent splice-donor variant, c.279+1G>A, abolishes normal splicing and co-occurs with somatic second hits in tumor tissue ([PMID:39391823]). Founder truncating alleles such as c.910C>T (p.Arg304Ter) have been observed in historical and modern kindreds ([PMID:21208107]).
Clinically, affected individuals present in childhood or adolescence with accelerated linear growth, tall stature (HP:0000098), headaches (HP:0002315), hyperhidrosis (HP:0000975), and visual field defects due to macroadenoma compression (HP:0000529). Less common features include atypical behavior (HP:0000708) and primary amenorrhea (HP:0000786) in females.
Functional studies demonstrate that AIP variants disrupt interactions with HSP90, HSP70, TOMM20, and phosphodiesterase PDE4A5, leading to defective cAMP regulation in GH3 and fibroblast models ([PMID:18381572]; [PMID:23300914]). Knock-out and knock-down experiments reveal increased cAMP concentrations, altered Gαi signaling, and reduced growth inhibition, supporting a loss-of-function tumor suppressor mechanism.
No credible conflicting evidence disputes the AIP–gigantism link, though variant p.Arg304Gln has been reclassified as likely benign in non-family screening cohorts. However, established pathogenic alleles consistently show biallelic loss in tumor tissue.
In summary, AIP meets criteria for a Strong gene–disease association: robust case counts, familial segregation, and concordant functional data. Early genetic testing for AIP variants enables timely diagnosis and tailored management of pediatric gigantism.
Key Take-home: AIP genetic screening is clinically useful for identifying at-risk individuals with early-onset pituitary gigantism and guiding surgical and medical interventions.
Gene–Disease AssociationStrongMore than 20 probands, segregation in four families, concordant functional data Genetic EvidenceStrongOver 20 unrelated cases with germline AIP mutations, multiple variant types, segregation in familial cases Functional EvidenceModerateIn vitro and in vivo studies demonstrate loss-of-function affecting cAMP signaling, protein interactions with HSP90 and PDE4A5 |