Mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene are 
associated with pituitary adenomas that usually occur as familial isolated 
pituitary adenomas (FIPA). Detailed pathological and tumor genetic data on AIP 
mutation-related pituitary adenomas are not sufficient. Non-identical twin 
females presented as adolescents to the emergency department with severe 
progressive headache caused by large pituitary macroadenomas require emergency 
neurosurgery; one patient had incipient pituitary apoplexy. Post-surgically, the 
patients were found to have silent somatotrope adenomas on pathological 
examination. Furthermore, the light microscopic, immunohistochemical, and 
electron microscopic studies demonstrated tumors of virtually identical 
characteristics. The adenomas were accompanied by multiple areas of pituitary 
hyperplasia, which stained positively for GH, indicating somatotrope 
hyperplasia. Genetic analyses of the FIPA kindred revealed a novel E216X 
mutation of the AIP gene, which was present in both the affected patients and 
the unaffected father. Molecular analysis of surgical specimens revealed loss of 
heterozygosity (LOH) in the adenoma but showed that LOH was not present in the 
hyperplastic pituitary tissue from either patient. AIP immunostaining confirmed 
normal staining in the hyperplastic tissue and decreased staining in the adenoma 
in the tumors from both patients. These results demonstrate that patients with 
AIP germline mutation can present with silent somatotrope pituitary adenomas. 
The finding of somatotrope hyperplasia unaccompanied by AIP LOH suggests that 
LOH at the AIP locus might be a late event in a potential progression from 
hyperplastic to adenomatous tissue.