Acromegaly is almost always due to a sporadic growth-hormone secreting pituitary adenoma, but familial acromegaly has been reported occasionally. Linkage and loss of heterozygosity studies have suggested that it is caused by a tumour suppressor gene located at 11q13. Recently mutations have been identified in a gene in some families with acromegaly alone or acromegaly and prolactinoma. The gene codes for the aryl hydrocarbon receptor interactive protein (AIP), a molecular chaperone, which has been linked to the induction of hepatic detoxifying gene products in response to environmental toxins such as dioxin. However, the mechanism how this gene causes pituitary tumours is not known.
We studied 20 families with familial pituitary adenoma and identified heterozygote sequence changes in the AIP gene in 5 of them. These changes were not detected in 100 normal subjects. More than half of the studied family members who harboured a mutation had manifest disease, suggesting higher prevalence than suggested earlier. We also studied sporadic acromegalic patients, including 4 with gigantism, and detected no germline mutations. AIP mRNA and protein is expressed in both normal pituitary and in various types of sporadic pituitary adenomas. We are currently conducting functional studies with the mutations which have been described and the ones we have identified.
The majority of familial acromegaly patients do not have a mutation in the coding region of the AIP gene and it is possible that apart from the AIP and menin genes, a third gene causing pituitary adenomas is located in the 11q13 area.
In summary, AIP mutation has been identified in one in four of familial acromegaly kindreds and we observed a relatively high penetrance. In addition, we cannot rule out that another gene in the 11q13 area is involved in the pathogenesis of familial acromegaly.