CONTEXT: Germline AIP mutations usually cause young-onset acromegaly with low 
penetrance in a subset of familial isolated pituitary adenoma families. We 
describe our experience with a large family with R304* AIP mutation and discuss 
some of the diagnostic dilemmas and management issues.
OBJECTIVE: The aim of the study was to identify and screen mutation carriers in 
the family.
PATIENTS: Forty-three family members participated in the study.
SETTING: The study was performed in university hospitals.
OUTCOME: We conducted genetic and endocrine screening of family members.
RESULTS: We identified 18 carriers of the R304* mutation, three family members 
with an AIP-variant A299V, and two family members who harbored both changes. One 
of the two index cases presented with gigantism and pituitary apoplexy, the 
other presented with young-onset acromegaly, and both had surgery and 
radiotherapy. After genetic and clinical screening of the family, two R304* 
carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery 
after a short period of somatostatin analog treatment. One of these two patients 
is in remission; the other achieved successful pregnancy despite suboptimal 
control of acromegaly. One of the A299V carrier family members was previously 
diagnosed with a microprolactinoma; we consider this case to be a phenocopy. 
Height of the unaffected R304* carrier family members is not different compared 
to noncarrier relatives.
CONCLUSIONS: Families with AIP mutations present particular problems such as the 
occurrence of large invasive tumors, poor response to medical treatment, 
difficulties with fertility and management of pregnancy, and the finding of AIP 
sequence variants of unknown significance. Because disease mostly develops at a 
younger age and penetrance is low, the timing and duration of the follow-up of 
carriers without overt disease requires further study. The psychological and 
financial impact of prolonged clinical screening must be considered. Excellent 
relationships between the family, endocrinologists, and geneticists are 
essential, and ideally these families should be managed in centers with 
specialist expertise.