Phenotypic and genotypic features of a large kindred with a germline AIP variant.

Context Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved. OBJECTIVE: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant. METHODS: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants. RESULTS: We identified 31 p.R304Q carriers and based on two cases with somatotropinomas the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum Insulin-like Growth Factor-I (IGF-I) levels in all family members were above the mean for age and sex [IGF-I SDS: +0.6 (CI95% +0.4-0.9), p 50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons. CONCLUSIONS: This large family adds new information on the p.R304Q AIP variant and data suggest two new candidate genes could be associated with growth hormone excess.