SFEBES2009 Poster Presentations Pituitary (65 abstracts)
The R304X mutation of the Aryl hydrocarbon receptor interacting protein (AIP) gene in familial isolated pituitary adenomas: mutational Hot-Spot or founder effect?
Giampaolo Trivellin 1 , Gianluca Occhi 1 , Marie-Lise Jaffrain-Rea 2, , Nora Albiger 1 , Filippo Ceccato 1 , Ernesto De Menis 4 , Mariolina Angelini 2 , Sergio Ferasin 1 , Franco Mantero 1 , Albert Beckers 5 & Carla Scaroni 1
1Endocrinology Division, Department of Medical and Surgical Sciences, Padova Hospital/University, Padova, Italy; 2Department of Experimental Medicine University of L’Aquila, L’ Aquila, Italy; 3Neuromed Institute IRRCS, Pozzilli, Italy; 4Department of Internal Medicine General Hospital, Montebelluna (Treviso), Treviso, Italy; 5Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium.
Background: Familial isolated pituitary adenomas (FIPA) is a rare inherited disorder accounting for about 2% of pituitary adenomas. Mutations in the Aryl hydrocarbon receptor Interacting Protein (AIP) gene have been described in about 15% of FIPA families and rarely in early onset sporadic pituitary adenomas. Among the AIP mutations reported so far, the R304X represents, after the Finnish founder mutation Q14X, the second most common one.
Methods: Three Italian families carrying the R304X mutation, including a newly reported kindred, have been genotyped for 12 genetic markers surrounding the AIP gene on chromosome 11 in order to look for a potential founder effect in Italy. Disease penetrance was studied by familial screening and genotype-phenotype correlation in affected patients has also been performed.
Results: Analysis of chromosome 11’s genetic markers revealed that two out of three R304X kindreds shared a common haplotype. Overall, seven patients and ten healthy mutation carriers were identified among subjects, indicating a disease penetrance of 41% in AIP mutation-positive subjects. Mean age at diagnosis was 19.1±6.7 and even though most R304X pituitary adenomas were somatotropinomas (6/7), a great variability in disease severity was observed, also between the subjects sharing the same at-risk haplotype. All patients received pharmacological therapy, but only two experienced disease control.
Conclusions: Despite convincing evidences support the hypothesis that AIP codon 304 represents a mutational hot-spot, the presence of a common haplotype surrounding the AIP gene between two Italian FIPA families carrying the R304X mutation provides strong evidences for a new founder effect in a region of central Italy. We therefore suggest that special attention should be paid to young acromegalics in this region in order to determine the magnitude of this founder effect and favour precocious diagnosis, given the potential aggressiveness and common pharmacological resistance of pituitary tumors harbouring this mutation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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