SFEBES2009 Oral Communications Neuroendocrine tumours/pituitary (8 abstracts)
Geographical cluster of familial isolated pituitary adenoma kindreds with an identical AIP mutation
Zehra Ozfirat 1 , Josh Cain 1 , Harvinder Chahal 1 , Karen Stals 2 , Sian Ellard 2 , Trevor Howlett 3 , Miles Levy 3 , Brew Atkinson 4 , Patrick Morrison 5 , Scott Akker 1 , Ashley Grossman 1 & Marta Korbonits 1
1Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK; 2Department of Molecular Genetics, Royal Devon and Exeter Foundation Trust, Exeter, UK; 3University Hospitals of Leicester, Leicester, UK; 4Royal Victoria Hospital Belfast, Belfast, UK; 5Department of Genetics, Queens University, Belfast, UK.
Mutations in the co-chaperone molecule AIP account for a predisposition to pituitary tumours in some families with familial isolated pituitary adenomas (FIPA). We now report on four apparently-unrelated families with the same mutation and originating from the same geographical area, suggesting a possible founder mutation.
The index patient had gigantism (19 years, 208 cm) and had a female 4th cousin, once removed (13 years, 191 cm) with a large pituitary macroadenoma. A patient born in the same village was diagnosed with acromegaly (16 years), and had a first cousin with acromegaly (20 years) and a female first cousin with a prolactinoma (30 years). A 3rd family was noted to have five affected members (three with childhood-onset acromegaly, one adult-onset acromegaly and one childhood-onset macroprolactinoma) and a 4th family with two childhood-onset cases of acromegaly were both originated from the same geographical area.
All of these affected subjects have a mutation in the AIP gene: R304X. A number of families from various countries have been reported to harbour a mutation at the 304 aminoacid locus. This is a typical CpG-site where both the C and the G base-pairs have been reported to be mutated, one causing a stop mutation (c.910C>T,p.R304X) while the other is an aminoacid change (c.911G>A,p.R304Q). As this locus is a mutational hotspot, we are currently using microsatellite markers to study the level of relatedness between these families.
The penetrance of AIP mutations is reported to be variable, with around 30% in large kindreds. In family one we found nine heterozygote carrier subjects with two affected patients, while in family 2 two out of the nine known carriers have manifest disease, while in the other two families the penetrance seems to be lower. It remains unclear as to what other factors influence penetrance.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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