Endocrine Abstracts (2012) 28 P245

Results and challenges of genetic testing in a large familial isolated pituitary adenoma (FIPA) kindred with an R304X AIP mutation

Fred Williams1, Steven Hunter1, Lisa Bradley2, Patrick Morrison2, Harvinder Chahal3, Marta Korbonits3 & A Atkinson1

1Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, United Kingdom; 2Department of Medical Genetics, Belfast HSC Trust, Belfast, United Kingdom; 3Department of Endocrinology, Barts and London School of Medicine, Queen Mary university of London, London, United Kingdom.

20% of cases of FIPA have AIP gene mutations. These adenomas are often large and invasive. Our index case presented aged 13 with pituitary apoplexy. Histology showed necrotic tissue. He continued to grow and was 195 cm 4 y later. GH excess was confirmed. After treatment with octreotide and radiotherapy remission was achieved. His first cousin had also been successfully treated for acromegaly. This led to the original familial diagnosis. Subsequently, the c.910C>T, p.R304X AIP mutation was identified. In 3 generations 34 of 52 living members required screening. Of these, 31 have been screened. Another AIP variant has also been identified in the family A299V, with 2 asymptomatic subjects carrying both alterations. Out of 17 gene carriers, 2 have been shown to have macroadenomas on screening. A female family member previously diagnosed with a microprolactinoma carries the A299V variant but not the R304X mutation. Of the 2 cases identified on screening, both have acromegaly associated with a macroadenoma. One was being treated elsewhere for subfertility. Neither suppressed IGF1 across 4 months of octreotide. After transsphenoidal surgery IGF1 and 24 h GH improved but remained elevated at 89nmol/l (normal 11–40) and 4.15 ng/ml (24 y female) and 65 nmol/l and 0.6 ng/ml (21 y Male). Management of the residual GH excess is problematic in subfertility. A trial of cabergoline has been offered. The 2nd case is presently on no therapy and is being followed carefully. In summary the family presently has 4 cases of GH excess, 2 having presented clinically and 2 during our screening. Thirteen other mutation carriers are endocrinologically normal presently. Unresolved issues in AIP families are: intensity of screening workload, uncertainties about ongoing frequency and duration of endocrine screening in carriers, issues of phenocopy (positive phenotype in genotype negative members), non-disease causing variants and choices regarding further therapy when surgery does not normalise biochemistry.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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