Endocrine Abstracts

Introduction

Aryl hydrocarbon receptor Interacting Protein (AIP), a pituitary tumour suppressing gene located in 11q13, is the most common predisposing gene for early-onset and familial acromegaly. Fifteen years after its identification, there is little evidence of AIP involvement in non-pituitary tumors. We had the opportunity to study AIP status in a cortisol-producing adenoma operated in an AIP mutation carrier.

Case-report

A 43-year-old woman was followed-up as a carrier of a familial R304X AIP mutation. Her sister, first degree cousin and son had developed acromegaly but she had no evidence of pituitary disease. However, an incidental and asymptomatic right adrenal mass of 26 mm was found on abdominal US, with MRI suggesting an adrenocortical adenoma. The only biochemical abnormality was abnormal suppression of cortisol after a 1mg O/N dexamethasone suppression test. At the age of 46, because of a progressive mass increase with autonomous cortisol secretion confirmed by a I131-norcholesterol scintigraphy, she was operated on by laparoscopic surgery. The diagnosis of adrenocortical adenoma, larger than expected (max 45 mm), without cellular atypia, was confirmed, with multiple foci of mielopoma. The patient gave consent for the study of AIP status in the tumour. RT-PCR amplification of the AIP gene (exon6) on tumour and adjacent normal adrenocortical tissue DNA showed the presence of the wild-type and mutated allele in both samples, as confirmed on leukocyte DNA. AIP-immunostaining was positive on normal and tumour cells. After post-operative corticotroph insufficiency, glucocorticoid replacement therapy was progressively reduced and withdrawn 5 months later. She is currently eucortisolic, and the left adrenal gland is normal. None of her acromegalic relatives had evidence of adrenal abnormalities.

Discussion

Adrenocortical adenomas may be encountered more frequently in acromegalics. To the best of our knowledge, four cases of adrenocortical tumors (1 non-functioning, 3 androgen-secreting) were reported with sufficient details in AIP-related acromegalics and LOH at the AIP locus was found only in a corticosurrenaloma.

Conclusion

The study of tumour AIP status in an unusual cortisol-secreting adenoma developing in a familial context of germline AIP mutations, in the absence of acromegaly, favors the hypothesis that the R304X mutation was not involved in adrenal tumorigenesis. Rather, it suggests LOH at the AIP locus is not an early event in adrenocortical tumors, although AIP expression may be lost due to somatic chromosomal abnormalities, including loss of genetic material in chr 11 and in particular LOH in 11q13.