Endocrine Abstracts

A 51 year old woman presented with severe Cushing’s syndrome. In addition to a typically Cushingoid appearance she demonstrated increased cutaneous pigmentation in her face and upper chest. Biochemical investigation confirmed elevated serum cortisol levels with loss of circadian variation, and failure to suppress with low dose dexamethasone (0.5 mg 6 hourly for 48 hours). Serum ACTH levels were undetectable. Cross-sectional imaging revealed bilateral macronodular adrenal hyperplasia (R=5 cm and L=2 cm diameter) and a mass lesion arising from the lesser curvature of the stomach consistent with a gastro-intestinal stromal tumour (GIST). The larger right adrenal was excised with the GIST, and post-operative cortisol levels were below 50 nmol/l. Immunohistochemical staining for c-Kit and DOG-1 confirmed the gastric lesion to be a GIST, and a somatic mutation in PDGFRA (pAsp842Val) was identified through Sanger sequencing. Cell supernatant from a primary culture of the GIST stimulated cortisol release from the adrenocortical cell line NCI-H295R and dispersed human adrenal cells. GIST immunostaining was negative for ACTH, but positive for α-MSH. α-MSH was identified in the GIST culture supernatant using sandwich ELISA. RT-PCR demonstrated GIST expression of POMC processing enzymes proprotein convertases 1/3 and 2. The right adrenal contained multiple large pigmented nodules: this was identified as melanin using a series of histological stains. The pattern of pigmentation correlated with immunostaining for 11-beta hydroxylase (CYP11B1), melanocortin 1 receptor (MC1R), and the melanosome marker HMB-45. This suggested that α-MSH binding to MC1R was driving cortisol production, and both skin and adrenal pigmentation. The ability of α-MSH to stimulate cortisol release in vitrowas confirmed by incubating dispersed human adrenal cells with the peptide. This is the first recorded case of Cushing’s syndrome as a result of alpha-MSH secretion alone, and the first as a result of any hormone secreted from a GIST.