Pituitary acrogigantism and ectopic Cushing's syndrome
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A 21-year-old man presented for evaluation of Cushing's syndrome. His medical history was notable for an incidental diagnosis of acrogigantism at the age of 18 years, when he presented for an unrelated illness. At that time, investigations showed hypersecretion of growth hormone (somatotropin), normal serum cortisol, and a 1·6×1·8×2·0 cm sellar-suprasellar mass without parasellar extension. He underwent transnasal transsphenoidal resection of the pituitary lesion, after which biochemical remission was reached at the cost of panhypopituitarism, including central diabetes insipidus.

Histopathological examination showed a densely granulated somatomammotrophic adenoma with positive immunostaining for growth hormone and prolactin and negative staining for ACTH. The patient was prescribed replacement therapy with levothyroxine, prednisolone, injectable testosterone ester, and oral desmopressin. Repeat imaging 3 months after surgery showed a partial empty sella and a thin rim of pituitary tissue, suggesting complete resection of the pituitary lesion. 6 months after surgery, features of hypercortisolism were evident, including prominent weight gain (about 40 kg), extensive broad purple and dehiscent striae, severe proximal myopathy, tinea corporis, and repeated episodes of hypokalaemic periodic paresis. Glucocorticoid replacement was therefore discontinued (6 months before the patient presented to us).

The clinical examination of this man, height 2·12 m, weight 163 kg, and BMI 36·3 kg/m2, showed several catabolic features of Cushing's syndrome and residual features of previous growth hormone excess. Biochemical evaluation showed ACTH-dependent Cushing's syndrome (post-low-dose dexamethasone suppression test: serum cortisol 604·1 nmol/L; plasma ACTH 29·5 pmol/L). Biochemical remission of acromegaly was confirmed by low serum IGF1 and random growth hormone concentrations. Functional imaging with 68Ga-DOTANOC PET-CT scan showed a large pancreatic neuroendocrine tumor (NET) and multiple liver metastases and bilateral adrenal hyperplasia. Biopsy of liver nodules was suggestive of a grade I NET, with negative immunostaining for ACTH.

Growth hormone-releasing hormone plasma concentration was normal (9 pg/mL). A diagnosis of pituitary acrogigantism and ectopic ACTH-dependent Cushing's syndrome (secondary to metastatic pancreatic NET) was considered. Exome sequencing showed no mutations in MEN1, CDKN1B, PRKAR1A, AIP, SDH, or MAX. Considering the metastatic nature of his disease, the patient was prescribed depot, long-acting release intramuscular injections of somatostatin analogue (octreotide 30 mg per month). He developed clinical and biochemical hypocortisolism (0800 h serum cortisol: less than 13·7 nmol/L; plasma ACTH: less than 1·0 pmol/L) and started physiological glucocorticoid replacement. Bilateral adrenal hyperplasia was resolved on the follow-up 68Ga-DOTANOC PET-CT scan.

This case highlights a rare presentation of multiple endocrine tumours in a young man. The patient had two of the three classic multiple endocrine neoplasia type 1-associated tumours (ie, pituitary and pancreatic), satisfying the clinical definition of the disease, even with a wild-type MEN1. About 10–30% of patients with clinical multiple endocrine neoplasia type 1 have no mutations on gene sequencing, although they might have large coding-region deletions or duplications in MEN1.

Source: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00085-1/fulltext?rss=yes