{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:42:09Z","timestamp":1788964929598,"version":"build-2803163510"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Multiple endocrine neoplasia type 2 (MEN 2)-related ectopic Cushing\u2019s syndrome (ECS) continues to present a clinical challenge due to its rarity and complexity. This study combines case analysis with a systematic literature review to elucidate the disease patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>\n                      We present a 55-year-old male with MEN 2-associated ECS caused by metastatic medullary thyroid carcinoma (MTC) and review 21 literature cases. The mean age of ECS diagnosis was 37.0 years (range: 13-72), with a male predominance (64%). MEN 2A (16 cases) and MEN2B (6 cases) involved\n                      <jats:italic>RET<\/jats:italic>\n                      exons 10, 11, 16, with MEN2B patients developed ECS earlier than MEN 2A (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.002). Of these, 14 presented ECS due to advanced-MTC (50% with distant metastasis), with the diagnosis of ECS following that of MTC in 57% of patients after an average interval of 72 months, while 43% had concurrent diagnoses. 7 were due to pheochromocytoma (PHEO), all presenting with concomitant diagnosis of PHEO and ECS, and 14% had metastasis. One case involved both PHEO and MTC. Severe hypercortisolemia and elevated adrenocorticotropic hormone were common. 64% of the 11 patients tested positive for adrenocorticotropic hormone (55%) or corticotrophin-releasing hormone (9%) immunostaining, while proopiomelanocortin mRNA or corticotropin-releasing factor\/urocortin1\/urocortin3 was detected in 2 others. Bilateral adrenalectomy (BLA, 13 patients) or unilateral adrenalectomy (1 patients) was performed in 14 out of 18 patients, with 83% of PHEO-related ECS achieving a cure, while advanced-MTC required multimodal therapy and 64% requiring eventual BLA treatment; One biphasic MTC\/PHEO achieved good control. Evidence of tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in ECS and MTC remains limited. Mortality primarily resulted from ECS complications or MTC progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      MEN 2-related ECS should be considered in differentials. Adrenalectomy typically achieved cure in most ECS due to PHEO, but vigilance is required for the double risk of both hypercatecholaminemia and hypercortisolism during the perioperative period. Whereas most ECS due to advanced-MTC eventually required BLA to improve symptoms, yet prognosis remained generally poor. TKIs might offer benefits in the management of both MTC and hypercortisolism. The integration of\n                      <jats:italic>RET<\/jats:italic>\n                      testing, early diagnosis, and precise treatment can help prevent ECS complications and improve outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2025.1644751","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:59:36Z","timestamp":1762865976000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Presentation of multiple endocrine neoplasia type 2A-associated ectopic cushing\u2019s syndrome: case report and a systematic 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