Pheochromocytoma as the Index Presentation of Multiple Endocrine Neoplasia Type 2B in a Young Woman with New-Onset Diabetes Mellitus: A Case Report

Pheochromocytoma as the Index Presentation of Multiple Endocrine Neoplasia Type 2B in a Young Woman with New-Onset Diabetes Mellitus: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Pheochromocytoma as the Index Presentation of Multiple Endocrine Neoplasia Type 2B in a Young Woman with New-Onset Diabetes Mellitus: A Case Report Satyaki Mandal, Dibyodyuti Samaddar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9110743/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Pheochromocytoma is a rare catecholamine-secreting neuroendocrine tumour of the adrenal medulla that can present with episodic headaches, palpitations, sweating, and hypertension. Catecholamine excess can induce hyperglycemia by suppressing insulin secretion and promoting hepatic gluconeogenesis, thereby mimicking primary diabetes mellitus. Approximately 40% of pheochromocytomas harbour a hereditary basis, most notably in the context of Multiple Endocrine Neoplasia type 2 (MEN2) syndromes caused by activating mutations of the RET proto-oncogene. Case Presentation: A 35-year-old female presented with a four-month history of episodic headaches, palpitations, sweating, and dizziness, alongside recently diagnosed diabetes mellitus. Clinical examination revealed resting tachycardia and significant orthostatic hypotension. Biochemical evaluation demonstrated markedly elevated urinary and plasma metanephrines, and cross-sectional and functional imaging confirmed a unilateral adrenal mass. A family history of medullary thyroid carcinoma prompted genetic testing, which revealed a RET proto-oncogene mutation consistent with MEN2B syndrome, despite the absence of classical phenotypic features such as mucosal neuromas or marfanoid habitus. The patient underwent successful laparoscopic adrenalectomy following adequate adrenergic blockade. Conclusion This case highlights the importance of suspecting pheochromocytoma as a secondary cause of new-onset diabetes in young patients presenting with episodic sympathoadrenal symptoms. Systematic genetic evaluation of all pheochromocytoma patients is essential to identify hereditary syndromes, enabling timely surveillance and screening of at-risk family members. Pheochromocytoma Multiple Endocrine Neoplasia Type 2B RET Proto-oncogene Secondary Diabetes Mellitus Catecholamine Excess Laparoscopic Adrenalectomy Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Pheochromocytoma is a rare catecholamine-secreting neuroendocrine tumour arising from the chromaffin cells of the adrenal medulla, with a pooled global incidence of approximately 1.9 cases per million person-years [ 1 ]. The classic clinical presentation comprises episodic headaches, palpitations, and diaphoresis; however, the phenotypic spectrum extends well beyond cardiovascular manifestations [ 2 ]. Catecholamine excess suppresses pancreatic insulin secretion via alpha-2 adrenergic receptor stimulation, promotes hepatic gluconeogenesis, and induces peripheral insulin resistance — collectively resulting in glucose intolerance in up to 50% and overt diabetes mellitus in 23–33% of affected patients [ 3 , 4 ]. This secondary hyperglycemia can mimic primary diabetes and may be the sole presenting feature, posing a significant diagnostic challenge [ 5 ]. Importantly, the traditional assumption that only 10% of pheochromocytomas are hereditary has been revised; contemporary evidence demonstrates that 25–40% of cases harbour germline pathogenic variants in known susceptibility genes [ 2 , 6 ]. Among hereditary syndromes, Multiple Endocrine Neoplasia type 2 (MEN2), caused by activating mutations of the RET proto-oncogene on chromosome 10q11.2, accounts for a substantial proportion, with pheochromocytoma occurring in 40–50% of MEN2A and MEN2B patients [ 7 , 8 ]. MEN2B — constituting approximately 5% of all MEN2 cases — is characterised by medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and marfanoid habitus, although incomplete phenotypic expression can delay diagnosis [ 8 , 9 ]. Current guidelines from the Endocrine Society and the American Thyroid Association recommend genetic testing for all patients diagnosed with pheochromocytoma, irrespective of family history, to identify hereditary syndromes and enable cascade screening of at-risk relatives [ 2 , 10 ]. We herein report a case of unilateral adrenal pheochromocytoma presenting as new-onset diabetes mellitus with autonomic dysfunction in a 35-year-old female, subsequently diagnosed as MEN2B through RET proto-oncogene mutation analysis prompted by a family history of medullary thyroid carcinoma. This report is prepared in accordance with the CARE (CAse REport) guidelines [ 11 ]. CASE PRESENTATION A 35-year-old female with no significant prior medical history presented to our institution with a four-month history of episodic throbbing headaches, paroxysmal palpitations, excessive sweating, and recurrent episodes of dizziness. She had been diagnosed with diabetes mellitus two weeks prior to presentation, following a random blood glucose of 225 mg/dL and a glycated haemoglobin (HbA1c) of 6.5%. She had no previously known comorbidities, including hypertension or thyroid disease, and reported no use of exogenous steroids, oral contraceptives, or any other medication prior to the diagnosis of diabetes. On clinical examination, the patient appeared anxious and diaphoretic. Her resting heart rate was 126 beats per minute, and blood pressure recorded in the supine position was 130/80 mmHg, which dropped to 118/68 mmHg upon standing — a postural fall of 12 mmHg systolic and 12 mmHg diastolic, indicative of significant orthostatic hypotension. Notably, a detailed systemic examination revealed no clinical evidence of diabetic microvascular complications such as retinopathy, peripheral neuropathy, or nephropathy, nor were there any signs of macrovascular disease. The absence of end-organ damage in a newly diagnosed diabetic raised suspicion for a secondary aetiology of hyperglycemia rather than longstanding type 2 diabetes mellitus. Baseline laboratory investigations revealed a haemoglobin of 15 g/dL with a red blood cell count of 4.5 million/µL, suggestive of relative erythrocytosis — a subtle but clinically relevant finding in the context of catecholamine-secreting tumours, as chronic catecholamine excess is known to stimulate erythropoietin production. The total leucocyte count was 5,436/µL and platelets were 234,000/µL, both within normal limits. Liver function tests, renal function tests, serum calcium, and serum phosphate were all unremarkable. A twelve-lead electrocardiogram confirmed sinus tachycardia without any ST-T wave changes, conduction abnormalities, or arrhythmias. Two-dimensional echocardiography demonstrated normal cardiac chamber dimensions and preserved biventricular systolic function, with no evidence of catecholamine-induced cardiomyopathy. A chest radiograph was unremarkable. Nerve conduction velocity studies of bilateral upper and lower limbs were within normal limits, effectively excluding diabetic peripheral neuropathy, and fundoscopic examination revealed no evidence of diabetic retinopathy. Given the constellation of episodic headaches, palpitations, diaphoresis, tachycardia, and orthostatic hypotension in a young woman with unexplained new-onset diabetes, a clinical suspicion of pheochromocytoma was entertained. An abdominal ultrasonography including kidneys and urinary bladder was performed as the initial imaging modality, which revealed a well-defined suprarenal mass on the right side (Fig. 1 ). To further characterize the lesion, a contrast-enhanced computed tomography of the abdomen was obtained, which confirmed the presence of a suprarenal mass demonstrating a pre-contrast attenuation of greater than 20 Hounsfield Units with avid contrast enhancement — imaging characteristics consistent with a lipid-poor adrenal adenoma or pheochromocytoma rather than a benign cortical adenoma (Fig. 2 ). Biochemical confirmation was subsequently sought through measurement of catecholamine metabolites. A 24-hour urine collection for fractionated metanephrines returned a value of 580 µg/24 hours, markedly exceeding the upper limit of normal (74–250 µg/24 hours). Plasma free metanephrines were measured at 527 pg/mL against a reference range of less than 57 pg/mL — representing an approximately nine-fold elevation, which carries a diagnostic sensitivity and specificity exceeding 95% for pheochromocytoma. For functional localization and exclusion of multifocal or metastatic disease, a Gallium-68 DOTATATE positron emission tomography/computed tomography was performed. This demonstrated intense somatostatin receptor-mediated tracer uptake in the adrenal mass, confirming the diagnosis of pheochromocytoma (Fig. 3 ). Importantly, no extra-adrenal paraganglioma or distant metastatic disease was identified. Upon further detailed history-taking, it was elicited that the patient's maternal aunt had been previously diagnosed with medullary thyroid carcinoma — a finding of considerable significance, as medullary thyroid carcinoma is a hallmark component of the MEN2 syndromes. This family history, combined with the confirmed pheochromocytoma, mandated genetic evaluation. Testing for the RET proto-oncogene mutation was performed and returned positive, establishing the diagnosis of MEN2B syndrome. Notably, the patient did not exhibit the classical phenotypic features of MEN2B such as mucosal neuromas, marfanoid habitus, or any ophthalmological or dermatological abnormalities — representing an incomplete phenotypic expression of the syndrome. Management was initiated with a structured preoperative pharmacological preparation protocol. Phenoxybenzamine, a non-selective irreversible alpha-adrenergic antagonist, was commenced at least fourteen days prior to the planned surgical intervention to achieve adequate alpha-adrenergic blockade and prevent life-threatening intraoperative hypertensive crises. Only after the establishment of satisfactory alpha-blockade was propranolol, a non-selective beta-adrenergic blocker, introduced to control the resting tachycardia — a sequencing that is critical, as premature beta-blockade in the absence of alpha-blockade carries the risk of unopposed alpha-receptor stimulation and precipitous hypertensive crisis. The patient was also placed on a liberal salt and fluid intake regimen to expand the chronically contracted intravascular volume. The definitive treatment was a laparoscopic adrenalectomy, which was performed without intraoperative complications. Continuous invasive arterial blood pressure monitoring and serial glucose monitoring were maintained throughout the perioperative period, with particular vigilance for post-resection rebound hypoglycemia and hypotension following the abrupt withdrawal of the catecholamine source. The postoperative course was uneventful, with normalization of heart rate and blood pressure. Serial measurements of plasma and urinary metanephrines in the postoperative period demonstrated a return to within normal reference ranges, confirming biochemical cure and complete tumour resection. DISCUSSION The present case illustrates several clinically instructive features of pheochromocytoma that merit discussion in comparison with existing literature. Our patient's new-onset diabetes (HbA1c 6.5%, random glucose 225 mg/dL) in the absence of microvascular or macrovascular complications was the initial diagnostic clue pointing towards a secondary aetiology rather than longstanding primary diabetes. Catecholamine-induced hyperglycemia is a well-recognised metabolic consequence of pheochromocytoma, mediated through alpha-2 adrenergic suppression of pancreatic beta-cell insulin secretion, beta-2 stimulated hepatic gluconeogenesis, and peripheral insulin resistance [ 12 , 13 ]. Elenkova et al., in a 40-year single-centre retrospective analysis of 204 patients with histologically proven pheochromocytoma, reported carbohydrate disorders in 49.5% of cases, with overt diabetes in 30.4% [ 4 ]. Importantly, surgical resection has been shown to reverse this metabolic derangement; Beninato et al. demonstrated in a cohort of 153 patients that diabetes was present preoperatively in 23.4%, and complete resolution occurred in 78.6% following tumour resection over a median follow-up of 52.1 months [ 14 ]. A comparable resolution rate of 78.7% was independently corroborated by Liu et al. in a series of 185 patients [ 15 ]. These data support the secondary nature of hyperglycemia in our patient and underscore the expectation of glycaemic improvement following adrenalectomy. Notably, the young age of our patient, absence of obesity, and lack of diabetic end-organ damage contrast sharply with the typical profile of type 2 diabetes and should alert clinicians to investigate a catecholamine-secreting tumour, as emphasised by Bole and Simon in their report of pheochromocytoma misdiagnosed as type 1 diabetes [ 5 ]. Equally noteworthy was the presence of significant orthostatic hypotension — a postural systolic blood pressure drop of 12 mmHg — which is seemingly paradoxical in the setting of a catecholamine-excess state. However, this finding is far more prevalent in pheochromocytoma than commonly appreciated. Streeten and Anderson, in their seminal study of 18 patients with subsequently proven pheochromocytoma, demonstrated that orthostatic hypotension and orthostatic tachycardia were present in 83% and 61% of cases respectively, attributable to downregulation of alpha-adrenergic receptors resulting from chronic exposure to elevated norepinephrine levels and concurrent intravascular volume contraction from sustained vasoconstriction [ 16 ]. Additionally, epinephrine-predominant tumours may induce vasodilation through beta-2 receptor stimulation, further contributing to orthostatic symptoms [ 17 ]. This presentation can closely mimic diabetic autonomic neuropathy — a diagnostic pitfall that was actively excluded in our patient through normal nerve conduction velocity studies and fundoscopic examination, effectively ruling out peripheral neuropathy and retinopathy at a stage when the diabetes was only recently diagnosed. Another subtle but clinically relevant finding was the elevated haemoglobin of 15 g/dL, suggestive of relative erythrocytosis. Pheochromocytoma-related secondary polycythemia, although rare, has been attributed to tumour-mediated erythropoietin secretion, with documented regression of elevated haematocrit following surgical resection [ 18 ]. More recently, the pheochromocytoma–polycythemia syndrome has been mechanistically linked to gain-of-function mutations in HIF2A (EPAS1), although this pathway is more relevant to pseudohypoxia-driven paragangliomas than to RET-associated tumours such as in MEN2 [ 19 ]. Nevertheless, even a modest erythrocytosis in a young patient with episodic sympathoadrenal symptoms should prompt consideration of a catecholamine-secreting neoplasm, and clinicians should be mindful of this often-overlooked laboratory finding. Perhaps the most distinctive and instructive aspect of our case is the identification of MEN2B in the complete absence of classical phenotypic hallmarks. MEN2B, which constitutes approximately 5% of all MEN2 cases, is classically characterised by mucosal neuromas of the lips and tongue, a marfanoid habitus, ganglioneuromatosis of the gastrointestinal tract, and the most aggressive form of medullary thyroid carcinoma, typically caused by the M918T mutation in exon 16 of the RET proto-oncogene [ 8 , 9 ]. Our patient exhibited none of these features — no mucosal neuromas, no marfanoid body habitus, and no ophthalmological or dermatological abnormalities — representing an incomplete phenotypic expression that can significantly delay clinical recognition. Castinetti et al. have emphasised in their comprehensive review that delayed diagnosis of MEN2B remains a major clinical challenge, with a median diagnostic delay of several years even in contemporary practice, often because the condition is not suspected in the absence of the full phenotype [ 9 ]. In our case, the diagnosis was made possible solely because a meticulous family history revealed medullary thyroid carcinoma in the patient's maternal aunt, which prompted targeted RET proto-oncogene mutation analysis. This observation reinforces the current Endocrine Society and American Thyroid Association recommendations that all patients diagnosed with pheochromocytoma — irrespective of apparent sporadic presentation or absence of syndromic features — should undergo comprehensive genetic testing, as contemporary evidence indicates that up to 40% may harbour germline pathogenic variants in known susceptibility genes [ 6 , 10 ]. Furthermore, first-degree relatives of confirmed RET mutation carriers require lifelong structured surveillance including annual measurement of plasma metanephrines for pheochromocytoma and serum calcitonin for medullary thyroid carcinoma, along with periodic imaging [ 8 , 10 ]. While several case reports in the literature have described pheochromocytoma presenting as new-onset diabetes [ 5 , 20 ], the simultaneous convergence of catecholamine-induced secondary diabetes, orthostatic hypotension mimicking autonomic neuropathy, relative erythrocytosis, and an incomplete MEN2B phenotype unmasked exclusively through family history in a single patient is, to our knowledge, rarely documented. This unique constellation of findings in one individual underscores the value of a systematic and thorough clinical approach — from meticulous history-taking and astute recognition of subtle laboratory abnormalities to comprehensive biochemical, imaging, and genetic evaluation — in arriving at a unifying diagnosis that carries profound implications for both the patient and their family. CONCLUSION This case illustrates that new-onset diabetes mellitus in a young patient accompanied by episodic headaches, palpitations, diaphoresis, and orthostatic hypotension should prompt clinicians to consider pheochromocytoma as a secondary endocrine cause of hyperglycemia. The paradoxical presence of orthostatic hypotension in the setting of a catecholamine-secreting tumour, often mistaken for diabetic autonomic neuropathy, should not dissuade from this diagnosis. Furthermore, genetic evaluation is indispensable in every patient diagnosed with pheochromocytoma, as it may uncover hereditary syndromes such as MEN2B, even in the absence of classical phenotypic features. Early identification enables structured surveillance for associated malignancies, particularly medullary thyroid carcinoma, and facilitates timely genetic screening of at-risk first-degree relatives. A coordinated multidisciplinary approach involving endocrinology, endocrine surgery, medical genetics, and oncology remains the cornerstone of optimal long-term management. Abbreviations MEN2 Multiple Endocrine Neoplasia type 2 MEN2B Multiple Endocrine Neoplasia type 2B RET Rearranged during Transfection HbA1c Glycated haemoglobin CECT Contrast-enhanced computed tomography USG Ultrasonography Ga-68 DOTATATE PET/CT Gallium-68 DOTATATE positron emission tomography/computed tomography HIF2A Hypoxia-inducible factor 2 alpha EPAS1 Endothelial PAS domain-containing protein 1 Declarations Ethics approval and consent to participate Ethical approval was not required for this case report as per institutional guidelines. Written informed consent was obtained from the patient for participation and publication. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Competing interests The authors declare that they have no competing interests. Clinical trial number Not applicable. Funding No funding was received for this study. Author Contribution SM conceptualised and designed the case report. SM and DS collected the clinical data and performed the literature review. SM wrote the initial draft of the manuscript. DS critically reviewed and revised the manuscript for intellectual content. Both authors read and approved the final manuscript. Acknowledgements Not applicable. Availability of data and materials All data generated or analysed during this study are included in this published article. References Saavedra TJS, Nati-Castillo HA, Valderrama Cometa LA, et al. Pheochromocytoma: an updated scoping review from clinical presentation to management and treatment. Front Endocrinol (Lausanne). 2024;15:1433582. 10.3389/fendo.2024.1433582 . Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. 10.1210/jc.2014-1498 . Tsirlin A, Oo Y, Sharma R, Kansara A, Gliber A, Levanon Sela MA. Pheochromocytoma: a review. Maturitas. 2014;77(3):229–38. 10.1016/j.maturitas.2013.12.009 . Elenkova A, Matrozova J, Vasilev V, Robeva R, Zacharieva S. Prevalence and progression of carbohydrate disorders in patients with pheochromocytoma/paraganglioma: retrospective single-center study. Ann Endocrinol (Paris). 2020;81(1):3–10. 10.1016/j.ando.2020.01.001 . Bole D, Simon B. Pheochromocytoma-induced hyperglycemia leading to misdiagnosis of type 1 diabetes mellitus. AACE Clin Case Rep. 2017;3(1):e83–6. 10.4158/EP161210.CR . Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and paraganglioma. N Engl J Med. 2019;381(6):552–65. 10.1056/NEJMra1806651 . Aygun N, Uludag M. Pheochromocytoma and paraganglioma: from epidemiology to clinical findings. Sisli Etfal Hastan Tip Bul. 2020;54(2):159–68. 10.14744/SEMB.2020.18794 . Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610. 10.1089/thy.2014.0335 . Castinetti F, Moley J, Mulligan L, et al. A comprehensive review on MEN2B. Endocr Relat Cancer. 2018;25(2):T29–39. 10.1530/ERC-17-0209 . Nölting S, Bechmann N, Taieb D, et al. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev. 2022;43(2):199–239. 10.1210/endrev/bnab019 . Gagnier JJ, Kienle G, Altman DG, et al. The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep. 2013;2013:bcr2013201554. 10.1136/bcr-2013-201554 . Abe I, Islam F, Lam AK-Y. Glucose intolerance on phaeochromocytoma and paraganglioma — the current understanding and clinical perspectives. Front Endocrinol (Lausanne). 2020;11:593780. 10.3389/fendo.2020.593780 . Tsiavos V, Markou A, Giannakopoulos A, et al. Secondary diabetes mellitus in pheochromocytomas and paragangliomas. Endocrine. 2024;83(1):43–55. 10.1007/s12020-023-03492-7 . Beninato T, Kluijfhout WP, Drake FT, et al. Resection of pheochromocytoma improves diabetes mellitus in the majority of patients. Ann Surg Oncol. 2017;24(5):1208–13. 10.1245/s10434-016-5701-6 . Liu J, Li Y, Ye Q, et al. Will the resection of pheochromocytoma improve preoperative diabetes mellitus? Asian J Surg. 2020;43(4):578–82. 10.1016/j.asjsur.2019.09.006 . Streeten DHP, Anderson GH. Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. Am J Hypertens. 1996;9(8):760–9. 10.1016/0895-7061(96)00057-X . Zuber SM, Kantorovich V, Pacak K. Hypertension in pheochromocytoma: characteristics and treatment. Endocrinol Metab Clin North Am. 2011;40(2):295–311. 10.1016/j.ecl.2011.02.002 . Dagartzikas MI, Sprague K, Carter G, Bhambhani KJ. Erythropoietin production by a pheochromocytoma in a child with polycythemia. J Pediatr Hematol Oncol. 2002;24(7):568–70. 10.1097/00043426-200210000-00013 . Pacak K, Jochmanova I, Prodanov T, et al. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol. 2013;31(13):1690–8. 10.1200/JCO.2012.47.1912 . Economou M, Devine A. Pheochromocytoma presenting with resistant hyperglycemia. J Endocr Soc. 2024;8(Suppl 1). 10.1210/jendso/bvae163.262 . bvae163.262. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9110743","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":615012053,"identity":"cde9feb0-e0cd-4065-990b-37c04389b32b","order_by":0,"name":"Satyaki Mandal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYNCCAxIMfAzJB4AsCRkilDNDtLAxpCWAtPAQq4UBqCXHAMQlrEW+/fwxiR9nLKLZ2HM+v7pRY8HDwH746AZ8WgzOJLNJ9tyQyG3jebvNOucY0GE8aWk38GphSGaT4PkA1CKRu804B8gGescMrxb5/sdskn/AWnKeGef8I0ILw41kNmmeG2AtzI+BJGEtBjceG1vLnAH55ZkZc26fBA8bIb/I9yc+vPnmWF1uP3vy48853+rk+NkPH8PvMAYGFgkogw3MYCOgHASYP6AzRsEoGAWjYBSgAADU2UY6Ll0S5QAAAABJRU5ErkJggg==","orcid":"","institution":"Institute of Medical Sciences, Banaras Hindu University (IMS, BHU)","correspondingAuthor":true,"prefix":"","firstName":"Satyaki","middleName":"","lastName":"Mandal","suffix":""},{"id":615012054,"identity":"564c53a8-e5ba-46f1-9484-93c1301d7927","order_by":1,"name":"Dibyodyuti Samaddar","email":"","orcid":"","institution":"Institute of Medical Sciences, Banaras Hindu University (IMS, BHU)","correspondingAuthor":false,"prefix":"","firstName":"Dibyodyuti","middleName":"","lastName":"Samaddar","suffix":""}],"badges":[],"createdAt":"2026-03-13 06:09:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9110743/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9110743/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106095041,"identity":"660f0303-2861-4ba3-b0d0-34798dbafecd","added_by":"auto","created_at":"2026-04-03 11:44:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":19700,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal ultrasonography (axial view) demonstrating a well-defined right suprarenal mass with heterogeneous echotexture.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9110743/v1/7ce38efbfad27e0bd5d4bc36.jpg"},{"id":106067895,"identity":"097df72a-50d7-4f77-a222-8f8481034e11","added_by":"auto","created_at":"2026-04-03 06:07:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32592,"visible":true,"origin":"","legend":"\u003cp\u003eContrast-enhanced computed tomography of the abdomen (axial section) showing a well-defined right suprarenal mass (arrow) with pre-contrast attenuation greater than 20 Hounsfield Units and avid contrast enhancement, consistent with pheochromocytoma.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9110743/v1/e0372b702114b5b52e4be280.jpg"},{"id":106094297,"identity":"59f976c6-2c25-4c44-9c26-31f914d2b875","added_by":"auto","created_at":"2026-04-03 11:42:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34233,"visible":true,"origin":"","legend":"\u003cp\u003eGallium-68 DOTATATE positron emission tomography/computed tomography (axial fused image) demonstrating intense somatostatin receptor-mediated tracer uptake in the right adrenal mass (arrow), confirming the neuroendocrine nature of the lesion. No extra-adrenal paraganglioma or distant metastatic disease was identified.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9110743/v1/a6aade19a7323980e8319931.jpg"},{"id":106401807,"identity":"33a717a1-6962-4f72-a6c5-ead41e314335","added_by":"auto","created_at":"2026-04-08 09:09:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":495758,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9110743/v1/92b8e53c-23b5-47ce-9100-88fa1e2b792b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pheochromocytoma as the Index Presentation of Multiple Endocrine Neoplasia Type 2B in a Young Woman with New-Onset Diabetes Mellitus: A Case Report","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePheochromocytoma is a rare catecholamine-secreting neuroendocrine tumour arising from the chromaffin cells of the adrenal medulla, with a pooled global incidence of approximately 1.9 cases per million person-years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The classic clinical presentation comprises episodic headaches, palpitations, and diaphoresis; however, the phenotypic spectrum extends well beyond cardiovascular manifestations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Catecholamine excess suppresses pancreatic insulin secretion via alpha-2 adrenergic receptor stimulation, promotes hepatic gluconeogenesis, and induces peripheral insulin resistance \u0026mdash; collectively resulting in glucose intolerance in up to 50% and overt diabetes mellitus in 23\u0026ndash;33% of affected patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This secondary hyperglycemia can mimic primary diabetes and may be the sole presenting feature, posing a significant diagnostic challenge [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImportantly, the traditional assumption that only 10% of pheochromocytomas are hereditary has been revised; contemporary evidence demonstrates that 25\u0026ndash;40% of cases harbour germline pathogenic variants in known susceptibility genes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among hereditary syndromes, Multiple Endocrine Neoplasia type 2 (MEN2), caused by activating mutations of the RET proto-oncogene on chromosome 10q11.2, accounts for a substantial proportion, with pheochromocytoma occurring in 40\u0026ndash;50% of MEN2A and MEN2B patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. MEN2B \u0026mdash; constituting approximately 5% of all MEN2 cases \u0026mdash; is characterised by medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and marfanoid habitus, although incomplete phenotypic expression can delay diagnosis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Current guidelines from the Endocrine Society and the American Thyroid Association recommend genetic testing for all patients diagnosed with pheochromocytoma, irrespective of family history, to identify hereditary syndromes and enable cascade screening of at-risk relatives [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe herein report a case of unilateral adrenal pheochromocytoma presenting as new-onset diabetes mellitus with autonomic dysfunction in a 35-year-old female, subsequently diagnosed as MEN2B through RET proto-oncogene mutation analysis prompted by a family history of medullary thyroid carcinoma. This report is prepared in accordance with the CARE (CAse REport) guidelines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA 35-year-old female with no significant prior medical history presented to our institution with a four-month history of episodic throbbing headaches, paroxysmal palpitations, excessive sweating, and recurrent episodes of dizziness. She had been diagnosed with diabetes mellitus two weeks prior to presentation, following a random blood glucose of 225 mg/dL and a glycated haemoglobin (HbA1c) of 6.5%. She had no previously known comorbidities, including hypertension or thyroid disease, and reported no use of exogenous steroids, oral contraceptives, or any other medication prior to the diagnosis of diabetes.\u003c/p\u003e \u003cp\u003eOn clinical examination, the patient appeared anxious and diaphoretic. Her resting heart rate was 126 beats per minute, and blood pressure recorded in the supine position was 130/80 mmHg, which dropped to 118/68 mmHg upon standing \u0026mdash; a postural fall of 12 mmHg systolic and 12 mmHg diastolic, indicative of significant orthostatic hypotension. Notably, a detailed systemic examination revealed no clinical evidence of diabetic microvascular complications such as retinopathy, peripheral neuropathy, or nephropathy, nor were there any signs of macrovascular disease. The absence of end-organ damage in a newly diagnosed diabetic raised suspicion for a secondary aetiology of hyperglycemia rather than longstanding type 2 diabetes mellitus.\u003c/p\u003e \u003cp\u003eBaseline laboratory investigations revealed a haemoglobin of 15 g/dL with a red blood cell count of 4.5\u0026nbsp;million/\u0026micro;L, suggestive of relative erythrocytosis \u0026mdash; a subtle but clinically relevant finding in the context of catecholamine-secreting tumours, as chronic catecholamine excess is known to stimulate erythropoietin production. The total leucocyte count was 5,436/\u0026micro;L and platelets were 234,000/\u0026micro;L, both within normal limits. Liver function tests, renal function tests, serum calcium, and serum phosphate were all unremarkable. A twelve-lead electrocardiogram confirmed sinus tachycardia without any ST-T wave changes, conduction abnormalities, or arrhythmias. Two-dimensional echocardiography demonstrated normal cardiac chamber dimensions and preserved biventricular systolic function, with no evidence of catecholamine-induced cardiomyopathy. A chest radiograph was unremarkable. Nerve conduction velocity studies of bilateral upper and lower limbs were within normal limits, effectively excluding diabetic peripheral neuropathy, and fundoscopic examination revealed no evidence of diabetic retinopathy.\u003c/p\u003e \u003cp\u003eGiven the constellation of episodic headaches, palpitations, diaphoresis, tachycardia, and orthostatic hypotension in a young woman with unexplained new-onset diabetes, a clinical suspicion of pheochromocytoma was entertained. An abdominal ultrasonography including kidneys and urinary bladder was performed as the initial imaging modality, which revealed a well-defined suprarenal mass on the right side (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). To further characterize the lesion, a contrast-enhanced computed tomography of the abdomen was obtained, which confirmed the presence of a suprarenal mass demonstrating a pre-contrast attenuation of greater than 20 Hounsfield Units with avid contrast enhancement \u0026mdash; imaging characteristics consistent with a lipid-poor adrenal adenoma or pheochromocytoma rather than a benign cortical adenoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBiochemical confirmation was subsequently sought through measurement of catecholamine metabolites. A 24-hour urine collection for fractionated metanephrines returned a value of 580 \u0026micro;g/24 hours, markedly exceeding the upper limit of normal (74\u0026ndash;250 \u0026micro;g/24 hours). Plasma free metanephrines were measured at 527 pg/mL against a reference range of less than 57 pg/mL \u0026mdash; representing an approximately nine-fold elevation, which carries a diagnostic sensitivity and specificity exceeding 95% for pheochromocytoma. For functional localization and exclusion of multifocal or metastatic disease, a Gallium-68 DOTATATE positron emission tomography/computed tomography was performed. This demonstrated intense somatostatin receptor-mediated tracer uptake in the adrenal mass, confirming the diagnosis of pheochromocytoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Importantly, no extra-adrenal paraganglioma or distant metastatic disease was identified.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eUpon further detailed history-taking, it was elicited that the patient's maternal aunt had been previously diagnosed with medullary thyroid carcinoma \u0026mdash; a finding of considerable significance, as medullary thyroid carcinoma is a hallmark component of the MEN2 syndromes. This family history, combined with the confirmed pheochromocytoma, mandated genetic evaluation. Testing for the RET proto-oncogene mutation was performed and returned positive, establishing the diagnosis of MEN2B syndrome. Notably, the patient did not exhibit the classical phenotypic features of MEN2B such as mucosal neuromas, marfanoid habitus, or any ophthalmological or dermatological abnormalities \u0026mdash; representing an incomplete phenotypic expression of the syndrome.\u003c/p\u003e \u003cp\u003eManagement was initiated with a structured preoperative pharmacological preparation protocol. Phenoxybenzamine, a non-selective irreversible alpha-adrenergic antagonist, was commenced at least fourteen days prior to the planned surgical intervention to achieve adequate alpha-adrenergic blockade and prevent life-threatening intraoperative hypertensive crises. Only after the establishment of satisfactory alpha-blockade was propranolol, a non-selective beta-adrenergic blocker, introduced to control the resting tachycardia \u0026mdash; a sequencing that is critical, as premature beta-blockade in the absence of alpha-blockade carries the risk of unopposed alpha-receptor stimulation and precipitous hypertensive crisis. The patient was also placed on a liberal salt and fluid intake regimen to expand the chronically contracted intravascular volume. The definitive treatment was a laparoscopic adrenalectomy, which was performed without intraoperative complications. Continuous invasive arterial blood pressure monitoring and serial glucose monitoring were maintained throughout the perioperative period, with particular vigilance for post-resection rebound hypoglycemia and hypotension following the abrupt withdrawal of the catecholamine source. The postoperative course was uneventful, with normalization of heart rate and blood pressure. Serial measurements of plasma and urinary metanephrines in the postoperative period demonstrated a return to within normal reference ranges, confirming biochemical cure and complete tumour resection.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present case illustrates several clinically instructive features of pheochromocytoma that merit discussion in comparison with existing literature. Our patient's new-onset diabetes (HbA1c 6.5%, random glucose 225 mg/dL) in the absence of microvascular or macrovascular complications was the initial diagnostic clue pointing towards a secondary aetiology rather than longstanding primary diabetes. Catecholamine-induced hyperglycemia is a well-recognised metabolic consequence of pheochromocytoma, mediated through alpha-2 adrenergic suppression of pancreatic beta-cell insulin secretion, beta-2 stimulated hepatic gluconeogenesis, and peripheral insulin resistance [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Elenkova et al., in a 40-year single-centre retrospective analysis of 204 patients with histologically proven pheochromocytoma, reported carbohydrate disorders in 49.5% of cases, with overt diabetes in 30.4% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Importantly, surgical resection has been shown to reverse this metabolic derangement; Beninato et al. demonstrated in a cohort of 153 patients that diabetes was present preoperatively in 23.4%, and complete resolution occurred in 78.6% following tumour resection over a median follow-up of 52.1 months [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A comparable resolution rate of 78.7% was independently corroborated by Liu et al. in a series of 185 patients [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These data support the secondary nature of hyperglycemia in our patient and underscore the expectation of glycaemic improvement following adrenalectomy. Notably, the young age of our patient, absence of obesity, and lack of diabetic end-organ damage contrast sharply with the typical profile of type 2 diabetes and should alert clinicians to investigate a catecholamine-secreting tumour, as emphasised by Bole and Simon in their report of pheochromocytoma misdiagnosed as type 1 diabetes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEqually noteworthy was the presence of significant orthostatic hypotension \u0026mdash; a postural systolic blood pressure drop of 12 mmHg \u0026mdash; which is seemingly paradoxical in the setting of a catecholamine-excess state. However, this finding is far more prevalent in pheochromocytoma than commonly appreciated. Streeten and Anderson, in their seminal study of 18 patients with subsequently proven pheochromocytoma, demonstrated that orthostatic hypotension and orthostatic tachycardia were present in 83% and 61% of cases respectively, attributable to downregulation of alpha-adrenergic receptors resulting from chronic exposure to elevated norepinephrine levels and concurrent intravascular volume contraction from sustained vasoconstriction [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, epinephrine-predominant tumours may induce vasodilation through beta-2 receptor stimulation, further contributing to orthostatic symptoms [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This presentation can closely mimic diabetic autonomic neuropathy \u0026mdash; a diagnostic pitfall that was actively excluded in our patient through normal nerve conduction velocity studies and fundoscopic examination, effectively ruling out peripheral neuropathy and retinopathy at a stage when the diabetes was only recently diagnosed.\u003c/p\u003e \u003cp\u003eAnother subtle but clinically relevant finding was the elevated haemoglobin of 15 g/dL, suggestive of relative erythrocytosis. Pheochromocytoma-related secondary polycythemia, although rare, has been attributed to tumour-mediated erythropoietin secretion, with documented regression of elevated haematocrit following surgical resection [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. More recently, the pheochromocytoma\u0026ndash;polycythemia syndrome has been mechanistically linked to gain-of-function mutations in HIF2A (EPAS1), although this pathway is more relevant to pseudohypoxia-driven paragangliomas than to RET-associated tumours such as in MEN2 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Nevertheless, even a modest erythrocytosis in a young patient with episodic sympathoadrenal symptoms should prompt consideration of a catecholamine-secreting neoplasm, and clinicians should be mindful of this often-overlooked laboratory finding.\u003c/p\u003e \u003cp\u003ePerhaps the most distinctive and instructive aspect of our case is the identification of MEN2B in the complete absence of classical phenotypic hallmarks. MEN2B, which constitutes approximately 5% of all MEN2 cases, is classically characterised by mucosal neuromas of the lips and tongue, a marfanoid habitus, ganglioneuromatosis of the gastrointestinal tract, and the most aggressive form of medullary thyroid carcinoma, typically caused by the M918T mutation in exon 16 of the RET proto-oncogene [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our patient exhibited none of these features \u0026mdash; no mucosal neuromas, no marfanoid body habitus, and no ophthalmological or dermatological abnormalities \u0026mdash; representing an incomplete phenotypic expression that can significantly delay clinical recognition. Castinetti et al. have emphasised in their comprehensive review that delayed diagnosis of MEN2B remains a major clinical challenge, with a median diagnostic delay of several years even in contemporary practice, often because the condition is not suspected in the absence of the full phenotype [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In our case, the diagnosis was made possible solely because a meticulous family history revealed medullary thyroid carcinoma in the patient's maternal aunt, which prompted targeted RET proto-oncogene mutation analysis. This observation reinforces the current Endocrine Society and American Thyroid Association recommendations that all patients diagnosed with pheochromocytoma \u0026mdash; irrespective of apparent sporadic presentation or absence of syndromic features \u0026mdash; should undergo comprehensive genetic testing, as contemporary evidence indicates that up to 40% may harbour germline pathogenic variants in known susceptibility genes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, first-degree relatives of confirmed RET mutation carriers require lifelong structured surveillance including annual measurement of plasma metanephrines for pheochromocytoma and serum calcitonin for medullary thyroid carcinoma, along with periodic imaging [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile several case reports in the literature have described pheochromocytoma presenting as new-onset diabetes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], the simultaneous convergence of catecholamine-induced secondary diabetes, orthostatic hypotension mimicking autonomic neuropathy, relative erythrocytosis, and an incomplete MEN2B phenotype unmasked exclusively through family history in a single patient is, to our knowledge, rarely documented. This unique constellation of findings in one individual underscores the value of a systematic and thorough clinical approach \u0026mdash; from meticulous history-taking and astute recognition of subtle laboratory abnormalities to comprehensive biochemical, imaging, and genetic evaluation \u0026mdash; in arriving at a unifying diagnosis that carries profound implications for both the patient and their family.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis case illustrates that new-onset diabetes mellitus in a young patient accompanied by episodic headaches, palpitations, diaphoresis, and orthostatic hypotension should prompt clinicians to consider pheochromocytoma as a secondary endocrine cause of hyperglycemia. The paradoxical presence of orthostatic hypotension in the setting of a catecholamine-secreting tumour, often mistaken for diabetic autonomic neuropathy, should not dissuade from this diagnosis. Furthermore, genetic evaluation is indispensable in every patient diagnosed with pheochromocytoma, as it may uncover hereditary syndromes such as MEN2B, even in the absence of classical phenotypic features. Early identification enables structured surveillance for associated malignancies, particularly medullary thyroid carcinoma, and facilitates timely genetic screening of at-risk first-degree relatives. A coordinated multidisciplinary approach involving endocrinology, endocrine surgery, medical genetics, and oncology remains the cornerstone of optimal long-term management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMEN2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultiple Endocrine Neoplasia type 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMEN2B\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultiple Endocrine Neoplasia type 2B\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRearranged during Transfection\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHbA1c\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlycated haemoglobin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCECT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eContrast-enhanced computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUSG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUltrasonography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGa-68 DOTATATE PET/CT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGallium-68 DOTATATE positron emission tomography/computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIF2A\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHypoxia-inducible factor 2 alpha\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEPAS1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndothelial PAS domain-containing protein 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eEthical approval was not required for this case report as per institutional guidelines. Written informed consent was obtained from the patient for participation and publication.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eClinical trial number\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was received for this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSM conceptualised and designed the case report. SM and DS collected the clinical data and performed the literature review. SM wrote the initial draft of the manuscript. DS critically reviewed and revised the manuscript for intellectual content. Both authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSaavedra TJS, Nati-Castillo HA, Valderrama Cometa LA, et al. Pheochromocytoma: an updated scoping review from clinical presentation to management and treatment. 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J Endocr Soc. 2024;8(Suppl 1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1210/jendso/bvae163.262\u003c/span\u003e\u003cspan address=\"10.1210/jendso/bvae163.262\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. bvae163.262.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pheochromocytoma, Multiple Endocrine Neoplasia Type 2B, RET Proto-oncogene, Secondary Diabetes Mellitus, Catecholamine Excess, Laparoscopic Adrenalectomy","lastPublishedDoi":"10.21203/rs.3.rs-9110743/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9110743/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePheochromocytoma is a rare catecholamine-secreting neuroendocrine tumour of the adrenal medulla that can present with episodic headaches, palpitations, sweating, and hypertension. Catecholamine excess can induce hyperglycemia by suppressing insulin secretion and promoting hepatic gluconeogenesis, thereby mimicking primary diabetes mellitus. Approximately 40% of pheochromocytomas harbour a hereditary basis, most notably in the context of Multiple Endocrine Neoplasia type 2 (MEN2) syndromes caused by activating mutations of the RET proto-oncogene.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 35-year-old female presented with a four-month history of episodic headaches, palpitations, sweating, and dizziness, alongside recently diagnosed diabetes mellitus. Clinical examination revealed resting tachycardia and significant orthostatic hypotension. Biochemical evaluation demonstrated markedly elevated urinary and plasma metanephrines, and cross-sectional and functional imaging confirmed a unilateral adrenal mass. A family history of medullary thyroid carcinoma prompted genetic testing, which revealed a RET proto-oncogene mutation consistent with MEN2B syndrome, despite the absence of classical phenotypic features such as mucosal neuromas or marfanoid habitus. The patient underwent successful laparoscopic adrenalectomy following adequate adrenergic blockade.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case highlights the importance of suspecting pheochromocytoma as a secondary cause of new-onset diabetes in young patients presenting with episodic sympathoadrenal symptoms. Systematic genetic evaluation of all pheochromocytoma patients is essential to identify hereditary syndromes, enabling timely surveillance and screening of at-risk family members.\u003c/p\u003e","manuscriptTitle":"Pheochromocytoma as the Index Presentation of Multiple Endocrine Neoplasia Type 2B in a Young Woman with New-Onset Diabetes Mellitus: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-03 06:07:33","doi":"10.21203/rs.3.rs-9110743/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-23T17:28:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-13T21:46:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-12T01:42:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79081753910582266902074247046264083232","date":"2026-04-03T16:12:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-31T05:50:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"133667927781611111737417343619968487386","date":"2026-03-31T02:36:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"297596451772594255014068513926326161516","date":"2026-03-29T16:34:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-29T05:14:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-14T17:10:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-14T10:41:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-14T10:40:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2026-03-13T06:03:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"91a618cb-1b27-400c-ad3b-fa0669e25c91","owner":[],"postedDate":"April 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T09:38:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-03 06:07:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9110743","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9110743","identity":"rs-9110743","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}