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Eka Melson Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Sidra Amir University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Lisa Shepherd Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Samina Kauser University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Bethan Freestone University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Punith Kempegowda University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Summary

Although pheochromocytoma classically presents with headaches, palpitations and paroxysmal hypertension, atypical presentations such as cardiomyopathy, stroke and subarachnoid haemorrhage have been infrequently documented. We present in this case report, an uncommon presentation of pheochromocytoma with myocardial infarction with normal coronary arteries (MINOCA). A 79-year-old woman presented with central crushing chest pain radiating to left arm associated with headache, palpitations, sweating and difficulty in breathing. For 2 years, she experienced brief episodes of headache, tinnitus, dizziness, palpitations, and sweating that spontaneously resolved. Clinical examination was unremarkable except for high blood pressure (210/105 mmHg). Her electrocardiogram showed T wave inversions from V1 to V6 and elevated troponins (774 ng/L at baseline and 932 ng/L 3 h from baseline (normal <16 ng/L) in keeping with a diagnosis of non-ST elevated myocardial infarction. Coronary angiography showed normal coronary arteries. Patient was hence treated as myocardial infarction with normal coronaries (MINOCA). Despite appropriate treatment for MINOCA, she continued to experience episodic headaches, palpitations, dizziness and erratic blood pressures (particularly severe hypertension shortly after beta-blocker administration). Further investigations revealed raised urine noradrenaline of 4724 nmol/24 h (<554 nmol/24 h) and urine adrenaline of 92863 nmol/24 h (<77 nmol/24 h). Computerised tomography demonstrated a well-defined rounded mass in right adrenal gland morphological of pheochromocytoma. She underwent laparoscopic right adrenalectomy with histology confirming pheochromocytoma. This case highlights the importance of thorough investigation for the underlying cause for MINOCA. In patients with unexplained erratic blood pressure control, pheochromocytoma should be considered as a differential diagnosis.

Learning points:

  • Pheochromocytoma is rare tumour that often presents with non-specific symptoms.

  • It is important to investigate underlying cause of MINOCA.

  • Thorough history is the key to diagnosis.

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Aisling McCarthy University Hospital Galway, Galway, Ireland

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Sophie Howarth Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Serena Khoo Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Julia Hale Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Sue Oddy Department of Clinical Biochemistry, Cambridge University NHS Foundation Trust, Cambridge, UK

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David Halsall Department of Clinical Biochemistry, Cambridge University NHS Foundation Trust, Cambridge, UK

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Brian Fish Department of Head and Neck Surgery, Cambridge University NHS Foundation Trust, Cambridge, UK

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Sashi Mariathasan Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Katrina Andrews East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

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Samson O Oyibo Department of Diabetes and Endocrinology, Peterborough City Hospital, North West Anglia NHS Foundation Trust, Peterborough, UK

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Manjula Samyraju Department of Obstetrics and Gynecology, Peterborough City Hospital, North West Anglia NHS Foundation Trust, Peterborough, UK

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Katarzyna Gajewska-Knapik Department of Obstetrics and Gynecology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Soo-Mi Park East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

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Diana Wood Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Carla Moran Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK

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Ruth T Casey Department of Diabetes and Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK
Department of Medical Genetics, Cambridge University, Cambridge, UK

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Summary

Primary hyperparathyroidism (PHPT) is characterised by the overproduction of parathyroid hormone (PTH) due to parathyroid hyperplasia, adenoma or carcinoma and results in hypercalcaemia and a raised or inappropriately normal PTH. Symptoms of hypercalcaemia occur in 20% of patients and include fatigue, nausea, constipation, depression, renal impairment and cardiac arrythmias. In the most severe cases, uraemia, coma or cardiac arrest can result. Primary hyperparathyroidism in pregnancy is rare, with a reported incidence of 1%. Maternal and fetal/neonatal complications are estimated to occur in 67 and 80% of untreated cases respectively. Maternal complications include nephrolithiasis, pancreatitis, hyperemesis gravidarum, pre-eclampsia and hypercalcemic crises. Fetal complications include intrauterine growth restriction; preterm delivery and a three to five-fold increased risk of miscarriage. There is a direct relationship between the degree of severity of hypercalcaemia and miscarriage risk, with miscarriage being more common in those patients with a serum calcium greater than 2.85 mmol/L. Neonatal complications include hypocalcemia. Herein, we present a case series of three women who were diagnosed with primary hyperparathyroidism in pregnancy. Case 1 was diagnosed with multiple endocrine neoplasia type 1 (MEN1) in pregnancy and required a bilateral neck exploration and subtotal parathyroidectomy in the second trimester of her pregnancy due to symptomatic severe hypercalcaemia. Both case 2 and case 3 were diagnosed with primary hyperparathyroidism due to a parathyroid adenoma and required a unilateral parathyroidectomy in the second trimester. This case series highlights the work-up and the tailored management approach to patients with primary hyperparathyroidism in pregnancy.

Learning points:

  • Primary hyperparathyroidism in pregnancy is associated with a high incidence of associated maternal fetal and neonatal complications directly proportionate to degree of maternal serum calcium levels.

  • Parathyroidectomy is the definitive treatment for primary hyperparathyroidism in pregnancy and was used in the management of all three cases in this series. It is recommended when serum calcium is persistently greater than 2.75 mmol/L and or for the management of maternal or fetal complications of hypercalcaemia. Surgical management, when necessary is ideally performed in the second trimester.

  • Primary hyperparathyroidism is genetically determined in ~10% of cases, where the likelihood is increased in those under 40 years, where there is relevant family history and those with other related endocrinopathies. Genetic testing is a useful diagnostic adjunct and can guide treatment and management options for patients diagnosed with primary hyperparathyroidism in pregnancy, as described in case 1 in this series, who was diagnosed with MEN1 syndrome.

  • Women of reproductive age with primary hyperparathyroidism need to be informed of the risks and complications associated with primary hyperparathyroidism in pregnancy and pregnancy should be deferred and or avoided until curative surgery has been performed and calcium levels have normalised.

Open access
Peter Novodvorsky Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

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Ziad Hussein Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Muhammad Fahad Arshad Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Ahmed Iqbal Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Malee Fernando Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Alia Munir Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

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Sabapathy P Balasubramanian Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Department of General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Summary

Spontaneous remission of primary hyperparathyroidism (PHPT) due to necrosis and haemorrhage of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’ is a very rare, but previously described phenomenon. Patients usually undergo parathyroidectomy or remain under close clinical and biochemical surveillance. We report two cases of parathyroid auto-infarction diagnosed in the same tertiary centre; one managed surgically and the other conservatively up to the present time. Case #1 was a 51-year old man with PHPT (adjusted (adj.) calcium: 3.11 mmol/L (reference range (RR): 2.20–2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6–6.9 pmol/L) and urine calcium excretion consistent with PHPT) referred for parathyroidectomy. Repeat biochemistry 4 weeks later at the surgical clinic showed normal adj. calcium (2.43 mmol/L) and reduced PTH. Serial ultrasound imaging demonstrated reduction in size of the parathyroid lesion from 33 to 17 mm. Twenty months later, following recurrence of hypercalcaemia, he underwent neck exploration and resection of an enlarged right inferior parathyroid gland. Histology revealed increased fibrosis and haemosiderin deposits in the parathyroid lesion in keeping with auto-infarction. Case #2 was a 54-year-old lady admitted with severe hypercalcaemia (adj. calcium: 4.58 mmol/L, PTH 51.6 pmol/L (RR: 1.6–6.9 pmol/L)) and severe vitamin D deficiency. She was treated with intravenous fluids and pamidronate and 8 days later developed symptomatic hypocalcaemia (1.88 mmol/L) with dramatic decrease of PTH (17.6 pmol/L). MRI of the neck showed a 44 mm large cystic parathyroid lesion. To date, (18 months later), she has remained normocalcaemic.

Learning points:

  • Primary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), diffuse parathyroid hyperplasia (<15%) and in 1–2% of cases from parathyroid carcinoma.

  • PHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia.

  • Spontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ is a very rare in clinical practice but has been previously reported in the literature.

  • In most cases, patients with parathyroid auto-infarction undergo parathyroidectomy. Those who are managed conservatively need to remain under close clinical and biochemical surveillance long-term as in most cases PHPT recurs, sometimes several years after auto-infarction.

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Chad Bisambar NHS Ayrshire and Arran, Ayr, UK

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Andrew Collier NHS Ayrshire and Arran, Ayr, UK

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Fraser Duthie NHS Greater Glasgow and Clyde, Glasgow, UK

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Carron Meney NHS Ayrshire and Arran, Ayr, UK

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Summary

A 40-year-old Caucasian female presented with hyperglycaemia, polyuria, polydipsia and weight loss of 6 kg over a 1-month period. There was no personal or family history of malignancy or diabetes mellitus. On examination, she was jaundiced with pale mucous membranes and capillary glucose was 23.1 mmol/L. Initial investigations showed iron deficiency anaemia and obstructive pattern of liver function tests. HbA1c was diagnostic of diabetes mellitus at 79 mmol/mol. Malignancy was suspected and CT chest, abdomen and pelvis showed significant dilatation of intra- and extra-hepatic biliary tree including pancreatic duct, with periampullary 30 mm mass lesion projecting into lumen of duodenum. Enlarged nodes were seen around the superior mesenteric artery. This was confirmed on MRI liver. Fasting gut hormones were normal except for a mildly elevated somatostatin level. Chromogranin A was elevated at 78 pmol/L with normal chromogranin B. Duodenoscopy and biopsy showed possible tubovillous adenoma with low-grade dysplasia, but subsequent endoscopic ultrasound and biopsy revealed a grade 1, well differentiated neuroendocrine tumour. The patient was started on insulin, transfused to Hb >8 g/dL and Whipple’s pancreatico-duodenectomy was undertaken. This showed a well-differentiated neuroendocrine carcinoma arising in duodenum (Grade G1 with Ki67: 0.5%), with areas of chronic pancreatitis and preservation of pancreatic islet cells. There was complete resolution of diabetes post Whipple’s procedure and patient was able to come of insulin treatment. Her last HBA1C was 31 mmol/mol, 4 months post tumour resection.

Learning points:

  • Diabetes mellitus and malignancy can be related.

  • A high index of suspicion is needed when diabetes mellitus presents atypically.

  • Non-functional neuroendocrine tumours can present with diabetes mellitus.

Open access
Caroline Bachmeier Endocrinology Department, Townsville Hospital, Townsville, Queensland, Australia

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Chirag Patel Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia

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Peter Kanowski Clinical Pathology/Histopathology, Sullivan Nicolaides Pathology, Townsville, Queensland, Australia

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Kunwarjit Sangla Endocrinology Department, Townsville Hospital, Townsville, Queensland, Australia
James Cook University, Townsville, Queensland, Australia

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Summary

Primary hyperparathyroidism (PH) is a common endocrine abnormality and may occur as part of a genetic syndrome. Inactivating mutations of the tumour suppressor gene CDC73 have been identified as accounting for a large percentage of hyperparathyroidism-jaw tumour syndrome (HPT-JT) cases and to a lesser degree account for familial isolated hyperparathyroidism (FIHP) cases. Reports of CDC73 whole gene deletions are exceedingly rare. We report the case of a 39 year-old woman with PH secondary to a parathyroid adenoma associated with a large chromosomal deletion (2.5 Mb) encompassing the entire CDC73 gene detected years after parathyroidectomy. This case highlights the necessity to screen young patients with hyperparathyroidism for an underlying genetic aetiology. It also demonstrates that molecular testing for this disorder should contain techniques that can detect large deletions.

Learning points:

  • Necessity of genetic screening for young people with hyperparathyroidism.

  • Importance of screening for large, including whole gene CDC73 deletions.

  • Surveillance for patients with CDC73 gene mutations includes regular calcium and parathyroid hormone levels, dental assessments and imaging for uterine and renal tumours.

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Yasutaka Takeda Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Yukihiro Fujita Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Kentaro Sakai Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Tomoe Abe Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Tomonobu Nakamura Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Tsuyoshi Yanagimachi Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Hidemitsu Sakagami Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Jun Honjo Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Atsuko Abiko Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Yuichi Makino Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Masakazu Haneda Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Summary

MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation.

Learning points:

  • To date, it has been shown that different hormone-producing tumors coexist in MEN1-associated pNETs; however, the underlying mechanism of the hormone production in MEN1-associated pNETs has not been well elucidated.

  • Although this case presented symptomatic hypoglycemia, several hormone-producing pNETs other than insulinoma also coexisted in the pancreas.

  • Immunohistochemical analysis showed MafA and Pdx1 expressions distinctly in insulinoma, and Arx expression particularly in a glucagon-positive NET, while a multiple hormone-positive NET expressed MafA, Pdx1 and Arx.

  • Collectively, clinicians should consider that several hormone-producing pNETs may coexist in a MEN1 case and examine both endocrinological and histopathological analysis of pNETs, regardless of whether symptoms related to the excess of hormones are observed or not.

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Run Yu Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, USA

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Danielle Sharaga Cancer Center of Santa Barbara with Sansum Clinic, Santa Barbara, California, USA

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Christopher Donner Sansum Clinic, Santa Barbara, California, USA

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M Fernando Palma Diaz Department of Pathology

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Masha J Livhits Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, USA

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Michael W Yeh Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, USA

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Summary

Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1–1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case.

Learning points:

  • Pheochromocytomatosis is a very rare form of pheochromocytoma recurrence.

  • Pheochromocytomatosis refers to new, multiple and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma.

  • Tumor capsule rupture during adrenalectomy predisposes a patient to develop pheochromocytomatosis.

  • Surgical resection of the multiple tumors of pheochromocytomatosis is recommended.

  • Pheochromocytoma recurrence should prompt genetic testing for syndromic pheochromocytoma.

Open access
Eva Krčálová Nuclear Medicine Department, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Academic Department of Internal Medicine, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic

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Jiří Horáček 4th Department of Internal Medicine, Charles University in Prague, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Academic Department of Internal Medicine, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic

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Lubomír Kudlej Internal Medicine Department, Hospital Trutnov, Trutnov, Czech Republic

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Viera Rousková Nuclear Medicine Department, Hospital Trutnov, Trutnov, Czech Republic

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Blanka Michlová Nuclear Medicine Department, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic

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Irena Vyhnánková Nuclear Medicine Department, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic

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Jiří Doležal Nuclear Medicine Department, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic

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Jaroslav Malý 4th Department of Internal Medicine, Charles University in Prague, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Academic Department of Internal Medicine, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic

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Pavel Žák 4th Department of Internal Medicine, Charles University in Prague, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Academic Department of Internal Medicine, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic

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Summary

Radioiodine (RAI) has played a crucial role in differentiated thyroid cancer treatment for more than 60years. However, the use of RAI administration in patients with papillary thyroid microcarcinoma (even multifocal) is now being widely discussed and often not recommended. In accordance with European consensus, and contrary to the American Thyroid Association (ATA) guidelines, we recently performed RAI thyroid remnant ablation in a patient with differentiated papillary multifocal microcarcinoma. The post-therapeutic whole-body scan and SPECT/CT revealed the real and unexpected extent of disease, with metastases to upper mediastinal lymph nodes. This finding led to the patient’s upstaging from stage I to stage IVa according to the American Joint Committee on Cancer/International Union Against Cancer criteria.

Learning points

  • 131I is a combined beta–gamma emitter, thus allowing not only residual thyroid tissue ablation but also metastatic tissue imaging.

  • RAI remnant ablation omission also means post-treatment whole-body scan omission, which may lead to disease underestimation, due to incorrect nodal and metastatic staging.

  • RAI should be considered also in “low-risk” patients, especially when the lymph node involvement is not reliably documented.

  • Lower administered RAI activity (30mCi, 1.1GBq) may be a workable compromise in low-risk patients, not indicated for RAI remnant ablation according to ATA guidelines.

Open access
Jin-Ying Lu Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan

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Po-Ju Hung Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan

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Pei-Lung Chen Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
Department of Medical Genetics, National Taiwan University Hospital, Taipei, 100, Taiwan
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, 100, Taiwan
Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, 100, Taiwan
Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan

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Ruoh-Fang Yen Department of Nuclear Medicine, National Taiwan University, Taipei, 100, Taiwan

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Kuan-Ting Kuo Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
Department of Pathology, National Taiwan University Hospital, Taipei, 100, Taiwan

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Tsung-Lin Yang Department of Otolaryngology, National Taiwan University Hospital, Taipei, 100, Taiwan

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Chih-Yuan Wang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan

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Tien-Chun Chang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
Department of Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan

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Tien-Shang Huang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
Department of Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
Department of Social Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
Department of Medicine, Cathay General Hospital, Taipei, 106, Taiwan

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Ching-Chung Chang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
Department of Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan
Department of Internal Medicine, China Medical University, Taichung, 404, Taiwan

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Summary

We report a case of follicular thyroid carcinoma with concomitant NRAS p.Q61K and GNAS p.R201H mutations, which manifested as a 13.5 cm thyroid mass with lung, humerus and T9 spine metastases, and exhibited good response to radioactive iodine treatment.

Learning points

  • GNAS p.R201H somatic mutation is an activating or gain-of-function mutation resulting in constitutively activated Gs-alpha protein and downstream cAMP cascade, independent of TSH signaling, causing autonomously functioning thyroid nodules.

  • NRAS p.Q61K mutations with GNAS p.R201H mutations are known for a good radioactive iodine treatment response.

  • Further exploration of the GNAS-activating pathway may provide therapeutic insights into the treatment of metastatic follicular carcinoma.

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Benjamin G Challis Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Nicolai J Wewer Albrechtsen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark

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Vishakha Bansiya Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Keith Burling Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Peter Barker Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Bolette Hartmann Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark

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Fiona Gribble Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Stephen O'Rahilly Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Jens J Holst Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark

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Helen L Simpson Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Summary

Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year-old woman presented with necrolytic migratory erythema, anorexia, constipation and hyperinsulinaemic hypoglycaemia. She was found to have a grade 1 pNET, small bowel mucosal thickening and hyperglucagonaemia. Somatostatin analogue (SSA) therapy improved appetite, abolished hypoglycaemia and improved the rash. Case 2, a 48-year-old male presented with diabetes mellitus, diarrhoea, weight loss, nausea, vomiting and perineal rash due to a grade 1 metastatic pNET and hyperglucagonaemia. In both cases, plasma levels of all measured PGDPs were elevated and attenuated following SSA therapy. In case 1, there was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET.

Learning points

  • PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.

  • The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.

  • Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.

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