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Summary: A 53-year-old man who used growth hormone (GH), anabolic steroids and testosterone (T) for over 20 years presented with severe constipation and hypercalcaemia. He had benign prostatic hyperplasia and renal stones but no significant family history. Investigations showed - (1) corrected calcium (reference range) 3.66 mmol/L (2.2-2.6), phosphate 1.39 mmol/L (0.80-1.50), and PTH 2 pmol/L (1.6-7.2); (2) urea 21.9 mmol/L (2.5-7.8), creatinine 319 mmol/L (58-110), eGFR 18 mL/min (>90), and urine analysis (protein 4+, glucose 4+, red cells 2+); (3) creatine kinase 7952 U/L (40-320), positive anti Jo-1, and Ro-52 antibodies; (4) vitamin D 46 nmol/L (30-50), vitamin D3 29 pmol/L (55-139), vitamin A 4.65 mmol/L (1.10-2.60), and normal protein electrophoresis; (5) normal CT thorax, abdomen and pelvis and MRI of muscles showed 'inflammation', myositis and calcification; (6) biopsy of thigh muscles showed active myositis, chronic myopathic changes and mineral deposition and of the kidneys showed positive CD3 and CD45, focal segmental glomerulosclerosis and hypercalcaemic tubular changes; and (7) echocardiography showed left ventricular hypertrophy (likely medications and myositis contributing), aortic stenosis and an ejection fraction of 44%, and MRI confirmed these with possible right coronary artery disease. Hypercalcaemia was possibly multifactorial - (1) calcium release following myositis, rhabdomyolysis and acute kidney injury; (2) possible primary hyperparathyroidism (a low but detectable PTH); and (3) hypervitaminosis A. He was hydrated and given pamidronate, mycophenolate and prednisolone. Following initial biochemical and clinical improvement, he had multiple subsequent admissions for hypercalcaemia and renal deterioration. He continued taking GH and T despite counselling but died suddenly of a myocardial infarction., Learning Points: The differential diagnosis of hypercalcaemia is sometimes a challenge. Diagnosis may require multidisciplinary expertise and multiple and invasive investigations. There may be several disparate causes for hypercalcaemia, although one usually predominates. Maintaining 'body image' even with the use of harmful drugs may be an overpowering emotion despite counselling about their dangers.

Summary: Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders., Learning Points: Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism. Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions. Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis. A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index. If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment. In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.

Summary: Brown tumors (BTs) are expansile osteolytic lesions complicating severe primary hyperparathyroidism (PHPT). Clinical, radiological and histological features of BTs share many similarities with other giant cell-containing lesions of the bone, which can make their diagnosis challenging. We report the case of a 32-year-old man in whom an aggressive osteolytic lesion of the iliac crest was initially diagnosed as a giant cell tumor by biopsy. The patient was scheduled for surgical curettage, with a course of neoadjuvant denosumab. Routine biochemical workup prior to denosumab administration incidentally revealed high serum calcium levels. The patient was diagnosed with PHPT and a parathyroid adenoma was identified. In light of these findings, histological slices of the iliac lesion were reviewed and diagnosis of a BT was confirmed. Follow-up CT-scans performed 2 and 7 months after parathyroidectomy showed regression and re-ossification of the bone lesion. The aim of this case report is to underline the importance of distinguishing BTs from other giant cell-containing lesions of the bone and to highlight the relevance of measuring serum calcium as part of the initial evaluation of osteolytic bone lesions. This can have a major impact on patients' management and can prevent unnecessary invasive surgical interventions., Learning Points: Although rare, brown tumors should always be considered in the differential diagnosis of osteolytic giant cell-containing bone lesions. Among giant cell-containing lesions of the bone, the main differential diagnoses of brown tumors are giant cell tumors and aneurysmal bone cysts. Clinical, radiological and histological characteristics can be non-discriminating between brown tumors and giant cell tumors. One of the best ways to distinguish these two diagnoses appears to be through biochemical workup. Differentiating brown tumors from giant cell tumors and aneurysmal bone cysts is crucial in order to ensure better patient care and prevent unnecessary morbid surgical interventions.

Summary: Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients., Learning Points: 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients. Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions. MEN1 is implicated in the tumorigenesis of PHEO in this patient.

Summary: A 40-year-old woman was hospitalised at 25-week gestation following a diagnosis of severe symptomatic hypercalcaemia (adjusted serum calcium 3.02 mmol/L). A diagnosis of primary hyperparathyroidism (PHP) was made on the basis of elevated parathyroid hormone (PTH) 11.2 pmol/L (reference range 1.5-6.9) and exclusion of familial hypocalciuric hypercalcaemia. Ultrasound examination of the neck did not convincingly demonstrate an abnormal or enlarged parathyroid gland and parathyroid scintigraphy was not performed due to maternal choice relating to perceived radiation risk to the foetus. At neck exploration during the 28th week of pregnancy a right lower pole parathyroid lesion was excised together with two abnormal lymph nodes (largest 1.6 cm). Histology confirmed a parathyroid adenoma and also papillary thyroid carcinoma deposits in the two resected lymph nodes. Post-operatively, levels of adjusted serum calcium normalised and pregnancy progressed uneventfully to term. Total thyroidectomy was performed 2 weeks after delivery revealing two small foci of papillary micro-carcinoma (largest 2.3 mm, one in each thyroid lobe) with no evidence of further metastatic tumour in lymph nodes removed during functional neck dissection. Radioiodine remnant ablation (RRA) was performed 2 months post thyroidectomy to allow for breast involution. The patient remains in full clinical and biochemical remission 9 years later. We present and review the difficult management decisions faced in relation to the investigation and treatment of PHP in pregnancy, further complicated by incidentally discovered locally metastatic pT1aN1aM0 papillary thyroid carcinoma., Learning Points: PHP may have serious consequences during pregnancy and usually requires surgical management during pregnancy to reduce the risk of maternal and foetal complications. The indications for and optimal timing of surgical management are discussed. Localisation by parathyroid scintigraphy is controversial during pregnancy: modified dose regimes may be considered in preference as an alternative to unguided neck exploration. Breastfeeding is contraindicated for 6-8 weeks before radioactive-iodine remnant ablation (RRA) to prevent increased breast uptake. Breastfeeding is further contra-indicated until after a subsequent pregnancy. Incidentally discovered differentiated thyroid carcinoma (DTC) in cervical lymph nodes in some cases may be managed expectantly because in one quarter of thyroidectomies the primary tumour remains occult.

Summary: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5-15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF)., Learning Points: Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET. Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins. Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence. Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.

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.

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.

The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution., Learning Points: Learning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes.

We report a case of elderly Chinese lady with neurofibromatosis type-1 presenting with longstanding palpitation, paroxysmal hypertension and osteoporosis. Biochemical testing showed mild hypercalcaemia with non-suppressed parathyroid hormone level suggestive of primary hyperparathyroidism, and mildly elevated urinary fractionated normetanephrine and plasma-free normetanephrine pointing to a catecholamine-secreting pheochromocytoma/paraganglioma. Further scintigraphic investigation revealed evidence of a solitary parathyroid adenoma causing primary hyperparathyroidism and a left pheochromocytoma. Resection of the parathyroid adenoma and pheochromocytoma resulted in normalization of biochemical abnormalities and hypertension. The rare concurrence of primary hyperparathyroidism and pheochromocytoma in neurofibromatosis type-1 is discussed., Learning Points: All NF-1 patients who have symptoms suggestive of a pheochromocytoma/paraganglioma (PPGL), even remotely, should undergo biochemical testing.The initial biochemical tests of choice for PPGL in NF-1 are either plasma-free metanephrines or urinary fractionated metanephrines. Any elevations of metanephrines should be carefully evaluated for the presence of PPGLs in NF-1 patients.Primary hyperparathyroidism (PHPT) is described in subjects with NF-1. Due to the lack of epidemiological and functional studies, their association is yet to be substantiated. Meanwhile, PHPT may further exacerbate the metabolic bone defect in these patients and should be treated when present according to published guidelines.Coexistence of PPGL and PHPT can occur in subjects with NF-1, mimicking multiple endocrine neoplasia type 2 (MEN2).

Unlabelled: We report of a male patient aged 32 years who presented with primary hyperparathyroidism. Three parathyroid glands were resected. At the age of 46 years, nervus facialis irritation was noted, and an MRI scan incidentally revealed a non-functioning pituitary adenoma with affection of the chiasma opticum. The patient underwent transsphenoidal operation resulting in pituitary insufficiency postoperatively. At the same time, primary hyperparathyroidism reoccurred and a parathyroid adenoma located at the thymus was resected. The mother of the patient died early due to multiple tumors. The patient was suspected to have multiple endocrine neoplasia type 1 (MEN1) and genetic analysis was performed. In addition, on clinical examination, multiple exostoses were noticed and an additional genetic analysis was performed. His father was reported to have multiple osteochondromas too. MEN1 was diagnosed in the patient showing a novel heterozygote mutation c.2T>A in exon 2, codon 1 (start codon ATG>AAG;p.Met1?) of the MEN1 gene. In genetic mutational analysis of the EXT1 gene, another not yet known mutation c.1418-2A>C was found in intron 5 of the EXT1 gene (heterozygotic). In conclusion, we report novel mutations of the EXT1 and the MEN1 genes causing hereditary multiple osteochondromas and MEN1 in one patient., Learning Points: It is important to ask for the patient's family history in detail.Patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues, most frequently parathyroid (95%), enteropancreatic neuroendocrine (50%), and anterior pituitary (40%) tissues.Familiar MEN1 has a high degree of penetrance (80-95%) by the age over 50; however, combinations of the tumors may be different in members of the same family.Patients with EXT1 gene mutations should be monitored for possible transformation of bone lesions into osteochondrosarcoma.