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Search for other papers by Pranav Gupta in
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Division of Endocrinology, Department of Pediatrics, Connecticut Childrens Medical Center, Farmington, Connecticut, USA
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Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
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Summary
Insulinomas are a rare cause of persistent hypoglycemia in a previously healthy child. In addition to symptoms of hypoglycemia, individuals with insulinomas usually present with a history of incessant caloric intake and weight gain due to a constant need to counter hypoglycemia. In addition to an extensive review of the literature, we report the first case of an insulinoma coexisting with reduced appetite secondary to anorexia nervosa in an adolescent female.
Learning points
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Eliciting a detailed family history is important in hypoglycemia cases.
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Obtaining a thorough dietary intake, weight history, and menstrual cycles (in females) and considering a psychiatric consultation for an eating disorder when indicated.
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Although rare in the pediatric population, multiple endocrine neoplasia type 1 syndrome should be considered in the evaluation of children and adolescents with hypoglycemia who also have a family history of pituitary, pancreatic, and/or parathyroid endocrinopathies.
The Faculty of Medicine, Technion, Haifa, Israel
Search for other papers by Said Darawshi in
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The Faculty of Medicine, Technion, Haifa, Israel
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Severe hypocalcaemia in breast cancer with bone metastasis is a rare finding usually associated with an advanced stage of the disease. We report a case of a 45-year-old woman with a history of local ductal carcinoma in situ (DCIS) of the breast, who presented with muscle tremors and general weakness. Hypocalcaemia was evident, with a positive Chvostek sign and a serum calcium level of 5.9 mg/dL (1.47 mmol/L), phosphorus 5.9 mg/dL (normal range: 2.3–4.7 mg/dL) with normal levels of albumin, magnesium and parathyroid hormone. High oral doses of alpha calcitriol and calcium with i.v. infusion of high calcium doses were instituted, altogether sufficient to maintain only mild hypocalcaemia. A whole-body CT revealed bone lesions along the axial skeleton. A biopsy from a bone lesion revealed a metastasis of breast carcinoma. With this pathological finding, leuprolide (GNRH analogue) and chlorambucil (alkylating agent) were initiated, followed by prompt tapering of infused calcium down to full discontinuation. Serum calcium was kept stable close to the low normal range by high doses of oral alpha calcitriol and calcium. This course raises suspicion that breast metastases to the skeleton caused tumour-induced hypocalcaemia by a unique mechanism. We assume that hypocalcaemia in this case was promoted by a combination of hypoparathyroidism and bone metastasis.
Learning points
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Severe hypocalcaemia can a presenting symptom for breast cancer relapse.
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Medical Genetics, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cambridgeshire, UK
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Summary
A 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy).
Learning points
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We describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen.
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Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3.
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Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .
Search for other papers by Marina Tsoli in
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Search for other papers by Gregory Kaltsas in
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Summary
Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 × 3 × 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment.
Learning points:
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Metastases can develop many years after parathyroid cancer diagnosis.
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Surgery is the only curative treatment for parathyroid carcinoma.
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Chemotherapy and radiotherapy prove to be ineffective in parathyroid cancer treatment.
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Patient registering is required in order to delineate underlining pathology and offer specific treatment.
Search for other papers by Rowena Speak in
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Endocrinology
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Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification.
Learning points:
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C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.
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C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.
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There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.
Search for other papers by Jerena Manoharan in
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Search for other papers by Caroline L Lopez in
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German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany
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German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany
Search for other papers by Evelin Schröck in
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Search for other papers by Detlef K Bartsch in
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Summary
We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation.
Learning points
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Our patient presents an extraordinary course of disease.
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Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.
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This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.
Search for other papers by Lara Ulrich in
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Search for other papers by Graham Knee in
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Search for other papers by Colin Todd in
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Summary
Haemorrhage of a parathyroid adenoma is a rare clinical presentation. This report describes a previously fit and well 54-year-old woman who presented with acute neck swelling and pain with an overlying ecchymosis. Admission laboratory tests revealed a raised parathyroid hormone and hypercalcaemia. A computed tomography (CT) scan showed widespread anterior cervical haemorrhage and a lesion at the inferior pole of the left thyroid gland. A working diagnosis of spontaneous haemorrhage from a parathyroid adenoma was made. As she was haemodynamically stable, she was treated conservatively with a period of observation in hospital to monitor for signs of neck organ compression. Follow-up imaging with CT, ultrasound and sestamibi confirmed the likely source of haemorrhage as a parathyroid nodule with significant vascularity. The diagnosis was confirmed on histopathological analysis after elective surgical exploration of the neck 6 months after her presentation. This revealed a benign parathyroid adenoma with evidence of acute and chronic bleeding. The patient made a full recovery with immediate normalisation of her biochemistry post-operatively. Despite developing a hoarse voice in the immediate post-operative period, this resolved completely within 1 month. This case report provides further evidence to support a minimal delay for elective surgery after conservative management to reduce the risks associated with recurrent bleeding.
Learning points
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Haemorrhage of a parathyroid adenoma should be a differential for all cases of acute cervical swelling or ecchymosis with no precipitating factor.
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The clerking should identify any risk factors for endocrine disease.
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Blood tests to screen for abnormal parathyroid biochemistry should be performed on admission.
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Detailed imaging of the neck is essential to identify the source of haemorrhage and risk of compression to vital neck organs.
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Conservative management is a suitable option for patients who remain haemodynamically stable but all should undergo a period of observation in hospital.
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Conservatively managed patients should be considered for definitive surgical exploration within a month of presentation to avoid the risks of recurrent bleeding.
