Clinical Overview > Condition/ Syndrome > Paraneoplastic syndromes

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Tejhmal Rehman Departments of Endocrinology Diabetes and Metabolism, St George’s University Hospitals NHS Trust, London, UK

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Ali Hameed Departments of Endocrinology Diabetes and Metabolism, St George’s University Hospitals NHS Trust, London, UK

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Nigel Beharry Departments of Radiology, St George’s University Hospitals NHS Trust, London, UK

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J Du Parcq Departments of Histopathology, St George’s University Hospitals NHS Trust, London, UK

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Gul Bano Departments of Endocrinology Diabetes and Metabolism, St George’s University Hospitals NHS Trust, London, UK

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Summary

Beta-human chorionic gonadotropin (βhCG) is normally produced by syncytiotrophoblasts of the placenta during pregnancy and aids embryo implantation. However, it is also secreted in varying amounts in non-pregnant conditions commonly heralding a neoplastic process. We present a case of 50-year-old man, who presented with bilateral gynaecomastia with elevated testosterone, oestradiol, suppressed gonadotropins with progressively increasing levels of human chorionic gonadotropin (hCG). Biochemical and radiological investigations including ultrasonography of testes, breast tissue, MRI pituitary and CT scan full body did not identify the source of hCG. FDG PET scan revealed a large mediastinal mass with lung metastasis. Immunostaining and histological analysis confirmed the diagnosis of primary choriocarcinoma of the mediastinum. It is highly aggressive and malignant tumor with poor prognosis. Early diagnosis and management are essential for the best outcome.

Learning points:

  • High βhCG in a male patient or a non-pregnant female suggests a paraneoplastic syndrome.

  • In the case of persistently positive serum hCG, exclude immunoassay interference by doing the urine hCG as heterophilic antibodies are not present in the urine.

  • Non-gestational choriocarcinoma is an extremely rare trophoblastic tumor and should be considered in young men presenting with gynaecomastia and high concentration of hCG with normal gonads.

  • A high index of suspicion and extensive investigations are required to establish an early diagnosis of extra-gonadal choriocarcinoma.

  • Early diagnosis is crucial to formulate optimal management strategy and to minimize widespread metastasis for best clinical outcome.

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Carine Ghassan Richa Department of Endocrinology, Mount Lebanon Hospital, Beirut, Lebanon
Lebanese University, Hadath, Lebanon

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Khadija Jamal Saad Department of Endocrinology, Mount Lebanon Hospital, Beirut, Lebanon
Lebanese University, Hadath, Lebanon

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Georges Habib Halabi Department of Endocrinology, Mount Lebanon Hospital, Beirut, Lebanon
Mount Lebanon Hospital, Beirut, Lebanon

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Elie Mekhael Gharios Department of Endocrinology, Mount Lebanon Hospital, Beirut, Lebanon
Mount Lebanon Hospital, Beirut, Lebanon

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Fadi Louis Nasr Mount Lebanon Hospital, Beirut, Lebanon

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Marie Tanios Merheb Department of Endocrinology, Mount Lebanon Hospital, Beirut, Lebanon
Mount Lebanon Hospital, Beirut, Lebanon

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Summary

The objective of this study is to report three cases of paraneoplastic or ectopic Cushing syndrome, which is a rare phenomenon of the adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. Three cases are reported in respect of clinical presentation, diagnosis and treatment in addition to relevant literature review. The results showed that ectopic ACTH secretion can be associated with different types of neoplasm most common of which are bronchial carcinoid tumors, which are slow-growing, well-differentiated neoplasms with a favorable prognosis and small-cell lung cancer, which are poorly differentiated tumors with a poor outcome. The latter is present in two out of three cases and in the remaining one, primary tumor could not be localized, representing a small fraction of patients with paraneoplastic Cushing. Diagnosis is established in the setting of high clinical suspicion by documenting an elevated cortisol level, ACTH and doing dexamethasone suppression test. Treatment options include management of the primary tumor by surgery and chemotherapy and treating Cushing syndrome. Prognosis is poor in SCLC. We concluded that in front of a high clinical suspicion, ectopic Cushing syndrome diagnosis should be considered, and identification of the primary tumor is essential.

Learning points:

  • Learning how to suspect ectopic Cushing syndrome and confirm it among all the causes of excess cortisol.

  • Distinguish between occult and severe ectopic Cushing syndrome and etiology.

  • Providing the adequate treatment of the primary tumor as well as for the cortisol excess.

  • Prognosis depends on the differentiation and type of the primary malignancy.

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Hans-Christof Schober Departments of Internal Medicine
Endocrinology, Rheumatology/Immunology, Klinikum Südstadt Rostock, Rostock, Germany

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Christian Kneitz Endocrinology, Rheumatology/Immunology, Klinikum Südstadt Rostock, Rostock, Germany

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Franziska Fieber Endocrinology, Rheumatology/Immunology, Klinikum Südstadt Rostock, Rostock, Germany

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Kathrin Hesse Departments of Internal Medicine
Endocrinology, Rheumatology/Immunology, Klinikum Südstadt Rostock, Rostock, Germany

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Henry Schroeder Department of Neurosurgery, Universitätsmedizin Greifswald, Greifswald, Germany

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Summary

Tumor-induced osteomalacia (TIO) is caused by the hormone fibroblast growth factor 23 (FGF-23). It is mainly produced in the tissue of mesenchymal tumors. Patients with TIO frequently suffer from a chronic decompensated pain syndrome and/or muscle weakness with postural deformity. Despite the severity of the disease, the diagnosis is frequently established late. In some cases, it takes several years to establish the condition. This case report concerning a 68-year old woman demonstrates the selective blood sampling for FGF-23 as path-breaking diagnostics to confirm the diagnosis of a neuroendocrine tumor.

Learning points:

  • Tumor-induced osteomalacia is a rare condition compared to other paraneoplastic syndromes.

  • It causes complex symptoms such as progressive reduction of physical capacity, exhaustion, fatigue, a decompensated pain syndrome of the musculoskeletal system and fractures of several bones.

  • Elevated serum levels of FGF-23 implicate massive phosphate elimination and resulting hypophosphatemia.

  • The diagnosis is often established over a period of several years because the localization of small FGF-23-producing tumors is complicated.

  • It is the combination of MRI and selective blood sampling for FGF-23 which permits reliable identification of tumors causing TIO and leads to accurate localization.

  • In a patient with generalized pain and reduced physical capacity, osteological parameters such as phosphate, 25-OH vitamin D3 and 1,25-(OH)2D3, as well as bone-specific alkaline phosphatase levels in serum should be determined. Hypophosphatemia should always lead to further diagnostic investigations aiming at the detection of an FGF-23-producing tumor.

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Shintaro Kawai The First Department of Medicine

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Hiroyuki Ariyasu The First Department of Medicine

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Yasushi Furukawa The First Department of Medicine

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Reika Yamamoto The First Department of Medicine

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Shinsuke Uraki The First Department of Medicine

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Ken Takeshima The First Department of Medicine

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Kenji Warigaya Department of Human Pathology, Wakayama Medical University, Wakayama, Japan

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Yuji Nakamoto Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

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Takashi Akamizu The First Department of Medicine

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Summary

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting leading to hypophosphatemia due to excessive actions of fibroblast growth factor 23 (FGF23) produced by the tumors. Although the best way of curing TIO is complete resection, it is usually difficult to detect the culprit tumors by general radiological modalities owing to the size and location of the tumors. We report a case of TIO in which the identification of the tumor by conventional imaging studies was difficult. Nonetheless, a diagnosis was made possible by effective use of multiple modalities. We initially suspected that the tumor existed in the right dorsal aspect of the scapula by 68Ga-DOTATOC positron emission tomography/computed tomography (68Ga-DOTATOC-PET/CT) and supported the result by systemic venous sampling (SVS). The tumor could also be visualized by 3T-magnetic resonance imaging (MRI), although it was not detected by 1.5T-MRI, and eventually be resected completely. In cases of TIO, a stepwise approach of 68Ga-DOTATOC-PET/CT, SVS and 3T-MRI can be effective for confirmation of diagnosis.

Learning points:

  • TIO shows impaired bone metabolism due to excessive actions of FGF23 produced by the tumor. The causative tumors are seldom detected by physical examinations and conventional radiological modalities.

  • In TIO cases, in which the localization of the culprit tumors is difficult, 68Ga-DOTATOC-PET/CT should be performed as a screening of localization and thereafter SVS should be conducted to support the result of the somatostatin receptor (SSTR) imaging leading to increased diagnosability.

  • When the culprit tumors cannot be visualized by conventional imaging studies, using high-field MRI at 3T and comparing it to the opposite side are useful after the tumor site was determined.

Open access
Maria P Yavropoulou Division of Clinical and Molecular Endocrinology, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilponos, Kyriakidi Street, Thessaloniki, 54636, Greece

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Nikolina Gerothanasi Division of Clinical and Molecular Endocrinology, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilponos, Kyriakidi Street, Thessaloniki, 54636, Greece

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Athanasios Frydas Division of Clinical and Molecular Endocrinology, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilponos, Kyriakidi Street, Thessaloniki, 54636, Greece

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Evangelia Triantafyllou Division of Clinical and Molecular Endocrinology, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilponos, Kyriakidi Street, Thessaloniki, 54636, Greece

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Chris Poulios Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Prodromos Hytiroglou Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Panagiotis Apostolou Research Genetic Cancer Centre Ltd (RGCC Ltd), Florina, Greece

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Ioannis Papasotiriou Research Genetic Cancer Centre Ltd (RGCC Ltd), Florina, Greece

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Symeon Tournis Laboratory of Research of Musculoskeletal System ‘Th. Garofalidis’, Medical School, KAT Hospital, University of Athens, Athens, Greece

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Isaak Kesisoglou 3rd Department of Surgery, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

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John G Yovos Division of Clinical and Molecular Endocrinology, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilponos, Kyriakidi Street, Thessaloniki, 54636, Greece

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Summary

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. These tumors typically follow a benign clinical course and local recurrence occurs in <5% of cases. We investigated a 49-year-old man with a recurrent mesenchymal phosphaturic tumor showing no signs of malignancy. The patient suffered from chronic muscle weakness, myalgia and cramps. His medical record included the diagnosis of oncogenic osteomalacia, for which he was submitted to tumor resection in the left leg three times before. Laboratory examination showed hypophosphatemia, hyperphosphaturia and an elevated serum FGF23 level. A radical surgical approach (amputation) was advised, however, complete biochemical and clinical remission was not reached. Molecular analysis of the tumor cells demonstrated overexpression of growth factor receptors implicated in tumor angiogenesis and metastatic potential (platelet derived growth factor type A (PDGFRA), PDGFRB and vascular endothelial growth factor receptor) together with increased expression of FGF23, x-linked-phosphate-regulating endopeptidase and KLOTHO. TIO is usually associated with benign phosphauturic tumors and, when identified, resection of the tumor leads to complete remission in the majority of cases. The underlying pathophysiology of recurrences in these tumors is not known. This is the first report showing increased expression of growth factor receptors in a locally aggressive but histopathologically benign phosphaturic mesenchymal tumor.

Learning points

  • TIO is usually associated with benign soft tissue or bone neoplasms of mesenchymal origin.

  • These tumors typically follow a benign clinical course and even in the rare malignant cases local recurrence occurs in <5%.

  • Successful identification and removal of the tumor leads to full recovery in the majority of cases.

Open access
Kamel Mohammedi Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Charbel Abi Khalil Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Sophie Olivier Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Imane Benabad Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Ronan Roussel Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Michel Marre Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Summary

Hypoglycemia is a common medical emergency. It is the most frequent complication induced by anti-diabetic treatment. However, it can be observed in other conditions unrelated to diabetes such as insulinoma, autoimmune disorders, and neoplasia. Herein, we report the case of a rare cause of severe and recurrent hypoglycemia in a 77-year-old woman with a malignant solitary fibrous tumor (MSFT). A 77-year-old woman was admitted to the emergency department for loss of consciousness induced by severe hypoglycemia. Her standard laboratory findings were unremarkable. HbA1c, albumin, renal, liver, thyroid, and adrenal function tests were normal. Cerebral CT scan was also normal. At the time of confirmed hypoglycemia, the serum level of insulin and C-peptide was low. On the basis of the past medical history and the absence of other comment etiologies, a paraneoplastic cause was suspected. Thus, the diagnosis of a non-islet cell tumor-induced hypoglycemia (NICTH) was established by the presence of incompletely processed precursors of IGF2 (big IGF2) in plasma electrophoresis. However, the IGF1 level was low. Therapy with corticosteroids improved hypoglycemia and clinical symptoms. NICTH is a rare cause of hypoglycemia. It should be considered in patients with mesenchymal or malignant epithelial tumors suffering from recurrent episodes of hypoglycemia. The diagnosis will be established in the case of low serum insulin concentrations and elevated levels of big IGF2. Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels.

Learning points

  • NICTH is a very rare condition that should be considered in patients known to have mesenchymal or malignant epithelial tumors and suffering from recurrent episodes of hypoglycemia.

  • The diagnosis of an NICTH is established on the basis of the hypoinsulinemic hypoglycemia, the MSFT history, and the presence of paraneoplastic secretion of IGF1 or an immature form of IGF2.

  • Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels in NICTH.

Open access
M A W Hermans
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B M L Stelten Department of Neurology, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532SZ, Nijmegen, The Netherlands

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H R Haak
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W W de Herder Department of Internal Medicine, Erasmus University Medical Centre, Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands

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M W Dercksen
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Summary

This paper reports on two patients with a long-standing diagnosis of an ENETS stage IV neuroendocrine tumour (NET) of the small intestine who developed neurological symptoms. The first patient only had bulbar symptoms and tested positive for acetylcholine receptor antibodies. The second patient had more classical symptoms of fatigable diplopia and muscle weakness of the legs, but no detectable antibodies. The diagnosis of paraneoplastical myasthenia gravis (MG) was postulated. Both patients were treated with pyridostigmine for MG and octreotide for the NETs. Interestingly, treatment of the NETs resulted in improvement of myasthenic symptoms. Paraneoplastic MG has been described to occur with certain malignancies, mainly thymoma. Herein, we prove that the association with gastrointestinal NETs, however, rare, is also one to be considered by clinicians dealing with either of these diseases. The pathogenesis has yet to be elucidated.

Learning points

  • NETs are rare malignancies with a wide variety of symptoms.

  • Paraneoplastic MG can occur with various types of malignancies.

  • Herein, we provide evidence of paraneoplastic MG in association with a grade IV NET of the small intestine.

  • Treatment of the NETs resulted in remission of myasthenic symptoms in one patient.

Open access
Pinaki Dutta Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Anuradha Aggarwal Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Yashpal Gogate Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Uma Nahar Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Viral N Shah Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Mandeep Singla Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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N Khandelwal Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Anil Bhansali Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Summary

We describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.

Learning points

  • NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.

  • Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.

  • IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

Open access