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Daphne Yau Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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Maria Salomon-Estebanez Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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Amish Chinoy Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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John Grainger Departments of Paediatric Haematology, Royal Manchester Children’s Hospital, Manchester, UK

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Ross J Craigie Departments of Paediatric Surgery, Royal Manchester Children’s Hospital, Manchester, UK

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Raja Padidela Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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Mars Skae Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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Mark J Dunne Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

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Philip G Murray Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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Indraneel Banerjee Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

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Summary

Congenital hyperinsulinism (CHI) is an important cause of severe hypoglycaemia in infancy. To correct hypoglycaemia, high concentrations of dextrose are often required through a central venous catheter (CVC) with consequent risk of thrombosis. We describe a series of six cases of CHI due to varying aetiologies from our centre requiring CVC for the management of hypoglycaemia, who developed thrombosis in association with CVC. We subsequently analysed the incidence and risk factors for CVC-associated thrombosis, as well as the outcomes of enoxaparin prophylaxis. The six cases occurred over a 3-year period; we identified an additional 27 patients with CHI who required CVC insertion during this period (n = 33 total), and a separate cohort of patients with CHI and CVC who received enoxaparin prophylaxis (n = 7). The incidence of CVC-associated thrombosis was 18% (6/33) over the 3 years, a rate of 4.2 thromboses/1000 CVC days. There was no difference in the frequency of genetic mutations or focal CHI in those that developed thromboses. However, compound heterozygous/homozygous potassium ATP channel mutations correlated with thrombosis (R2 = 0.40, P = 0.001). No difference was observed in CVC duration, high concentration dextrose or glucagon infused through the CVC. In patients receiving enoxaparin prophylaxis, none developed thrombosis or bleeding complications. The characteristics of these patients did not differ significantly from those with thrombosis not on prophylaxis. We therefore conclude that CVC-associated thrombosis can occur in a significant proportion (18%) of patients with CHI, particularly in severe CHI, for which anticoagulant prophylaxis may be indicated.

Learning points:

  • CVC insertion is one of the most significant risk factors for thrombosis in the paediatric population.

  • Risk factors for CVC-associated thrombosis include increased duration of CVC placement, malpositioning and infusion of blood products.

  • To our knowledge, this is the first study to evaluate CVC-associated thrombosis in patients with congenital hyperinsulinism (CHI).

  • The incidence of CVC-associated thrombosis development is significant (18%) in CHI patients and higher compared to other neonates with CVC. CHI severity may be a risk factor for thrombosis development.

  • Although effective prophylaxis for CVC-associated thrombosis in infancy is yet to be established, our preliminary experience suggests the safety and efficacy of enoxoaparin prophylaxis in this population and requires on-going evaluation.

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Xin Chen Division of Internal Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Dina Kamel Division of Endocrinology, Diabetes, and Metabolism, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Braden Barnett Division of Endocrinology, Diabetes, and Metabolism, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Evan Yung Division of Pathology, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Adrienne Quinn Keck School of Medicine, University of Southern California, Los Angeles, California, USA

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Caroline Nguyen Division of Endocrinology, Diabetes, and Metabolism, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Summary

There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). Histopathologic findings from such patients who underwent partial/total pancreatomy, however, can vary widely from minimal changes to classic nesidioblastosis, making the pathologic diagnosis challenging. PGBH typically presents as postprandial hypoglycemia, as opposed to insulinoma, which presents as fasting hypoglycemia. Herein, we describe an unusual case of a patient with PGBH who initially presented with postprandial hypoglycemia three years after surgery, but later developed fasting hyperinsulinemic hypoglycemia as the disease progressed. Our hypothesis for this phenomenon is that this disease is progressive, and later in its course, the insulin release becomes dissociated from food stimulation and is increased at baseline. Future studies are needed to investigate the prevalence as well as etiology of this progression from postprandial to fasting hypoglycemia.

Learning points:

  • There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH).

  • Histopathologically, PGBH can vary from minimal changes to nesidioblastosis.

  • Although uncommon, patients with PGBH after Roux-en-Y gastric bypass may present with both postprandial and fasting hyperinsulinemic hypoglycemia as disease progresses.

  • Our hypothesis for this phenomenon is that the insulin release becomes dissociated from food stimulation and is increased at baseline with disease progression.

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Tiago Nunes da Silva Department of Internal Medicine, ENETS Centre of Excellence, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands

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(Loes) M L F van Velthuysen Department of Pathology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands

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Casper H J van Eijck Department of Surgery, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands

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Jaap J Teunissen Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands

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(Hans) J Hofland Department of Internal Medicine, ENETS Centre of Excellence, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands

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Wouter W de Herder Department of Internal Medicine, ENETS Centre of Excellence, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands

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Summary

Non-functional pancreatic neuroendocrine tumours (NETs) can present with advanced local or distant (metastatic) disease limiting the possibility of surgical cure. Several treatment options have been used in experimental neoadjuvant settings to improve the outcomes in such cases. Peptide receptor radionuclide therapy (PPRT) using beta emitting radiolabelled somatostatin analogues has been used in progressive pancreatic NETs. We report a 55-year-old female patient with a 12.8 cm pancreatic NET with significant local stomach and superior mesenteric vein compression and liver metastases. The patient underwent treatment with [177Lutetium-DOTA0,Tyr3]octreotate (177Lu-octreotate) for the treatment of local and metastatic symptomatic disease. Six months after 4 cycles of 177lutetium-octreotate, resolution of the abdominal complaints was associated with a significant reduction in tumour size and the tumour was rendered operable. Histology of the tumour showed a 90% necrotic tumour with abundant hyalinized fibrosis and haemorrhage compatible with PPRT-induced radiation effects on tumour cells. This report supports that PPRT has a role in unresectable and metastatic pancreatic NET.

Learning points:

  • PRRT with 177Lu-octreotate can be considered a useful therapy for symptomatic somatostatin receptor-positive pancreatic NET.

  • The clinical benefits of PRRT with 177Lu-octreotate can be seen in the first months while tumour reduction can be seen up to a year after treatment.

  • PRRT with 177Lu-octreotate was clinically well tolerated and did not interfere with the subsequent surgical procedure.

  • PRRT with 177Lu-octreotate can result in significant tumour reduction and may improve surgical outcomes. As such, this therapy can be considered as a neoadjuvant therapy.

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Sarah Y Qian Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia

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Matthew J L Hare Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia

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Alan Pham Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Australia

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Duncan J Topliss Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia
Department of Medicine, Monash University, Melbourne, Australia

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Summary

Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an uncommon and challenging case of insulinoma soon after upper gastrointestinal surgery. A 63-year-old man presented with 6 months of post-prandial hypoglycaemia beginning after a laparoscopic revision of Toupet fundoplication. Hyperinsulinaemic hypoglycaemia was confirmed during a spontaneous episode and in a mixed-meal test. Localisation studies including magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and gallium dotatate positron emission tomography (68Ga Dotatate PET) were consistent with a small insulinoma in the mid-body of the pancreas. The lesion was excised and histopathology was confirmed a localised well-differentiated neuroendocrine pancreatic neoplasm. There have been no significant episodes of hypoglycaemia since. This case highlights several key points. Insulinoma should be sought in proven post-prandial hyperinsulinaemic hypoglycaemia – even in the absence of fasting hypoglycaemia. The use of nuclear imaging targeting somatostatin and GLP1 receptors has improved accuracy of localisation. Despite these advances, accurate surgical resection can remain challenging.

Learning points:

  • Hypoglycaemia is defined by Whipple’s triad and can be provoked by fasting or mixed-meal tests.

  • Although uncommon, insulinomas can present with post-prandial hypoglycaemia.

  • In hypoglycaemia following gastrointestinal surgery (i.e. bariatric surgery or less commonly Nissen fundoplication) dumping syndrome or non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) should be considered.

  • Improved imaging techniques including MRI, endoscopic ultrasound and functional nuclear medicine scans aid localisation of insulinomas.

  • Despite advances in imaging and surgical techniques, accurate resection of insulinomas remains challenging.

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E S Scott Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia

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G R Fulcher Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
University of Sydney, Sydney, Australia

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R J Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
University of Sydney, Sydney, Australia
Cancer Genetics Laboratory, Hormones & Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

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Pancreatogenic diabetes is characterised by recurrent severe hypoglycaemia due to changes in both endocrine and exocrine functions. There are no guidelines to manage these individuals. Herein, we describe the post-operative management of two people who developed pancreatogenic diabetes following total pancreatectomy for neuroendocrine malignancy. In both individuals, diabetes was managed using sensor-augmented predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII). We demonstrate the benefit of sensor-augmented CSII in averting hypoglycaemia whilst optimising glycaemic control. Expected rates of severe hypoglycaemia in individuals with pancreatogenic diabetes can be averted with the use of continuous glucose monitoring (CGM) technology, optimising quality of life and reducing the risk of diabetes-related complications.

Learning points:

  • There are no clear guidelines to manage people with pancreatogenic diabetes.

  • We describe the use of CGM with predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII) in the management of two individuals post-pancreatectomy.

  • Predictive low-glucose suspend technology can achieve excellent glycaemic control whilst avoiding recurrent and severe hypoglycaemia in people with pancreatogenic diabetes.

  • Predictive low-glucose suspend CGM should be considered as an effective therapeutic option for the management of pancreatogenic diabetes.

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Shinsuke Uraki The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Hiroyuki Ariyasu The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Asako Doi The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Hiroto Furuta The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Masahiro Nishi The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Takeshi Usui Department of Medical Genetics, Shizuoka General Hospital, Shizuoka City, Japan

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Hiroki Yamaue The 2nd Department of Surgery, Wakayama Medical University, Wakayama, Japan

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Takashi Akamizu The 1st Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

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Summary

A 54-year-old man had gastrinoma, parathyroid hyperplasia and pituitary tumor. His family history indicated that he might have multiple endocrine neoplasia type 1 (MEN1). MEN1 gene analysis revealed a heterozygous germline mutation (Gly156Arg). Therefore, we diagnosed him with MEN1. Endocrinological tests revealed that his serum prolactin (PRL) and plasma adrenocorticotropic hormone (ACTH) levels were elevated to 1699 ng/mL and 125 pg/mL respectively. Immunohistochemical analysis of the resected pancreatic tumors revealed that the tumors did not express ACTH. Overnight 0.5 and 8 mg dexamethasone suppression tests indicated that his pituitary tumor was a PRL-ACTH-producing plurihormonal tumor. Before transsphenoidal surgery, cabergoline was initiated. Despite no decrease in the volume of the pituitary tumor, PRL and ACTH levels decreased to 37.8 ng/mL and 57.6 pg/mL respectively. Owing to the emergence of metastatic gastrinoma in the liver, octreotide was initiated. After that, PRL and ACTH levels further decreased to 5.1 ng/mL and 19.7 pg/mL respectively. He died from liver dysfunction, and an autopsy of the pituitary tumor was performed. In the autopsy study, histopathological and immunohistochemical (IHC) analysis showed that the tumor was single adenoma and the cells were positive for ACTH, growth hormone (GH), luteinizing hormone (LH) and PRL. RT-PCR analysis showed that the tumor expressed mRNA encoding all anterior pituitary hormones, pituitary transcription factor excluding estrogen receptor (ER) β, somatostatin receptor (SSTR) 2, SSTR5 and dopamine receptor D (D2R). PRL-ACTH-producing tumor is a very rare type of pituitary tumor, and treatment with cabergoline and octreotide may be useful for controlling hormone levels secreted from a plurihormonal pituitary adenoma, as seen in this case of MEN1.

Learning points:

  • Although plurihormonal pituitary adenomas were reported to be more frequent in patients with MEN1 than in those without, the combination of PRL and ACTH is rare.

  • RT-PCR analysis showed that the pituitary tumor expressed various pituitary transcription factors and IHC analysis revealed that the tumor was positive for PRL, ACTH, GH and LH.

  • Generally, the effectiveness of dopamine agonist and somatostatin analog in corticotroph adenomas is low; however, if the plurihormonal pituitary adenoma producing ACTH expresses SSTR2, SSTR5 and D2R, medical therapy for the pituitary adenoma may be effective.

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Chun-Han Lo Chung Shan Medical University School of Medicine, Taichung, Taiwan

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Ding-Ping Sun Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan

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Summary

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. Traditionally, inappropriately elevated levels of insulin in the face of hypoglycemia are the key to diagnosis. However, contradictory levels of insulin and C-peptide do not necessarily exclude the diagnosis. A 50-year-old female was brought to our emergency department because of conscious disturbance on the previous night. She had no history of diabetes mellitus, and was not using any medications or alcohol. Laboratory data showed low sugar, a significantly low insulin level, and elevated C-peptide. After admission, she had multiple episodes of spontaneous hypoglycemia after overnight fasts without discomfort. It was considered that a neuroendocrine tumor was the source of her hypoglycemia. CT scan of the abdomen revealed a 1.1cm hypervascular nodule in the pancreatic tail. Elective laparoscopic distal pancreatectomy was incorporated into her treatment course. A 1.2×1.0cm homogenous well-encapsulated tumor was resected. We monitored her glucose levels in the outpatient clinic every month for a period of six months. She did not have another episode of spontaneous hypoglycemia.

Learning points

  • Insulinoma causes endogenous hypoglycemia – it cannot be ruled out in patients presenting with hypoglycemia and low insulin levels; history and imaging studies should be done for further assessment

  • A 24-h fast test has the same clinical significance as that of 72-h fast test

  • C-peptide is a useful biochemical marker in addition to serum insulin, which can be used to diagnose insulinomas

  • CT scan is used to measure the tumor size and localize the tumor. However, definitive diagnosis is only achieved through histopathologic evaluation of diseased tissue

Open access
Jerena Manoharan Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Caroline L Lopez Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Karl Hackmann Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Fetscherstrasse 7401307, Dresden, Germany
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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Max B Albers Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Anika Pehl Department of Pathology, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Peter H Kann Division of Endocrinology and Diabetology, Department of Gastroenterology and Endocrinology, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Emily P Slater Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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Evelin Schröck Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Fetscherstrasse 7401307, Dresden, Germany
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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Detlef K Bartsch Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse35043, Marburg, Germany

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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

  • Our patient presents an extraordinary course of disease.

  • Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.

  • 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.

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Suresh Chandran Departments of Neonatology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Fabian Yap Kok Peng Paediatric Endocrinology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Victor Samuel Rajadurai Departments of Neonatology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Yap Te Lu Paediatric Surgery, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Kenneth T E Chang Children's Pathology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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S E Flanagan Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK

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S Ellard Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK

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Khalid Hussain Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK

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Summary

background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia.

Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation.

Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease.

Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.

Learning points

  • HH is a cause of severe hypoglycaemia in the newborn period.

  • Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease.

  • 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions.

  • Gallium-68 tetra-aza-cyclododecane-N NNN-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions.

  • The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear.

  • Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.

Open access