DOI 10.1515/jpem-2013-0353 J Pediatr Endocr Met 2014; 27(7-8): 773–776
Patient report Karin Y. Winston* and Jonathan Dawrant
A rare case of hypoglycaemia due to insulinoma in an adolescent with acutely altered mental status Abstract Background: Multiple endocrine neoplasia type 1 (MEN1) is an inherited neoplasia syndrome that generally presents with hypercalcaemia due to hyperparathyroidism. Insulin-producing tumours are less common components of the syndrome that emerge later during the course of the disease. We report here a case of an adolescent who presented with symptomatic hypoglycaemia as the first indication of MEN1. Case: A 14-year-old boy, known to use illicit drugs, was brought to the hospital with altered mental status. He was hypoglycaemic and further investigations revealed two pancreatic insulinomas. Despite having no relevant family history, genetic evaluation showed a mutation consistent with MEN1. Conclusion: Insulinomas in adolescents are generally rare and even less common as a first presentation of MEN1. This diagnosis carries implications for potential future neoplasms, both benign and malignant. While intoxication is a more common case of altered mental status in adolescents, clinicians must maintain a high index of suspicion for organic disease. Keywords: adolescent; hypoglycaemia; insulinoma; multiple endocrine neoplasia type 1 (MEN1). *Corresponding author: Karin Y. Winston, MD, FRCPC, Department of Pediatrics, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, AB, Canada T3B 6A8, Phone: +1 403-955-7819, Fax: +1 403-955-5001, E-mail: [email protected] Karin Y. Winston and Jonathan Dawrant: Alberta Children’s Hospital, Calgary, AB, Canada; and University of Calgary, Calgary, AB, Canada
Introduction Multiple endocrine neoplasia type 1 (MEN1) results from mutations in a gene encoding the tumour suppressor protein menin on chromosome 11q13. It is inherited in
an autosomal dominant fashion with de novo mutations in about 10% of patients. Classically characterised by tumours of the parathyroid glands, endocrine pancreas and anterior pituitary gland, it has been associated with adrenal cortical tumours, carcinoid tumours, angiofibromas, collagenomas and lipomas (1). The most common first presentation is hypercalcaemia due to a parathyroid adenoma with fewer than 15% of patients presenting with other tumours. There is increased morbidity and mortality, associated with multiple tumours and the potential for malignant transformation.
Patient presentation A 14-year-old healthy patient on treatment for attention deficit hyperactivity disorder was brought into the hospital for abnormal behaviour and suspicion of drug use. He was found at home, incoherent and incompletely dressed, with the house in disarray. Shortly after arrival to emergency, a venous gas was drawn and he was placed in a psychiatric observation room. Approximately 1 h later, an emergency room physician reviewed the results of the gas: pH 7.35, PCO2 47 mmHg, PO2 26, HCO3– 26 mmol/L, sodium 141 mmol/L (same in meq/L; normal 133–145), potassium 4.3 mmol/L (same in meq/L; normal 3.3–5.1), chloride 102 mmol/L (same in meq/L; normal 98–111), glucose 2.0 mmol/L (36 mg/dL; normal 3.9–6.1 mmol/L, 70–110 mg/dL) and ionised calcium 1.31 mmol/L (5.24 mg/dL; norma1 15–1.35 mmol/L). She noted the blood glucose level and found the patient less responsive than at triage. Treatment with intravenous dextrose restored the normal level of consciousness. He was subsequently admitted for stabilisation and further investigation. Urine toxicology, including full tandem mass spectrometry, showed only his prescription methylphenidate. The patient admitted to frequent marijuana use but denied any drug use in the days preceding his admission. There was neither insulin nor oral hypoglycaemic agents in his home or in the home of any of his contacts. Hypoglycaemia recurred when the dextrose infusion was interrupted. A critical
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774 Winston and Dawrant: An adolescent with insulinoma causing altered mental status sample showed the following: blood glucose 2.1 mmol/L (38 mg/dL), insulin 82.9 pmol/L (13.8 μIU/mL; ref 500 nmol/L with hypoglycaemia). Growth hormone was 3.3 μg/L (3.3 ng/mL; normal > 6 μg/L with hypoglycaemia); this value is considered non-diagnostic. Urine ketones were 1+. Unfortunately, a c-peptide sample was not obtained. During his admission, blood glucose readings were stable and within the normal range. He was discharged with a plan to measure daily fasting blood glucose levels to better characterise his hypoglycaemic patterns. He had recurrent asymptomatic home blood glucose readings between 2.6 and 2.9 mmol/L (47–52 mg/dL). Repeat fasting labs showed glucose 1.7 mmol/L (31 mg/dL), insulin 128.1 pmol/L (18.4 μIU/mL), c-peptide 1.36 nmol/L (4.1 ng/mL; normal 0.4–1.4, insulin and c-peptide are normally undetectable with hypoglycaemia) and urine ketones were negative. Given the hyperinsulinaemic hypoglycaemia, an abdominal ultrasound was obtained showing a 3.5 cm lesion in the body of the pancreas. Contrast-enhanced visualisation of vascular flow was obtained, showing marked vascularity and rapid clearing of the contrast material. He was started on diazoxide (100 mg once daily, increased to 100 mg twice daily) and referred to a surgeon. Pre-operative planning included multiple imaging modalities. An octreotide scan showed a single focus of uptake consistent with an insulinoma corresponding to the mass seen on ultrasound. The magnetic resonance imaging (MRI) showed a 2.9 × 3.2 × 2.4 cm mass in the body of the pancreas and a second, 2.5 × 1.5 × 2 cm mass in the tail. I123 MIBG scan did not show any abnormal uptake. Positron emission tomography (PET) scanning is not available at our centre. Pre-operative blood was all normal, including serum calcium level of 2.48 mmol/L (9.9 mg/dL; normal 2.10–2.55 mmol/L). He had both lesions removed with a sub-total pancreatectomy. He remained euglycaemic after surgery and was discharged home on no medications. Genetic testing confirmed a germline-known pathogenic MEN1 mutation (c.493T > C; p.C165R) (1). Pathological examination of the larger tumour showed no staining for insulin, gastrin or somatostatin but positive staining for chromogranin, synaptophysin and glucagon. The smaller tumour stained positive for chromogranin, synaptophysin and insulin and negative for glucagon, gastrin and somatostatin. There were several microscopic foci of well-circumscribed neuroendocrine tumours located in the tail of the pancreas as well as enlarged islet cells resembling insulinomas.
Discussion Insulinomas are rare pancreatic tumours with an estimated incidence of 1/250,000–1/1,125,000 and occur primarily in older individuals (2–5). In one large case series, only 6% of patients were younger than 20 years of age at the time of diagnosis (2) and a 20-year retrospective study of pancreatic tumours at another major referral centre showed only two insulinomas (6). Neuroglycopenic symptoms are the most common presentation, yet the delay from first symptom to diagnosis is typically quite long with median times ranging from 2 to 4 years. Patients are commonly diagnosed with psychiatric or neurologic disorders before the true diagnosis is made and symptoms can occur at varying times of the day, not exclusively after prolonged fasts (7, 8). In children, recurrent hypoglycaemic episodes may be more concerning given the associated risk of cognitive impairment (4, 9). Risk of malignancy, as defined by metastases, size greater than 2 cm or grade 2 based on WHO classification is 4%–14% for all patients presenting with insulinoma (10) but may be higher in individuals with MEN1. Malignancy has been described in association with MEN1 as well as an increased recurrence risk of 21% at both 10 and 20 years compared to 5% and 7% for non-MEN1 patients (2). The tumours are typically solitary, although may be multiple in 7%–9% (2, 5, 11). They are more commonly multiple in patients with MEN1 (59%–63%) with a median number of seven tumours (2, 8). Tumours are almost exclusively localised to the pancreas, but may be found anywhere within the gland. Imaging modalities such as transabdominal or oesophageal/endoscopic ultrasound, computed tomography (CT) and MRI may be used to aid in pre-operative or intra-operative planning, for example, by identifying metastatic lesions that would alter the surgical approach (11–14). 111In-octreotide scintigraphy with SPECTMRI fusion can help identify primary neuroendocrine tumours and metastases. As many insulinomas are very small, intra-operative ultrasound has been shown to be more effective in finding small lesions than any pre-operative imaging modality or intra-operative palpation, even by very experienced surgeons (8, 11). 18F-DOPA PET scanning has been shown to be accurate in the localisation of hyperinsulinism, but is not yet universally implemented (15). Adrenal insufficiency has been reported very rarely (16) in association with insulinoma, therefore, assessment of appropriate adrenal response prior to surgery is important to avoid an intra-operative adrenal crisis. Additionally, calcium and parathyroid hormone (PTH) should be evaluated to ensure that hyperparathyroidism, if present, has been diagnosed and treated pre-operatively.
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Winston and Dawrant: An adolescent with insulinoma causing altered mental status 775
For temporisation prior to surgery or in patients with insulinoma for whom surgery is not an option, diazoxide is generally the first-line therapy with normalisation of blood glucose in 59% of patients. Approximately, 50% of patients experience side effects of oedema, gastrointestinal discomfort, palpitations and hirsutism that may limit its tolerability. Somatostatin analogues are used primarily in the setting of diazoxide failure. Drawbacks include subcutaneous administration and the potential for progression of cholelithiasis or gastrointestinal distress. Medical treatment after failure of both of these agents may include glucocorticoids or frequent meals to avoid prolonged fasting (17). MEN1 presents with hypercalcaemia due to primary hyperparathyroidism in approximately 85% of patients (1). In contrast, only 10% of patients will have developed an insulinoma by age 40, making hypoglycaemia as the first sign of MEN1 very rare (18). Association of insulinomas with MEN1 is found in 6%–10% of patients, underscoring the need to evaluate for other tumours. The natural history of younger patients is more atypical, with the highest proportion of pituitary and pancreas lesions at presentation in patients under the age of 25 years (19). Therefore, young patients in particular who present with an insulinoma should be evaluated for hereditary tumour syndromes, as this bears implications for current management and future screening. The extent of routine screening that is useful and cost effective has been debated. Proposed screening recommendations include annual or biannual biochemical monitoring (calcium and PTH, glucose and insulin, gastrin, prolactin, insulin-like growth factor-1) with additional tests proposed by some authors. Imaging is proposed every 1–5 years with MRI of the pituitary and abdomen with or without thoracic CT. Recommended ages for initiating screening in children with a confirmed mutation range from 5 to 20 years (1, 3, 18, 20). Genetic counselling is important due to the autosomal dominant inheritance of most cases of MEN1. Genetic testing can then identify family members at risk who require close monitoring and potentially prevent unnecessary screening of unaffected members. Over 1000 mutations have been identified, with a further 10% of patients with clinical MEN1 not having an identified mutation (18). The likelihood of finding a mutation increases in patients with multiple tumour types and a positive family history
(3). There does not appear to be good genotype-phenotype correlation with any of the mutations (1, 18). When pursuing genetic testing, it is important to anticipate potential emotion and psychological difficulties accompanying a diagnosis that implies a high risk of future neoplasm, potential malignancy, surgery and life-long screening. For some young people this may also impact family planning decisions. Involvement of a genetic counsellor is recommended. In conclusion, we report here a rare presentation of genetically confirmed MEN1 in an adolescent male presenting with symptomatic insulinomas. Although endogenous hyperinsulinism is a rare finding in young people, this cause of hypoglycaemia must be entertained in the differential diagnosis for patients being investigated for an acutely altered level of consciousness, along with the remainder of the appropriate metabolic, toxic and infectious investigations. While hypercalcaemia due to parathyroid adenoma is almost always the first presentation of MEN1, it is not the only presentation. Any patient presenting with an insulinoma should have genetic testing done, as a positive finding will affect future screening for both insulinoma recurrence and other associated tumours, and will impact genetic counselling advice for the patient and their family members. Conflict of interest statement Funding source: No external funding was secured for this study. Financial disclosure: The authors have no financial relationship relevant to this article to disclose. Authors’ conflict of interest disclosure: The authors have no conflicts of interest to disclose. Contributor’s statement: Karin Winston: Dr. Winston reviewed the case and literature, drafted the initial manuscript, revised the manuscript and approved the final manuscript as submitted. Jonathan Dawrant: Dr. Dawrant reviewed the case, reviewed and revised the manuscript and approved the final manuscript as submitted. Micheil Innes: Dr. Innes reviewed the genetics relevant to the case, reviewed and revised the manuscript and approved the final manuscript as submitted. Received August 30, 2013; accepted February 28, 2014; previously published online April 16, 2014
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776 Winston and Dawrant: An adolescent with insulinoma causing altered mental status
References 1. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 2010;24:355–70. 2. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insulinoma – incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc 1991;66:711–9. 3. Pieterman CR, Vriens MR, Dreijerink KM, van der Luijt RB, Valk GD. Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer 2011;10:157–71. 4. Ozen S, Saz EU, Celik A, Aydin A, Simsek DG, et al. Many admissions to the emergency departments with recurrent syncope attacks and seizures in an adolescent boy. Eur J Pediatr 2009;168:761–3. 5. Grant C, Pan J. A comparison of five transition programmes for youth with chronic illness in Canada. Child Care Health Dev 2011;37:815–20. 6. Jaksic T, Yaman M, Thorner P, Wesson DK, Filler RM, et al. A 20-year review of pediatric pancreatic tumors. J Pediatr Surg 1992;27:1315–7. 7. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med 1999;106:307–10. 8. Boukhman MP, Karam JH, Shaver J, Siperstein AE, Duh QY, et al. Insulinoma – experience from 1950 to 1995. West J Med 1998;169:98–104. 9. Jaladyan V, Darbinyan V. Insulinoma misdiagnosed as juvenile myoclonic epilepsy. Eur J Pediatr 2007;166:485–7. 10. Baudin E, Caron P, Lombard-Bohas C, Tabarin A, Mitry E, et al. Malignant insulinoma: recommendations for characterisation and treatment. Ann Endocrinol (Paris) 2013;74:523–33.
11. Grant CS. Insulinoma. Baillieres Best Pract Res Clin Gastroenterol 2005;19:783–98. 12. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, et al. Diagnosis and management of insulinoma. World J Gastroenterol 2013;19:829–37. 13. Machado MC. Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. Clinics 2012;67:145–8. 14. Moncayo VM, Martin DR, Sarmiento JM, Zbytek B, Fox T, et al. 111In Octreoscan SPECT-MRI fusion for the detection of a pancreatic insulinoma. Clin Nucl Med 2012;37:e53–6. 15. Pery C, Meurette G, Ansquer C, Frampas E, Regenet N. Role and limitations of 18F-FDG positron emission tomography (PET) in the management of patients with pancreatic lesions. Gastroenterol Clin Biol 2010;34:465–74. 16. Tang HY, Garcia JM. Association between insulinoma and adrenal insufficiency: a case report and review of the literature. Pancreas 2010;39:544–6. 17. Vezzosi D, Bennet A, Courbon F, Caron P. Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism. Clin Endocrinol (Oxf) 2008;68:904–11. 18. Falchetti A, Marini F, Luzi E, Giusti F, Cavalli L, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet Med 2009;11:825–35. 19. Shepherd JJ. The natural history of multiple endocrine neoplasia type 1: highly uncommon or highly unrecognized? Arch Surg 1991;126:935–52. 20. Burgess J. How should the patient with multiple endocrine neoplasia type 1 (MEN 1) be followed? Clin Endocrinol (Oxf) 2010;72:13–6.
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Patient report Karin Y. Winston* and Jonathan Dawrant
A rare case of hypoglycaemia due to insulinoma in an adolescent with acutely altered mental status Abstract Background: Multiple endocrine neoplasia type 1 (MEN1) is an inherited neoplasia syndrome that generally presents with hypercalcaemia due to hyperparathyroidism. Insulin-producing tumours are less common components of the syndrome that emerge later during the course of the disease. We report here a case of an adolescent who presented with symptomatic hypoglycaemia as the first indication of MEN1. Case: A 14-year-old boy, known to use illicit drugs, was brought to the hospital with altered mental status. He was hypoglycaemic and further investigations revealed two pancreatic insulinomas. Despite having no relevant family history, genetic evaluation showed a mutation consistent with MEN1. Conclusion: Insulinomas in adolescents are generally rare and even less common as a first presentation of MEN1. This diagnosis carries implications for potential future neoplasms, both benign and malignant. While intoxication is a more common case of altered mental status in adolescents, clinicians must maintain a high index of suspicion for organic disease. Keywords: adolescent; hypoglycaemia; insulinoma; multiple endocrine neoplasia type 1 (MEN1). *Corresponding author: Karin Y. Winston, MD, FRCPC, Department of Pediatrics, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, AB, Canada T3B 6A8, Phone: +1 403-955-7819, Fax: +1 403-955-5001, E-mail: [email protected] Karin Y. Winston and Jonathan Dawrant: Alberta Children’s Hospital, Calgary, AB, Canada; and University of Calgary, Calgary, AB, Canada
Introduction Multiple endocrine neoplasia type 1 (MEN1) results from mutations in a gene encoding the tumour suppressor protein menin on chromosome 11q13. It is inherited in
an autosomal dominant fashion with de novo mutations in about 10% of patients. Classically characterised by tumours of the parathyroid glands, endocrine pancreas and anterior pituitary gland, it has been associated with adrenal cortical tumours, carcinoid tumours, angiofibromas, collagenomas and lipomas (1). The most common first presentation is hypercalcaemia due to a parathyroid adenoma with fewer than 15% of patients presenting with other tumours. There is increased morbidity and mortality, associated with multiple tumours and the potential for malignant transformation.
Patient presentation A 14-year-old healthy patient on treatment for attention deficit hyperactivity disorder was brought into the hospital for abnormal behaviour and suspicion of drug use. He was found at home, incoherent and incompletely dressed, with the house in disarray. Shortly after arrival to emergency, a venous gas was drawn and he was placed in a psychiatric observation room. Approximately 1 h later, an emergency room physician reviewed the results of the gas: pH 7.35, PCO2 47 mmHg, PO2 26, HCO3– 26 mmol/L, sodium 141 mmol/L (same in meq/L; normal 133–145), potassium 4.3 mmol/L (same in meq/L; normal 3.3–5.1), chloride 102 mmol/L (same in meq/L; normal 98–111), glucose 2.0 mmol/L (36 mg/dL; normal 3.9–6.1 mmol/L, 70–110 mg/dL) and ionised calcium 1.31 mmol/L (5.24 mg/dL; norma1 15–1.35 mmol/L). She noted the blood glucose level and found the patient less responsive than at triage. Treatment with intravenous dextrose restored the normal level of consciousness. He was subsequently admitted for stabilisation and further investigation. Urine toxicology, including full tandem mass spectrometry, showed only his prescription methylphenidate. The patient admitted to frequent marijuana use but denied any drug use in the days preceding his admission. There was neither insulin nor oral hypoglycaemic agents in his home or in the home of any of his contacts. Hypoglycaemia recurred when the dextrose infusion was interrupted. A critical
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 10:30 AM
774 Winston and Dawrant: An adolescent with insulinoma causing altered mental status sample showed the following: blood glucose 2.1 mmol/L (38 mg/dL), insulin 82.9 pmol/L (13.8 μIU/mL; ref 500 nmol/L with hypoglycaemia). Growth hormone was 3.3 μg/L (3.3 ng/mL; normal > 6 μg/L with hypoglycaemia); this value is considered non-diagnostic. Urine ketones were 1+. Unfortunately, a c-peptide sample was not obtained. During his admission, blood glucose readings were stable and within the normal range. He was discharged with a plan to measure daily fasting blood glucose levels to better characterise his hypoglycaemic patterns. He had recurrent asymptomatic home blood glucose readings between 2.6 and 2.9 mmol/L (47–52 mg/dL). Repeat fasting labs showed glucose 1.7 mmol/L (31 mg/dL), insulin 128.1 pmol/L (18.4 μIU/mL), c-peptide 1.36 nmol/L (4.1 ng/mL; normal 0.4–1.4, insulin and c-peptide are normally undetectable with hypoglycaemia) and urine ketones were negative. Given the hyperinsulinaemic hypoglycaemia, an abdominal ultrasound was obtained showing a 3.5 cm lesion in the body of the pancreas. Contrast-enhanced visualisation of vascular flow was obtained, showing marked vascularity and rapid clearing of the contrast material. He was started on diazoxide (100 mg once daily, increased to 100 mg twice daily) and referred to a surgeon. Pre-operative planning included multiple imaging modalities. An octreotide scan showed a single focus of uptake consistent with an insulinoma corresponding to the mass seen on ultrasound. The magnetic resonance imaging (MRI) showed a 2.9 × 3.2 × 2.4 cm mass in the body of the pancreas and a second, 2.5 × 1.5 × 2 cm mass in the tail. I123 MIBG scan did not show any abnormal uptake. Positron emission tomography (PET) scanning is not available at our centre. Pre-operative blood was all normal, including serum calcium level of 2.48 mmol/L (9.9 mg/dL; normal 2.10–2.55 mmol/L). He had both lesions removed with a sub-total pancreatectomy. He remained euglycaemic after surgery and was discharged home on no medications. Genetic testing confirmed a germline-known pathogenic MEN1 mutation (c.493T > C; p.C165R) (1). Pathological examination of the larger tumour showed no staining for insulin, gastrin or somatostatin but positive staining for chromogranin, synaptophysin and glucagon. The smaller tumour stained positive for chromogranin, synaptophysin and insulin and negative for glucagon, gastrin and somatostatin. There were several microscopic foci of well-circumscribed neuroendocrine tumours located in the tail of the pancreas as well as enlarged islet cells resembling insulinomas.
Discussion Insulinomas are rare pancreatic tumours with an estimated incidence of 1/250,000–1/1,125,000 and occur primarily in older individuals (2–5). In one large case series, only 6% of patients were younger than 20 years of age at the time of diagnosis (2) and a 20-year retrospective study of pancreatic tumours at another major referral centre showed only two insulinomas (6). Neuroglycopenic symptoms are the most common presentation, yet the delay from first symptom to diagnosis is typically quite long with median times ranging from 2 to 4 years. Patients are commonly diagnosed with psychiatric or neurologic disorders before the true diagnosis is made and symptoms can occur at varying times of the day, not exclusively after prolonged fasts (7, 8). In children, recurrent hypoglycaemic episodes may be more concerning given the associated risk of cognitive impairment (4, 9). Risk of malignancy, as defined by metastases, size greater than 2 cm or grade 2 based on WHO classification is 4%–14% for all patients presenting with insulinoma (10) but may be higher in individuals with MEN1. Malignancy has been described in association with MEN1 as well as an increased recurrence risk of 21% at both 10 and 20 years compared to 5% and 7% for non-MEN1 patients (2). The tumours are typically solitary, although may be multiple in 7%–9% (2, 5, 11). They are more commonly multiple in patients with MEN1 (59%–63%) with a median number of seven tumours (2, 8). Tumours are almost exclusively localised to the pancreas, but may be found anywhere within the gland. Imaging modalities such as transabdominal or oesophageal/endoscopic ultrasound, computed tomography (CT) and MRI may be used to aid in pre-operative or intra-operative planning, for example, by identifying metastatic lesions that would alter the surgical approach (11–14). 111In-octreotide scintigraphy with SPECTMRI fusion can help identify primary neuroendocrine tumours and metastases. As many insulinomas are very small, intra-operative ultrasound has been shown to be more effective in finding small lesions than any pre-operative imaging modality or intra-operative palpation, even by very experienced surgeons (8, 11). 18F-DOPA PET scanning has been shown to be accurate in the localisation of hyperinsulinism, but is not yet universally implemented (15). Adrenal insufficiency has been reported very rarely (16) in association with insulinoma, therefore, assessment of appropriate adrenal response prior to surgery is important to avoid an intra-operative adrenal crisis. Additionally, calcium and parathyroid hormone (PTH) should be evaluated to ensure that hyperparathyroidism, if present, has been diagnosed and treated pre-operatively.
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Winston and Dawrant: An adolescent with insulinoma causing altered mental status 775
For temporisation prior to surgery or in patients with insulinoma for whom surgery is not an option, diazoxide is generally the first-line therapy with normalisation of blood glucose in 59% of patients. Approximately, 50% of patients experience side effects of oedema, gastrointestinal discomfort, palpitations and hirsutism that may limit its tolerability. Somatostatin analogues are used primarily in the setting of diazoxide failure. Drawbacks include subcutaneous administration and the potential for progression of cholelithiasis or gastrointestinal distress. Medical treatment after failure of both of these agents may include glucocorticoids or frequent meals to avoid prolonged fasting (17). MEN1 presents with hypercalcaemia due to primary hyperparathyroidism in approximately 85% of patients (1). In contrast, only 10% of patients will have developed an insulinoma by age 40, making hypoglycaemia as the first sign of MEN1 very rare (18). Association of insulinomas with MEN1 is found in 6%–10% of patients, underscoring the need to evaluate for other tumours. The natural history of younger patients is more atypical, with the highest proportion of pituitary and pancreas lesions at presentation in patients under the age of 25 years (19). Therefore, young patients in particular who present with an insulinoma should be evaluated for hereditary tumour syndromes, as this bears implications for current management and future screening. The extent of routine screening that is useful and cost effective has been debated. Proposed screening recommendations include annual or biannual biochemical monitoring (calcium and PTH, glucose and insulin, gastrin, prolactin, insulin-like growth factor-1) with additional tests proposed by some authors. Imaging is proposed every 1–5 years with MRI of the pituitary and abdomen with or without thoracic CT. Recommended ages for initiating screening in children with a confirmed mutation range from 5 to 20 years (1, 3, 18, 20). Genetic counselling is important due to the autosomal dominant inheritance of most cases of MEN1. Genetic testing can then identify family members at risk who require close monitoring and potentially prevent unnecessary screening of unaffected members. Over 1000 mutations have been identified, with a further 10% of patients with clinical MEN1 not having an identified mutation (18). The likelihood of finding a mutation increases in patients with multiple tumour types and a positive family history
(3). There does not appear to be good genotype-phenotype correlation with any of the mutations (1, 18). When pursuing genetic testing, it is important to anticipate potential emotion and psychological difficulties accompanying a diagnosis that implies a high risk of future neoplasm, potential malignancy, surgery and life-long screening. For some young people this may also impact family planning decisions. Involvement of a genetic counsellor is recommended. In conclusion, we report here a rare presentation of genetically confirmed MEN1 in an adolescent male presenting with symptomatic insulinomas. Although endogenous hyperinsulinism is a rare finding in young people, this cause of hypoglycaemia must be entertained in the differential diagnosis for patients being investigated for an acutely altered level of consciousness, along with the remainder of the appropriate metabolic, toxic and infectious investigations. While hypercalcaemia due to parathyroid adenoma is almost always the first presentation of MEN1, it is not the only presentation. Any patient presenting with an insulinoma should have genetic testing done, as a positive finding will affect future screening for both insulinoma recurrence and other associated tumours, and will impact genetic counselling advice for the patient and their family members. Conflict of interest statement Funding source: No external funding was secured for this study. Financial disclosure: The authors have no financial relationship relevant to this article to disclose. Authors’ conflict of interest disclosure: The authors have no conflicts of interest to disclose. Contributor’s statement: Karin Winston: Dr. Winston reviewed the case and literature, drafted the initial manuscript, revised the manuscript and approved the final manuscript as submitted. Jonathan Dawrant: Dr. Dawrant reviewed the case, reviewed and revised the manuscript and approved the final manuscript as submitted. Micheil Innes: Dr. Innes reviewed the genetics relevant to the case, reviewed and revised the manuscript and approved the final manuscript as submitted. Received August 30, 2013; accepted February 28, 2014; previously published online April 16, 2014
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 10:30 AM
776 Winston and Dawrant: An adolescent with insulinoma causing altered mental status
References 1. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 2010;24:355–70. 2. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insulinoma – incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc 1991;66:711–9. 3. Pieterman CR, Vriens MR, Dreijerink KM, van der Luijt RB, Valk GD. Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer 2011;10:157–71. 4. Ozen S, Saz EU, Celik A, Aydin A, Simsek DG, et al. Many admissions to the emergency departments with recurrent syncope attacks and seizures in an adolescent boy. Eur J Pediatr 2009;168:761–3. 5. Grant C, Pan J. A comparison of five transition programmes for youth with chronic illness in Canada. Child Care Health Dev 2011;37:815–20. 6. Jaksic T, Yaman M, Thorner P, Wesson DK, Filler RM, et al. A 20-year review of pediatric pancreatic tumors. J Pediatr Surg 1992;27:1315–7. 7. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med 1999;106:307–10. 8. Boukhman MP, Karam JH, Shaver J, Siperstein AE, Duh QY, et al. Insulinoma – experience from 1950 to 1995. West J Med 1998;169:98–104. 9. Jaladyan V, Darbinyan V. Insulinoma misdiagnosed as juvenile myoclonic epilepsy. Eur J Pediatr 2007;166:485–7. 10. Baudin E, Caron P, Lombard-Bohas C, Tabarin A, Mitry E, et al. Malignant insulinoma: recommendations for characterisation and treatment. Ann Endocrinol (Paris) 2013;74:523–33.
11. Grant CS. Insulinoma. Baillieres Best Pract Res Clin Gastroenterol 2005;19:783–98. 12. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, et al. Diagnosis and management of insulinoma. World J Gastroenterol 2013;19:829–37. 13. Machado MC. Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. Clinics 2012;67:145–8. 14. Moncayo VM, Martin DR, Sarmiento JM, Zbytek B, Fox T, et al. 111In Octreoscan SPECT-MRI fusion for the detection of a pancreatic insulinoma. Clin Nucl Med 2012;37:e53–6. 15. Pery C, Meurette G, Ansquer C, Frampas E, Regenet N. Role and limitations of 18F-FDG positron emission tomography (PET) in the management of patients with pancreatic lesions. Gastroenterol Clin Biol 2010;34:465–74. 16. Tang HY, Garcia JM. Association between insulinoma and adrenal insufficiency: a case report and review of the literature. Pancreas 2010;39:544–6. 17. Vezzosi D, Bennet A, Courbon F, Caron P. Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism. Clin Endocrinol (Oxf) 2008;68:904–11. 18. Falchetti A, Marini F, Luzi E, Giusti F, Cavalli L, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet Med 2009;11:825–35. 19. Shepherd JJ. The natural history of multiple endocrine neoplasia type 1: highly uncommon or highly unrecognized? Arch Surg 1991;126:935–52. 20. Burgess J. How should the patient with multiple endocrine neoplasia type 1 (MEN 1) be followed? Clin Endocrinol (Oxf) 2010;72:13–6.
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