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Инсулинпродуцирующая опухоль поджелудочной железы у пациента молодого возраста: поиск герминальной мутации. Клинический случай
Инсулинпродуцирующая опухоль поджелудочной железы у пациента молодого возраста: поиск герминальной мутации. Клинический случай
Юкина М.Ю., Нуралиева Н.Ф., Трошина Е.А. и др. Инсулинпродуцирующая опухоль поджелудочной железы у пациента молодого возраста: поиск герминальной мутации. Клинический случай. Consilium Medicum. 2019; 21 (4): 70–74. DOI: 10.26442/20751753.2019.4.190335
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Аннотация
Инсулинома – это наиболее часто встречающаяся функционирующая опухоль поджелудочной железы. Примерно в 5% случаев заболевание ассоциировано с синдромом множественных эндокринных неоплазий 1-го типа (МЭН-1), обусловленным мутацией в гене MEN1, который проявляется аденомами гипофиза и околощитовидных желез, панкреатическими нейроэндокринными опухолями, опухолями щитовидной железы, надпочечников, кишечника, карциноидами легких и других органов. У пациентов с МЭН-1 нередко встречаются ангиофибромы, коллагеномы и липомы. Однако у 5–10% пациентов с клиническими проявлениями данного синдрома не удается обнаружить мутаций в MEN1. В таких случаях причиной заболевания могут быть разные нарушения (мутации, полиморфизмы и пр.) в других генах. В литературе описаны более 10 генов, ассоциированных с инсулинпродуцирующей опухолью поджелудочной железы. В представленном клиническом случае молодому пациенту с инсулиномой и подозрительным фенотипом относительно МЭН-1 проведено расширенное генетическое исследование. В статье подчеркивается необходимость поиска новых генетических маркеров, предрасполагающих к развитию инсулиномы, и в последующем внедрения секвенирования панели генов у таких больных. Генетическое тестирование показано в первую очередь пациентам молодого возраста с мультифокальным поражением, отягощенным семейным анамнезом, и сопутствующей ассоциированной патологией.
Ключевые слова: инсулинома, герминальная мутация, спорадическая мутация, генетический скрининг.
Ключевые слова: инсулинома, герминальная мутация, спорадическая мутация, генетический скрининг.
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Insulinoma is the most common functioning tumor of the pancreas. Approximately 5% of cases of the disease is associated with the syndrome of multiple endocrine neoplasia type 1 (MEN-1), caused by mutation in the gene MEN1. The MEN-1 is manifested by pituitary adenomas and adenomas of parathyroid glands, pancreatic neuroendocrine tumors, tumors of thyroid gland, adrenal glands, intestine, carcinoids of lungs and other organs. Patients with MEN-1 often have angiofibromas, collagenomas and lipomas. However, in 5–10% of patients with clinical manifestations of this syndrome, mutations in MEN1 cannot be detected. In such cases, the disease can be caused by various disorders (mutations, polymorphisms, etc.) in other genes. More than 10 genes, associated with insulin-producing pancreatic tumor, are described in the literature. In the presented clinical case, an extended genetic study was performed in a young patient with insulinoma and a suspicious phenotype of MEN-1. The article emphasizes the need to search for new genetic markers that predispose to the development of insulinoma, and the subsequent introduction of panel of genes sequencing in such patients. Genetic testing is indicated primarily for young patients with multifocal lesions, family history and associated pathology.
Key words: insulinoma, germline mutation, sporadic mutation, genetic screening.
Полный текст
Список литературы
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6. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386 (1–2): 2–15. DOI: 10.1016/j.mce.2013.08.002
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8. Pardi E, Borsari S, Saponaro F et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS ONE 2017; 12 (10): e0186485. DOI: 10.1371/journal.pone.0186485
9. Falchetti A, Brandi ML. Multiple Endocrine Neoplasia Type I Variants and Phenocopies: More than a Nosological Issue? Clin Endocrinol Metab 2009; 94 (5): 1518–20. DOI: 10.1210/jc.2009-0494
10. Ono Y, Oda N, Ishihara S et al. Insulinoma cell calcium-sensing receptor influences insulin secretion in a case with concurrent familial hypocalciuric hypercalcemia and malignant metastatic insulinoma. Eur J Endocrinol 2008; 159: 81–6. DOI: 10.1530/EJE-08-0069
11. Afzal M, Kathuria P. Familial Hypocalciuric Hypercalcemia (FHH). StatPearls [Internet]. StatPearls Publishing, 2018. https://www.ncbi.nlm.nih.gov/books/NBK459190/
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13. Jonkers YMH. Molecular Alterations During Insulinoma Tumorigenesis. Maastricht: Universiteit Maastricht, 2007; p. 128.
14. Hrašćan R, Pećina-Šlaus N, Martić TN et al. Analysis of selected genes in neuroendocrine tumours: Insulinomas and phaeochromocytomas. J Neuroendocrinol 2008, 20 (8): 1015–22. DOI: 10.1111/j.1365-2826.2008.01755.x
2. Druce MR, Muthuppalaniappan VM, O'Leary B et al. Diagnosis and Localisation of Insulinoma : The value of Modern MRI in Conjunction with Calcium Stimulation Catheterisation. Eur J Endocrinol 2010; 162 (5): 971–8. DOI: 10.1530/EJE-10-0056
3. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 2008; 113 (Suppl. 7): 1807–43. DOI: 10.1002/cncr.23648
4. Shiihara M, Izumo W, Higuchi R et al. A case of long-survival insulinoma with multiple neuroendocline tumour type 1 controlled by multimodal therapy. J Surg Case Rep 2017; 12: 1–4. DOI: 10.1093/jscr/rjx244
5. Lee M, Pellegata NS. Multiple Endocrine Neoplasia Type 4. In.: Stratakis CA, editor. Endocrine Tumor Syndromes and Their Genetics. Front Horm Res 2013; 41: 63–78. DOI: 10.1159/000345670
6. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386 (1–2): 2–15. DOI: 10.1016/j.mce.2013.08.002
7. Şimşir IY, Ertan Y, Sözbilen M et al. Multiple Endocrine Neoplasia Type 4 (MEN4) Syndrome. J Clin Res Pediatr Endocrinol 2015; 7 (Suppl. 2): 77–92.
8. Pardi E, Borsari S, Saponaro F et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS ONE 2017; 12 (10): e0186485. DOI: 10.1371/journal.pone.0186485
9. Falchetti A, Brandi ML. Multiple Endocrine Neoplasia Type I Variants and Phenocopies: More than a Nosological Issue? Clin Endocrinol Metab 2009; 94 (5): 1518–20. DOI: 10.1210/jc.2009-0494
10. Ono Y, Oda N, Ishihara S et al. Insulinoma cell calcium-sensing receptor influences insulin secretion in a case with concurrent familial hypocalciuric hypercalcemia and malignant metastatic insulinoma. Eur J Endocrinol 2008; 159: 81–6. DOI: 10.1530/EJE-08-0069
11. Afzal M, Kathuria P. Familial Hypocalciuric Hypercalcemia (FHH). StatPearls [Internet]. StatPearls Publishing, 2018. https://www.ncbi.nlm.nih.gov/books/NBK459190/
12. Lubomierski N, Kersting M, Bert T et al. Tumor Suppressor Genes in the 9p21 Gene Cluster Are Selective Targets of Inactivation in Neuroendocrine Gastroenteropancreatic Tumors. Cancer Res 2001; 61: 5905–10.
13. Jonkers YMH. Molecular Alterations During Insulinoma Tumorigenesis. Maastricht: Universiteit Maastricht, 2007; p. 128.
14. Hrašćan R, Pećina-Šlaus N, Martić TN et al. Analysis of selected genes in neuroendocrine tumours: Insulinomas and phaeochromocytomas. J Neuroendocrinol 2008, 20 (8): 1015–22. DOI: 10.1111/j.1365-2826.2008.01755.x
2. Druce MR, Muthuppalaniappan VM, O'Leary B et al. Diagnosis and Localisation of Insulinoma : The value of Modern MRI in Conjunction with Calcium Stimulation Catheterisation. Eur J Endocrinol 2010; 162 (5): 971–8. DOI: 10.1530/EJE-10-0056
3. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 2008; 113 (Suppl. 7): 1807–43. DOI: 10.1002/cncr.23648
4. Shiihara M, Izumo W, Higuchi R et al. A case of long-survival insulinoma with multiple neuroendocline tumour type 1 controlled by multimodal therapy. J Surg Case Rep 2017; 12: 1–4. DOI: 10.1093/jscr/rjx244
5. Lee M, Pellegata NS. Multiple Endocrine Neoplasia Type 4. In.: Stratakis CA, editor. Endocrine Tumor Syndromes and Their Genetics. Front Horm Res 2013; 41: 63–78. DOI: 10.1159/000345670
6. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386 (1–2): 2–15. DOI: 10.1016/j.mce.2013.08.002
7. Şimşir IY, Ertan Y, Sözbilen M et al. Multiple Endocrine Neoplasia Type 4 (MEN4) Syndrome. J Clin Res Pediatr Endocrinol 2015; 7 (Suppl. 2): 77–92.
8. Pardi E, Borsari S, Saponaro F et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS ONE 2017; 12 (10): e0186485. DOI: 10.1371/journal.pone.0186485
9. Falchetti A, Brandi ML. Multiple Endocrine Neoplasia Type I Variants and Phenocopies: More than a Nosological Issue? Clin Endocrinol Metab 2009; 94 (5): 1518–20. DOI: 10.1210/jc.2009-0494
10. Ono Y, Oda N, Ishihara S et al. Insulinoma cell calcium-sensing receptor influences insulin secretion in a case with concurrent familial hypocalciuric hypercalcemia and malignant metastatic insulinoma. Eur J Endocrinol 2008; 159: 81–6. DOI: 10.1530/EJE-08-0069
11. Afzal M, Kathuria P. Familial Hypocalciuric Hypercalcemia (FHH). StatPearls [Internet]. StatPearls Publishing, 2018. https://www.ncbi.nlm.nih.gov/books/NBK459190/
12. Lubomierski N, Kersting M, Bert T et al. Tumor Suppressor Genes in the 9p21 Gene Cluster Are Selective Targets of Inactivation in Neuroendocrine Gastroenteropancreatic Tumors. Cancer Res 2001; 61: 5905–10.
13. Jonkers YMH. Molecular Alterations During Insulinoma Tumorigenesis. Maastricht: Universiteit Maastricht, 2007; p. 128.
14. Hrašćan R, Pećina-Šlaus N, Martić TN et al. Analysis of selected genes in neuroendocrine tumours: Insulinomas and phaeochromocytomas. J Neuroendocrinol 2008, 20 (8): 1015–22. DOI: 10.1111/j.1365-2826.2008.01755.x
________________________________________________
2. Druce MR, Muthuppalaniappan VM, O'Leary B et al. Diagnosis and Localisation of Insulinoma : The value of Modern MRI in Conjunction with Calcium Stimulation Catheterisation. Eur J Endocrinol 2010; 162 (5): 971–8. DOI: 10.1530/EJE-10-0056
3. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 2008; 113 (Suppl. 7): 1807–43. DOI: 10.1002/cncr.23648
4. Shiihara M, Izumo W, Higuchi R et al. A case of long-survival insulinoma with multiple neuroendocline tumour type 1 controlled by multimodal therapy. J Surg Case Rep 2017; 12: 1–4. DOI: 10.1093/jscr/rjx244
5. Lee M, Pellegata NS. Multiple Endocrine Neoplasia Type 4. In.: Stratakis CA, editor. Endocrine Tumor Syndromes and Their Genetics. Front Horm Res 2013; 41: 63–78. DOI: 10.1159/000345670
6. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386 (1–2): 2–15. DOI: 10.1016/j.mce.2013.08.002
7. Şimşir IY, Ertan Y, Sözbilen M et al. Multiple Endocrine Neoplasia Type 4 (MEN4) Syndrome. J Clin Res Pediatr Endocrinol 2015; 7 (Suppl. 2): 77–92.
8. Pardi E, Borsari S, Saponaro F et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS ONE 2017; 12 (10): e0186485. DOI: 10.1371/journal.pone.0186485
9. Falchetti A, Brandi ML. Multiple Endocrine Neoplasia Type I Variants and Phenocopies: More than a Nosological Issue? Clin Endocrinol Metab 2009; 94 (5): 1518–20. DOI: 10.1210/jc.2009-0494
10. Ono Y, Oda N, Ishihara S et al. Insulinoma cell calcium-sensing receptor influences insulin secretion in a case with concurrent familial hypocalciuric hypercalcemia and malignant metastatic insulinoma. Eur J Endocrinol 2008; 159: 81–6. DOI: 10.1530/EJE-08-0069
11. Afzal M, Kathuria P. Familial Hypocalciuric Hypercalcemia (FHH). StatPearls [Internet]. StatPearls Publishing, 2018. https://www.ncbi.nlm.nih.gov/books/NBK459190/
12. Lubomierski N, Kersting M, Bert T et al. Tumor Suppressor Genes in the 9p21 Gene Cluster Are Selective Targets of Inactivation in Neuroendocrine Gastroenteropancreatic Tumors. Cancer Res 2001; 61: 5905–10.
13. Jonkers YMH. Molecular Alterations During Insulinoma Tumorigenesis. Maastricht: Universiteit Maastricht, 2007; p. 128.
14. Hrašćan R, Pećina-Šlaus N, Martić TN et al. Analysis of selected genes in neuroendocrine tumours: Insulinomas and phaeochromocytomas. J Neuroendocrinol 2008, 20 (8): 1015–22. DOI: 10.1111/j.1365-2826.2008.01755.x
Авторы
М.Ю.Юкина*1, Н.Ф.Нуралиева1, Е.А.Трошина1, А.Р.Калдаров2, Т.В.Солдатова1, А.В.Воронцов1, В.П.Владимирова1, Н.В.Тарбаева1
1 ФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава России, Москва, Россия;
1 ФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава России, Москва, Россия;
2 ФГБУ «Национальный медицинский исследовательский центр хирургии им. А.В.Вишневского» Минздрава России, Москва, Россия
*kuronova@yandex.ru
*kuronova@yandex.ru
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Marina Yu. Yukina*1, Nurana F. Nuralieva1, Ekaterina A. Troshina1, Ayrat R. Kaldarov2, Tatjana V. Soldatova1, Alexander V. Vorontsov1, Victoria P. Vladimirova1, Natalya V. Tarbaeva1
1 Endocrinology Research Centre, Moscow, Russia;
1 Endocrinology Research Centre, Moscow, Russia;
2 A.V.Vishnevsky National Medical Center of Surgery, Moscow, Russia
*kuronova@yandex.ru
*kuronova@yandex.ru
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