clinmedКлиническая медицинаClinical Medicine (Russian Journal)0023-21492412-1339ООО «Медицинское информационное агентство»10.30629/0023-2149-2020-98-3-218-225clinmed-35Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL INVESTIGATIONSСложности дифференциальной диагностики синдрома множественных эндокринных неоплазий 1-го типа с семейным изолированным гиперпаратиреозомChallenges in the differential diagnosis of multiple endocrine neoplasia syndrome type 1 with isolated family hyperparathyroidismКрупиноваЮ. А.KrupinovaJ. A.

Крупинова Юлия Александровна — научный сотрудник отделения патологии околощитовидных желез НМИЦ эндокринологии 

117036, Москва

Julia A. Krupinova — MD; researcher of Endocrinology Research Centre

117036, Moscow

j.krupinova@gmail.comhttps://orcid.org/0000-0002-9717-9742МокрышеваН. Г.MokryshevaN. G.

117036, Москва

117036, Moscow

https://orcid.org/0000-0002-2000-7694КалинченкоН. Ю.KalinchenkoN. Y.

117036, Москва

117036, Moscow

https://orcid.org/0000-0001-6667-062XЕремкинаА. К.EremkinaA. K.

117036, Москва

117036, Moscow

https://orcid.org/0000-0001-5348-5011ПоляковА. Н.PolyakovA. N.

115478, Москва

115478, Moscow

https://orcid.org/0000-0003-3355-2744ВолодичеваВ. Л.VolodichevaV. L.

117036, Москва

117036, Moscow

https://orcid.org/0000-0002-3734-6510БровинД. Н.BrovinD. N.

117036, Москва

117036, Moscow

https://orcid.org/0000-0002-3322-4284КиршинА. А.KirshinA. A.

426009, Ижевск

426009, Izhevsk

https://orcid.org/0000-0002-8520-8702ТрошинаЕ. А.TroshinaE. A.

117036, Москва

117036, Moscow

https://orcid.org/0000-0001-8500-4841ТюльпаковА. Н.TiulpakovA. N.

117036, Москва

117036, Moscow

ФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава РоссииРоссияNational Medical Research Research Centre of EndocrinologyRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияN.N. Blokhin National Medical Research Centre of Oncology of the Health Ministry of RussiaRussian FederationБУЗ УР «Республиканский онкологический диспансер им. С.Г. Примушко Министерства здравоохранения Удмуртской Республики»РоссияUdmurtia Сancer СenterRussian Federation202015072020983218225Copyright © Крупинова Ю.А., Мокрышева Н.Г., Калинченко Н.Ю., Еремкина А.К., Поляков А.Н., Володичева В.Л., Бровин Д.Н., Киршин А.А., Трошина Е.А., Тюльпаков А.Н., 20202020Крупинова Ю.А., Мокрышева Н.Г., Калинченко Н.Ю., Еремкина А.К., Поляков А.Н., Володичева В.Л., Бровин Д.Н., Киршин А.А., Трошина Е.А., Тюльпаков А.Н.Krupinova J.A., Mokrysheva N.G., Kalinchenko N.Y., Eremkina A.K., Polyakov A.N., Volodicheva V.L., Brovin D.N., Kirshin A.A., Troshina E.A., Tiulpakov A.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.clinmedjournal.com/jour/article/view/35

Наиболее частой причиной наследственного варианта первичного гиперпаратиреоза (ПГПТ) является синдром множественных эндокринных неоплазий 1-го типа (МЭН-1). При подтверждении семейного варианта ПГПТ динамическое наблюдение пациентов и их ближайших родственников должно проводиться на протяжении всей их жизни. Мы представляем клинический случай «ядерной семьи», в которой четыре члена родословной наблюдались с диагнозом семейного изолированного первичного гиперпаратиреоза (СИГПТ). В дальнейшем диагноз был изменен на МЭН-1 в связи с выявленной нейроэндокринной опухолью поджелудочной железы у одной из пациенток. При проведении молекулярно-генетического исследования MEN1 путем прямого секвенирования по Сенгеру у шести членов семьи выявлена новая гетерозиготная мутация в экзоне 9: с. 1252 G>T р.D418Y.

Multiple endocrine neoplasia type 1 (MEN-1) is the most common cause of the hereditary type of primary hyperparathyroidism (PHPT). If a family type of PHPT is suspected, a dynamic monitoring of patients and their close relatives should be carried out throughout their lives. We present a clinical case of a family in which four members of a pedigree were diagnosed with familial isolated hyperparathyroidism (FIHP). The diagnosis was changed to MEN-1, because it appeared that one of the patients had pancreatic neuroendocrine tumor. Molecular genetic study of MEN1 by direct by means of Sanger sequencing revealed that six family members had a new heterozygous mutation in exon 9: s. 1252 G> T p. D418Y.

первичный гиперпаратиреозсиндром множественных эндокринных неоплазийМЭН-1семейный изолированный первичный гиперпаратиреозген MEN1primary hyperparathyroidismmultiple endocrine neoplasia type 1MEN1ReferencesThakker R.V. Genetics of parathyroid tumours. J. Intern. Med. 2016;280(6):574–83. doi:10.1111/joim.12523.Thakker R.V. Genetics of parathyroid tumours. J. Intern. Med. 2016;280(6):574–83. doi:10.1111/joim.12523.Mamedova E.O. Molecular and genetic features of primary hyperparathyroidism in young patients. Diss. kand. med. nauk. 2017. Moscow. (in Russian) [Мамедова Е.О. Молекулярно-генетические и клинические особенности первичного гиперпаратиреоза у пациентов молодого возраста: дис. … канд. мед. наук. М., 2017].Mamedova E.O. Molecular and genetic features of primary hyperparathyroidism in young patients. Diss. kand. med. nauk. 2017. Moscow. (in Russian) [Мамедова Е.О. Молекулярно-генетические и клинические особенности первичного гиперпаратиреоза у пациентов молодого возраста: дис. … канд. мед. наук. М., 2017].Kamilaris C.D.C., Stratakis C.A. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front. Endocrinol. (Lausanne). 2019;10:339. doi:10.3389/fendo.2019.00339.Kamilaris C.D.C., Stratakis C.A. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front. Endocrinol. (Lausanne). 2019;10:339. doi:10.3389/fendo.2019.00339.Giusti F., Cianferotti L., Boaretto F., Cetani F., Cioppi F., Colao A. et al. Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database. Endocrine. 2017;58(2):349–59. doi:10.1007/s12020-017-1234-4.Giusti F., Cianferotti L., Boaretto F., Cetani F., Cioppi F., Colao A. et al. Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database. Endocrine. 2017;58(2):349–59. doi:10.1007/s12020-017-1234-4.Sakurai A., Suzuki S., Kosugi S., Okamoto T., Uchino S., Miya A. et al. Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database. Clin. Endocrinol. (Oxf). 2012;76(4):533–9. doi:10.1111/j.1365-2265.2011.04227.x.Sakurai A., Suzuki S., Kosugi S., Okamoto T., Uchino S., Miya A. et al. Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database. Clin. Endocrinol. (Oxf). 2012;76(4):533–9. doi:10.1111/j.1365-2265.2011.04227.x.Goudet P., Murat A., Binquet C., Cardot-Bauters C., Costa A., Ruszniewski P. et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J. Surg. 2010;34(2):249–55. doi:10.1007/s00268-009-0290-1.Goudet P., Murat A., Binquet C., Cardot-Bauters C., Costa A., Ruszniewski P. et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J. Surg. 2010;34(2):249–55. doi:10.1007/s00268-009-0290-1.Triponez F., Sadowski S.M., Pattou F., Cardot-Bauters C., Mirallié E., Le Bras M. et al. Long-term Follow-up of MEN1 Patients Who Do Not Have Initial Surgery for Small </=2 cm Nonfunctioning Pancreatic Neuroendocrine Tumors, an AFCE and GTE Study: Association Francophone de Chirurgie Endocrinienne & Groupe d’Etude des Tumeurs Endocrines. Ann. Surg. 2018;268(1):158–64. doi:10.1097/SLA.0000000000002191.Triponez F., Sadowski S.M., Pattou F., Cardot-Bauters C., Mirallié E., Le Bras M. et al. Long-term Follow-up of MEN1 Patients Who Do Not Have Initial Surgery for Small </=2 cm Nonfunctioning Pancreatic Neuroendocrine Tumors, an AFCE and GTE Study: Association Francophone de Chirurgie Endocrinienne & Groupe d’Etude des Tumeurs Endocrines. Ann. Surg. 2018;268(1):158–64. doi:10.1097/SLA.0000000000002191.Schaaf L., Pickel J., Zinner K., Hering U., Höfler M., Goretzki P.E. et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp. Clin. Endocrinol. Diabetes Off J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc. 2007;115(8):509–17. doi:10.1055/s-2007-970160.Schaaf L., Pickel J., Zinner K., Hering U., Höfler M., Goretzki P.E. et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp. Clin. Endocrinol. Diabetes Off J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc. 2007;115(8):509–17. doi:10.1055/s-2007-970160.Thakker R.V.. Multiple endocrine neoplasia type 1. Indian. J. Endocrinol. Metab. 2012;16(Suppl 2):S272–S274. doi:10.4103/2230-8210.104058.Thakker R.V.. Multiple endocrine neoplasia type 1. Indian. J. Endocrinol. Metab. 2012;16(Suppl 2):S272–S274. doi:10.4103/2230-8210.104058.Pannett A.A., Kennedy A.M., Turner J.J., Forbes S.A., Cavaco B.M., Bassett J.H. et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2003;58(5):639–46. doi.org/10.1046/j.1365-2265.2003.01765.x.Pannett A.A., Kennedy A.M., Turner J.J., Forbes S.A., Cavaco B.M., Bassett J.H. et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2003;58(5):639–46. doi.org/10.1046/j.1365-2265.2003.01765.x.Guan B., Welch J.M., Sapp J.C., Ling H., Li Y., Johnston J.J. et al. GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism. Am. J. Hum. Genet. 2016;99(5):1034–44. doi:10.1016/j.ajhg.2016.08.018.Guan B., Welch J.M., Sapp J.C., Ling H., Li Y., Johnston J.J. et al. GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism. Am. J. Hum. Genet. 2016;99(5):1034–44. doi:10.1016/j.ajhg.2016.08.018.Simonds W.F., James-Newton L.A., Agarwal S.K., Yang B., Skarulis M.C., Hendy G.N. et al. Familial isolated hyperparathyroidism: clini cal and genetic characteristics of 36 kindreds. Medicine (Baltimore). 2002;81(1):1–26. doi:10.1097/00005792-200201000-00001.Simonds W.F., James-Newton L.A., Agarwal S.K., Yang B., Skarulis M.C., Hendy G.N. et al. Familial isolated hyperparathyroidism: clini cal and genetic characteristics of 36 kindreds. Medicine (Baltimore). 2002;81(1):1–26. doi:10.1097/00005792-200201000-00001.Hannan F.M., Nesbit M.A., Christie P.T., Fratter C., Dudley N.E., Sadler G.P. et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat. Clin. Pract. Endocrinol. Metab. 2008;4(1):53–8. doi:10.1038/ncpendmet0718.Hannan F.M., Nesbit M.A., Christie P.T., Fratter C., Dudley N.E., Sadler G.P. et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat. Clin. Pract. Endocrinol. Metab. 2008;4(1):53–8. doi:10.1038/ncpendmet0718.Mamedova E. O., Mokrysheva N. G., Rozhinskaya L. Ya. Hereditary forms of primary hyperparathyroidism. Osteoporoz i osteo patii. 2019;21(2):23–9. (in Russian) [Мамедова Е.О., Мокрышева Н.Г., Рожинская Л.Я. На следственные формы первичного гиперпаратиреоза. Остеопороз и остеопатии. 2018;21(2):23–9].Mamedova E. O., Mokrysheva N. G., Rozhinskaya L. Ya. Hereditary forms of primary hyperparathyroidism. Osteoporoz i osteo patii. 2019;21(2):23–9. (in Russian) [Мамедова Е.О., Мокрышева Н.Г., Рожинская Л.Я. На следственные формы первичного гиперпаратиреоза. Остеопороз и остеопатии. 2018;21(2):23–9].Warner J., Epstein M., Sweet A., Singh D., Burgess J., Stranks S. et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J. Med. Genet. 2004;41(3):155–60. doi: 10.1136/jmg.2003.016725.Warner J., Epstein M., Sweet A., Singh D., Burgess J., Stranks S. et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J. Med. Genet. 2004;41(3):155–60. doi: 10.1136/jmg.2003.016725.Agarwal S.K., Guru S.C., Heppner C., Erdos M.R., Collins R.M., Park S.Y. et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999;96(1):143–52. doi:10.1016/s0092-8674(00)80967-8.Agarwal S.K., Guru S.C., Heppner C., Erdos M.R., Collins R.M., Park S.Y. et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999;96(1):143–52. doi:10.1016/s0092-8674(00)80967-8.Agarwal S.K., Novotny E.A., Crabtree J.S., Weitzman J.B., Yaniv M., Burns A.L. et al. Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc. Natl. Acad. Sci USA. 2003;100(19):10770–5. doi:10.1073/pnas.1834524100.Agarwal S.K., Novotny E.A., Crabtree J.S., Weitzman J.B., Yaniv M., Burns A.L. et al. Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc. Natl. Acad. Sci USA. 2003;100(19):10770–5. doi:10.1073/pnas.1834524100.Lemos M.C., Thakker R.V. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum. Mutat. 2008;29(1):22–32. doi:10.1002/humu.20605.Lemos M.C., Thakker R.V. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum. Mutat. 2008;29(1):22–32. doi:10.1002/humu.20605.Mamedova E.O., Pigarova E.A., Mokrysheva N.G., Kuznetsov S N., Kim I.V., Kuznetsov N.S., and others. Multiple endocrine neoplasia type 1 syndrome and familial isolated hyperparathyroidism. Klinicheskaya meditsina. 2015;93(11):73–7. (in Russian) [Мамедова Е.О., Пигарова Е.А., Мокрышева Н.Г., Кузнецов С.Н., Ким И.В., Кузнецов Н.С. и др. Синдром множественных эндокринных неоплазий типа 1 и семейный изолированный гиперпаратиреоз. Клиническая медицина. 2015;93(11):73–7].Mamedova E.O., Pigarova E.A., Mokrysheva N.G., Kuznetsov S N., Kim I.V., Kuznetsov N.S., and others. Multiple endocrine neoplasia type 1 syndrome and familial isolated hyperparathyroidism. Klinicheskaya meditsina. 2015;93(11):73–7. (in Russian) [Мамедова Е.О., Пигарова Е.А., Мокрышева Н.Г., Кузнецов С.Н., Ким И.В., Кузнецов Н.С. и др. Синдром множественных эндокринных неоплазий типа 1 и семейный изолированный гиперпаратиреоз. Клиническая медицина. 2015;93(11):73–7].Bassett J.H., Forbes S.A., Pannett A.A., Lloyd S.E., Christie P.T., Wooding C. et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am. J. Hum. Genet. 1998;62(2):232– 44. doi:10.1086/301729.Bassett J.H., Forbes S.A., Pannett A.A., Lloyd S.E., Christie P.T., Wooding C. et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am. J. Hum. Genet. 1998;62(2):232– 44. doi:10.1086/301729.Karges W., Jostarndt K., Maier S., Flemming A., Weitz M., Wissmann A. et al. Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J. Endocrinol. 2000;166(1):1–9. doi:10.1677/joe.0.1660001.Karges W., Jostarndt K., Maier S., Flemming A., Weitz M., Wissmann A. et al. Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J. Endocrinol. 2000;166(1):1–9. doi:10.1677/joe.0.1660001.Teh B.T., Kytölä S., Farnebo F., Bergman L., Wong F.K., Weber G. et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J. Clin. Endocrinol. Metab. 1998;83(8):2621–6. doi:10.1210/jcem.83.8.5059.Teh B.T., Kytölä S., Farnebo F., Bergman L., Wong F.K., Weber G. et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J. Clin. Endocrinol. Metab. 1998;83(8):2621–6. doi:10.1210/jcem.83.8.5059.Scillitani A., Salcuni A.S., Clemente C., Di Candia L., Graziano P., De Martino D. et al. A rare case of multiple malignant parathyroid tumors in an atypical MEN1 family with a p.D418N mutation. Niederle B Scheuba C Bichler C Riss P Selberherr Strobl St Ed Wien Klin Wochensch. 2014;126(S 3):139–70. doi:10.1007/S00508-014-0578-5.Scillitani A., Salcuni A.S., Clemente C., Di Candia L., Graziano P., De Martino D. et al. A rare case of multiple malignant parathyroid tumors in an atypical MEN1 family with a p.D418N mutation. Niederle B Scheuba C Bichler C Riss P Selberherr Strobl St Ed Wien Klin Wochensch. 2014;126(S 3):139–70. doi:10.1007/S00508-014-0578-5.Warner J., Epstein M., Sweet A., Singh D., Burgess J., Stranks S. et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J. Med. Genet. 2004;41(3):155–60. doi: 10.1136/jmg.2003.016725.Warner J., Epstein M., Sweet A., Singh D., Burgess J., Stranks S. et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J. Med. Genet. 2004;41(3):155–60. doi: 10.1136/jmg.2003.016725.Cetani F., Pardi E., Ambrogini E., Lemmi M., Borsari S., Cianferotti L. et al. Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. Clin. Endocrinol. (Oxf). 2006;64(2):146–52. doi:10.1111/j.1365-2265.2006.02438.x.Cetani F., Pardi E., Ambrogini E., Lemmi M., Borsari S., Cianferotti L. et al. Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. Clin. Endocrinol. (Oxf). 2006;64(2):146–52. doi:10.1111/j.1365-2265.2006.02438.x.Chandrasekharappa S.C., Guru S.C., Manickam P., Olufemi S.E., Collins F.S., Emmert-Buck M.R. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–7. doi:10.1126/science.276.5311.404.Chandrasekharappa S.C., Guru S.C., Manickam P., Olufemi S.E., Collins F.S., Emmert-Buck M.R. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–7. doi:10.1126/science.276.5311.404.

The authors declare that there are no conflicts of interest present.