problendoПроблемы ЭндокринологииProblems of Endocrinology0375-96602308-1430Endocrinology Research Centre10.14341/probl201662242-45problendo-7767Research ArticleКлинические случаиCase ReportsСиндром Донахью. Описание клинического случая и краткий обзор литературы.Description of the first genetically confirming case with Donahue’s syndrome in RussiaТихоновичЮлия ВикторовнаTikhonovichYulia V.

к.м.н., н.с. отделения наследственных эндокринопатий Института клинической эндокринологии

MD, PhD, Assistant researcher

yuliatihonovich@mail.ruМалиевскийОлег АртуровичMalievskyOleg A.

д.м.н., проф. каф. госпитальной педиатрии

MD, PhD, Professor

malievsky@list.ruТюльпаковАнатолий НиколаевичTyul'pakovAnatoly

д.м.н., зав. отд. наследственных эндокринопатий Института детской эндокринологии

MD, PhD, Head of the Generic endocrinopathies department, Clinical Endocrinology Institute

ant@endocrincentr.ruФГБУ «Эндокринологический научный центр» Минздрава РоссииРоссияEndocrinology Research CentreRussian FederationГБУЗ РБ «Республиканская детская клиническая больница»РоссияRepublican Children Clinical HospitalRussian Federation2016040520166224245Copyright © Тихонович Ю.В., Малиевский О.А., Тюльпаков А.Н., 20162016Тихонович Ю.В., Малиевский О.А., Тюльпаков А.Н.Tikhonovich Y.V., Malievsky O.A., Tyul'pakov A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.probl-endojournals.ru/jour/article/view/7767

Cиндром Донахью (лепрехаунизм) — редкое аутосомно-рецессивное заболевание, ассоциированное с мутациями в гене рецептора инсулина (INSR). Частота заболевания неизвестна. Кроме синдрома Донахью, дефекты INSR ассоциированы с синдромом Рабсона—Менденхолла и инсулинорезистентностью типа А. Фенотипически эти состояния различаются по тяжести клинических проявлений, возрасту манифестации и прогнозу.

Для пациентов с синдромом Донахью характерны выраженная инсулинорезистентность, отсутствие подкожной жировой клетчатки, задержка роста, увеличение наружных гениталий, стигмы дизэмбриогенеза. Патогенетическая терапия отсутствует. Прогноз крайне неблагоприятный: большинство пациентов погибают в течение первых двух лет жизни на фоне тяжелой гипотрофии и рецидивирующих инфекций. Диагностика основана на характерной клинической картине, значительном повышении уровня инсулина и С-пептида в крови, а также данных молекулярно-генетического исследования. Ранняя генетическая верификация синдрома Донахью необходима для проведения дифференциальной диагностики с другими формами сахарного диабета с выраженной инсулинорезистентностью, выбора оптимальной тактики ведения таких пациентов, медико-генетического консультирования, касающегося дальнейшего планирования семьи.

Приведены основные данные по этиопатогенезу, клинико-лабораторным характеристикам, принципам диагностики и основам ведения пациентов с синдромом Донахью. Описан первый в РФ генетически подтвержденный случай заболевания.

Syndrome Donahue (leprechaunism) is a rare form of neonatal diabetes mellitus associated with INSR gene mutations. 

There are three types of insulin resistance syndrome: Donohue syndrome, Rabson—Mendenhall syndrome and insulin resistance type A. These syndromes are distinguished from one another by severity of symptoms, age of onset and age of death. Donohue and Rabson—Mendenhall syndromes are associated with biallelic mutations in the α-subunit or/and β-subunit of INSR gene and are characterized by more severe phenotype and poor prognosis. Patients with Donohue syndrome usually die within the first two years of life. Life expectancy of patients with Rabson—Mendenhall syndrome is 5—15 years. 

Most patients with insulin resistance type A have heterozygous mutations in the β-subunit and demonstrate mild phenotype. 

Here, we describe the first genetically confirmed case of syndrome Donahue in the Russian Federation.

перманентный неонатальный сахарный диабетсиндром Донахьюлепрехаунизммутации в INSRинсулинорезистентностьpermanent neonatal diabetes mellitus; donohue syndrome; leprechaunism; insr gene mutations; insulin resistanceReferencesDonohue WL. Clinicopathologic Conference at the Hospital for Sick Children. J Pediatr. 1948;32(6):739-748. doi: 10.1016/s0022-3476(48)80231-3.Donohue WL. Clinicopathologic Conference at the Hospital for Sick Children. J Pediatr. 1948;32(6):739-748. doi: 10.1016/s0022-3476(48)80231-3.Donohue WL, Uchida I. Leprechaunism: a euphemism for a rare familial disorder. J Pediatr. 1954;45(5):505-519. doi: 10.1016/s0022-3476(54)80113-2.Donohue WL, Uchida I. Leprechaunism: a euphemism for a rare familial disorder. J Pediatr. 1954;45(5):505-519. doi: 10.1016/s0022-3476(54)80113-2.Taylor SI, Kadowaki T, Kadowaki H, et al. Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients. Diabetes Care. 1990;13(3):257-279. doi: 10.2337/diacare.13.3.257.Taylor SI, Kadowaki T, Kadowaki H, et al. Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients. Diabetes Care. 1990;13(3):257-279. doi: 10.2337/diacare.13.3.257.Longo N, Wang Y, Smith SA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002;11(12):1465-1475. doi: 10.1093/hmg/11.12.1465.Longo N, Wang Y, Smith SA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002;11(12):1465-1475. doi: 10.1093/hmg/11.12.1465.Musso C, Cochran E, Moran SA, et al. Clinical Course of Genetic Diseases of the Insulin Receptor (Type A and Rabson—Mendenhall Syndromes). Medicine. 2004;83(4):209-222. doi: 10.1097/01.md.0000133625.73570.54.Musso C, Cochran E, Moran SA, et al. Clinical Course of Genetic Diseases of the Insulin Receptor (Type A and Rabson—Mendenhall Syndromes). Medicine. 2004;83(4):209-222. doi: 10.1097/01.md.0000133625.73570.54.Schilling EE, Rechler MM, Grunfeld C, Rosenberg AM. Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance. Proc Natl Acad Sci U S A. 1979;76(11):5877-5881. PMC411755.Schilling EE, Rechler MM, Grunfeld C, Rosenberg AM. Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance. Proc Natl Acad Sci U S A. 1979;76(11):5877-5881. PMC411755.Psiachou H, Mitton S, Alaghband-Zadeh J, et al. Leprechaunism and homozygous nonsense mutation In the insulin receptor gene. The Lancet. 1993;342(8876):924. doi: 10.1016/0140-6736(93)91970-w.Psiachou H, Mitton S, Alaghband-Zadeh J, et al. Leprechaunism and homozygous nonsense mutation In the insulin receptor gene. The Lancet. 1993;342(8876):924. doi: 10.1016/0140-6736(93)91970-w.Ebina Y, Ellis L, Jarnagin K, et al. The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signalling. Cell. 1985;40(4):747-758. doi: 10.1016/0092-8674(85)90334-4.Ebina Y, Ellis L, Jarnagin K, et al. The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signalling. Cell. 1985;40(4):747-758. doi: 10.1016/0092-8674(85)90334-4.Ullrich A, Bell JR, Chen EY, et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313(6005):756-761. doi: 10.1038/313756a0.Ullrich A, Bell JR, Chen EY, et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313(6005):756-761. doi: 10.1038/313756a0.White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994;269(1):1-4.White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994;269(1):1-4.Seino S, Seino M, Nishi S, Bell GI. Structure of the human insulin receptor gene and characterization of its promoter. Proc Nat Acad Sci. 1989;86(1):114-118.Seino S, Seino M, Nishi S, Bell GI. Structure of the human insulin receptor gene and characterization of its promoter. Proc Nat Acad Sci. 1989;86(1):114-118.Thiel CT, Knebel B, Knerr I, et al. Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson—Mendenhall syndrome. Mol Genet Metab. 2008;94(3):356-362. doi: 10.1016/j.ymgme.2008.02.013.Thiel CT, Knebel B, Knerr I, et al. Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson—Mendenhall syndrome. Mol Genet Metab. 2008;94(3):356-362. doi: 10.1016/j.ymgme.2008.02.013.Taylor SI, Kadowaki T, Kadowaki H, et al. Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients. Diabetes Care. 1990;13(3):257-279. doi: 10.2337/diacare.13.3.257.Taylor SI, Kadowaki T, Kadowaki H, et al. Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients. Diabetes Care. 1990;13(3):257-279. doi: 10.2337/diacare.13.3.257.Taylor SI. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes. 1992;41(11):1473-1490. doi: 10.2337/diabetes.41.11.1473.Taylor SI. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes. 1992;41(11):1473-1490. doi: 10.2337/diabetes.41.11.1473.Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: 2008 update. Genome Med. 2009;1(1):13. doi: 10.1186/gm13.Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: 2008 update. Genome Med. 2009;1(1):13. doi: 10.1186/gm13.Thiel CT, Knebel B, Knerr I, et al. Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson–Mendenhall syndrome. Mol Genet Metab. 2008;94(3):356-362. doi: 10.1016/j.ymgme.2008.02.013.Thiel CT, Knebel B, Knerr I, et al. Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson–Mendenhall syndrome. Mol Genet Metab. 2008;94(3):356-362. doi: 10.1016/j.ymgme.2008.02.013.Hovnik T, Bratanič N, Podkrajšek KT, et al. Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. Eur J Pediatr. 2012;172(8):1125-1129. doi: 10.1007/s00431-012-1901-7.Hovnik T, Bratanič N, Podkrajšek KT, et al. Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. Eur J Pediatr. 2012;172(8):1125-1129. doi: 10.1007/s00431-012-1901-7.Falik Zaccai TC, Kalfon L, Klar A, et al. Two novel mutations identified in familial cases with Donohue syndrome. Molecular Genetics & Genomic Medicine. 2014;2(1):64-72. doi: 10.1002/mgg3.43.Falik Zaccai TC, Kalfon L, Klar A, et al. Two novel mutations identified in familial cases with Donohue syndrome. Molecular Genetics & Genomic Medicine. 2014;2(1):64-72. doi: 10.1002/mgg3.43.Baykan A, Cansever M, Konuskan B, et al. Hypertrophic Cardiomyopathy with Leprechaunism. J Pediatr Endocrinol Metab. 2008;21(4). doi: 10.1515/jpem.2008.21.4.317.Baykan A, Cansever M, Konuskan B, et al. Hypertrophic Cardiomyopathy with Leprechaunism. J Pediatr Endocrinol Metab. 2008;21(4). doi: 10.1515/jpem.2008.21.4.317.Simpkin A, Cochran E, Cameron F, et al. Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations. Nephron Physiology. 2014;128(3-4):55-61. doi: 10.1159/000366225.Simpkin A, Cochran E, Cameron F, et al. Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations. Nephron Physiology. 2014;128(3-4):55-61. doi: 10.1159/000366225.Agarwal AK, Simha V, Oral EA, et al. Phenotypic and Genetic Heterogeneity in Congenital Generalized Lipodystrophy. J Clin Endocr Metab. 2003;88(10):4840-4847. doi: 10.1210/jc.2003-030855.Agarwal AK, Simha V, Oral EA, et al. Phenotypic and Genetic Heterogeneity in Congenital Generalized Lipodystrophy. J Clin Endocr Metab. 2003;88(10):4840-4847. doi: 10.1210/jc.2003-030855.Brown RJ, Cochran E, Gorden P. Metreleptin Improves Blood Glucose in Patients With Insulin Receptor Mutations. J Clin Endocr Metab. 2013;98(11):E1749-E1756. doi: 10.1210/jc.2013-2317.Brown RJ, Cochran E, Gorden P. Metreleptin Improves Blood Glucose in Patients With Insulin Receptor Mutations. J Clin Endocr Metab. 2013;98(11):E1749-E1756. doi: 10.1210/jc.2013-2317.Weber DR, Stanescu DE, Semple R, et al. Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome. J Pediatr Endocrinol Metab. 2014;0(0). doi: 10.1515/jpem-2013-0402.Weber DR, Stanescu DE, Semple R, et al. Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome. J Pediatr Endocrinol Metab. 2014;0(0). doi: 10.1515/jpem-2013-0402.Schoenle EJ, Zenobi PD, Torresani T, et al. Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. Diabetologia. 1991;34(9):675-679. doi: 10.1007/bf00400998.Schoenle EJ, Zenobi PD, Torresani T, et al. Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. Diabetologia. 1991;34(9):675-679. doi: 10.1007/bf00400998.Kitamei H, Yokoi M, Kase M, Ohno S. Retinal neovascularization during treatment with IGF-1 for insulin resistance syndrome. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2005;243(7):715-717. doi: 10.1007/s00417-004-1093-6.Kitamei H, Yokoi M, Kase M, Ohno S. Retinal neovascularization during treatment with IGF-1 for insulin resistance syndrome. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2005;243(7):715-717. doi: 10.1007/s00417-004-1093-6.Jo W, Sudo S, Nakamura A, et al. Development of Endometrial Carcinoma in a Patient with Leprechaunism (Donohue Syndrome). Clinical Pediatric Endocrinology. 2013;22(2):33-38. doi: 10.1297/cpe.22.33. doi: 10.14341/probl201662242-45Jo W, Sudo S, Nakamura A, et al. Development of Endometrial Carcinoma in a Patient with Leprechaunism (Donohue Syndrome). Clinical Pediatric Endocrinology. 2013;22(2):33-38. doi: 10.1297/cpe.22.33. doi: 10.14341/probl201662242-45

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