ometendoОжирение и метаболизмObesity and metabolism2071-87132306-5524Endocrinology Research Centre10.14341/omet13302ometendo-13302Research ArticleКЛИНИЧЕСКИЕ СЛУЧАИCASE REPORTSРедкий случай акрогигантизма вследствие Карни-комплекса: трудности диагностики и леченияA rare case of acrohygiantism caused by Carney’s complex: diagnostic and treatment challengeshttps://orcid.org/0009-0006-4490-8880ФилькинаЕ. Е.FilkinaE. E.

Филькина Екатерина Евгеньевна, клинический ординатор

117292, Москва, ул. Дм. Ульянова, д. 11

Ekaterina E. Filkina, Clinical resident

11 Dm. Ulyanova street, 117292 Moscow

katia.v.e@mail.ruhttps://orcid.org/0000-0001-9119-2447ПржиялковскаяЕ. Г.PrzhiyalkovskayaE. G.

Пржиялковская Елена Георгиевна, к.м.н., заведующая отделением нейроэндокринологии Москва

Elena G. Przhiyalkovskaya, MD, PhD

Moscow

przhiyalkovskaya.elena@gmail.comhttps://orcid.org/0000-0001-7736-5372КолодкинаА. А.KolodkinaA. A.

Колодкина Анна Александровна, к.м.н., заведующая отделением наследственных заболеваний и эндокринопатий раннего возраста

Москва

Anna A. Kolodkina, PhD, MD

Moscow

anna_kolodkina@mail.ruhttps://orcid.org/0000-0001-6891-0009УрусоваЛ. С.UrusovaL. S.

Урусова Лилия Сергеевна, д.м.н., заведующая отделом фундаментальной патоморфологии

Москва

Liliya Urusova, ScD

Moscow

liselivanova89@yandex.ruhttps://orcid.org/0000-0002-8520-8702ТрошинаЕ. А.TroshinaE. A.

Трошина Екатерина Анатольевна, д.м.н., член-корр. РАН, профессор, заместитель директора Центра - Директор Института клинической эндокринологии

Москва

Ekaterina A. Troshina, MD, PhD, Professor

Moscow

troshina@inbox.ruГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии им. академика И.И. Дедова»РоссияEndocrinology Research CenterRussian Federation202514022026224383390Copyright © Филькина Е.Е., Пржиялковская Е.Г., Колодкина А.А., Урусова Л.С., Трошина Е.А., 20262026Филькина Е.Е., Пржиялковская Е.Г., Колодкина А.А., Урусова Л.С., Трошина Е.А.Filkina E.E., Przhiyalkovskaya E.G., Kolodkina A.A., Urusova L.S., Troshina E.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.omet-endojournals.ru/jour/article/view/13302

Акромегалия и гигантизм — редкие нейроэндокринные заболевания, вызванные избыточной секрецией гормона роста (ГР) и/или высоким уровнем инсулиноподобного фактора роста (ИФР-1). Гигантизм развивается, когда избыток ГР или ИФР-1 приводит к ускоренному линейному росту до завершения полового созревания и закрытия эпифизов, что в большинстве случаев бывает вызвано соматотропной аденомой гипофиза. Особые трудности представляет диагностика соматотропиномы в детском возрасте ввиду стертой и неспецифической клинической картины. Соматотропиномы в молодом возрасте чаще вызваны генетическими аномалиями и имеют более агрессивное течение. В статье представлен клинический случай акрогигантизма у пациента с двумя выявленными гетерозиготными вариантами в генах PRKAR1A и SDHB. Научный интерес описываемого наблюдения обусловлен дебютом гигантизма в детском возрасте, сложным патогенетическим лечением, а также опытом применения антагониста рецепторов гормона роста пэгвисоманта у подростка в России.

Acromegaly and gigantism are rare neuroendocrine diseases caused by excessive secretion of growth hormone (GH) and/ or high levels of insulin-like growth factor (IGF-1). Gigantism develops when excess GH or IGF-1 leads to accelerated linear growth before the completion of puberty and the closure of the epiphyses, most commonly caused by a somatotropic pituitary adenoma. The diagnosis of somatotropinoma in childhood is particularly challenging due to its subtle and nonspecific clinical presentation. Somatotropinomas at a young age are more often caused by genetic abnormalities and have a more aggressive course.

The article presents a clinical case of acrogigantism in a patient with two identified heterozygous variants in the PRKAR1A and SDHB genes. The scientific interest of the described observation is due to the debut of gigantism in childhood, complex pathogenetic treatment, as well as the experience of using the growth hormone receptor antagonist pegvisomant in a teenager in Russia.

акрогигантизмКарни-комплексPRKAR1ASDHBacrogigantismCarney complexPRKAR1ASDHBРабота выполнена в рамках НИР 123021300096-3 «Новые генетические предикторы (варианты) опухолевых и неопухолевых эндокринных заболеваний у взрослых, определяемые методом полноэкзомного секвенирования, в том числе в ядерных семьях» (2023–2025 гг.).ReferencesRostomyan L, Beckers A. Screening for genetic causes of growth hormone hypersecretion. Growth Horm IGF Res. 2016;30-31:52-57. doi: 10.1016/j.ghir.2016.10.004 doi: https://doi.org/10.1016/j.ghir.2016.10.004Rostomyan, L., & Beckers, A. (2016). Screening for genetic causes of growth hormone hypersecretion. Growth Hormone & IGF Research, 30-31, 52–57. doi:10.1016/j.ghir.2016.10.004Vasilev V, Daly AF, Zacharieva S, Beckers A. Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas. Horm Metab Res. 2020;52(8):553-561. doi: https://doi.org/10.1055/a-1143-5930Vasilev V, Daly AF, Zacharieva S, Beckers A. Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas. Horm Metab Res. 2020 Aug;52(8):553-561. doi: 10.1055/a-1143-5930. Epub 2020 Apr 16. PMID: 32299111.Hernandez-Ramirez LC, Korbonits M. Familiar pituitary adenomas. In: Laws ER, Ezzat S, Asa SL, Rio ML, Michel L and Knutzen R, editors. Pituitary Disorders: Diagnosis and Management. 1st ed. John Wiley & Sons. 2013;87-110Hernandez-Ramirez LC, Korbonits M. Familiar pituitary adenomas. In: Laws ER, Ezzat S, Asa SL, Rio ML, Michel L and Knutzen R, editors. Pituitary Disorders: Diagnosis and Management. 1st ed. John Wiley & Sons. 2013;87-110.Hannah-Shmouni F, Trivellin G, Stratakis CA. Genetics of gigantism and acromegaly. Growth Horm IGF Res. 2016;30-31:37-41. doi: https://doi.org/10.1016/j.ghir.2016.08.002Hannah-Shmouni, F., Trivellin, G., & Stratakis, C. A. (2016). Genetics of gigantism and acromegaly. Growth Hormone & IGF Research, 30-31, 37–41. doi:10.1016/j.ghir.2016.08.002Nozières C, Berlier P, Dupuis C, Raynaud-Ravni C, Morel Y, Chazot FB, Nicolino M. Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature. Orphanet J Rare Dis. 2011;6:67. doi: https://doi.org/10.1186/1750-1172-6-67Nozières C, Berlier P, Dupuis C, Raynaud-Ravni C, Morel Y, Chazot FB, Nicolino M. Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature. Orphanet J Rare Dis. 2011 Oct 24;6:67. doi: 10.1186/1750-1172-6-67. PMID: 22024364; PMCID: PMC3234180.Kamilaris CDC, Faucz FR, Voutetakis A, Stratakis CA. Carney Complex. Exp Clin Endocrinol Diabetes. 2019;127(2-03):156-164. doi: https://doi.org/10.1055/a-0753-4943Kamilaris CDC, Faucz FR, Voutetakis A, Stratakis CA. Carney Complex. Exp Clin Endocrinol Diabetes. 2019 Feb;127(2-03):156-164. doi: 10.1055/a-0753-4943. Epub 2018 Nov 14. PMID: 30428497.Orlova EM, Kareva MA. Carney complex - multiple endocrine neoplasia syndrome. Problems of Endocrinology. 2012;58(3):22-30. doi: https://doi.org/10.14341/probl201258322-30Orlova E.M., Kareva M.A. Carney complex - multiple endocrine neoplasia syndrome. Problems of Endocrinology. 2012;58(3):22-30. https://doi.org/10.14341/probl201258322-30Stratakis CA. Carney Complex. 2003 Feb 5 [updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024Stratakis CA. Carney Complex. 2003 Feb 5 [updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301463.Mamedova EO, Przhiyalkovskaya EG, Pigarova EA, Mokrysheva NG, Dzeranova LK, Tyulpakov AN. Pituitary adenomas in the framework of hereditary syndromes. Problems of Endocrinology. 2014;60(4):51-59. (In Russ.) doi: https://doi.org/10.14341/probl201460438-46Mamedova E.O., Przhiyalkovskaya E.G., Pigarova E.A., Mokrysheva N.G., Dzeranova L.K., Tyulpakov A.N. Pituitary adenomas in the framework of hereditary syndromes. Problems of Endocrinology. 2014;60(4):51-59. (In Russ.) https://doi.org/10.14341/probl201460438-46Zhang YL, Wang XC, Yu W, Pei LP, Ma Y, Jiang S, Sun YP. A case of familial Carney complex. Arch Iran Med. 2015;18(5):324-8Zhang YL, Wang XC, Yu W, Pei LP, Ma Y, Jiang S, Sun YP. A case of familial Carney complex. Arch Iran Med. 2015 May;18(5):324-8. PMID: 25959917.Anselmo J, Medeiros S, Carneiro V, Greene E, Levy I, Nesterova M, Lyssikatos C, Horvath A, Carney JA, Stratakis CA. A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab. 2012;97(2):351-9. doi: https://doi.org/10.1210/jc.2011-2244Anselmo J, Medeiros S, Carneiro V, Greene E, Levy I, Nesterova M, Lyssikatos C, Horvath A, Carney JA, Stratakis CA. A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab. 2012 Feb;97(2):351-9. doi: 10.1210/jc.2011-2244. Epub 2011 Nov 23. PMID: 22112814; PMCID: PMC3275364.Maher M, Roncaroli F, Mendoza N, Meeran K, Canham N, et al. A patient with a germline SDHB mutation presenting with an isolated pituitary macroprolactinoma. Endocrinol Diabetes Metab Case Rep. 2018;2018:18-0078. doi: https://doi.org/10.1530/EDM-18-0078Maher M, Roncaroli F, Mendoza N, Meeran K, Canham N, Kosicka-Slawinska M, Bernhard B, Collier D, Drummond J, Skordilis K, Tufton N, Gontsarova A, Martin N, Korbonits M, Wernig F. A patient with a germline SDHB mutation presenting with an isolated pituitary macroprolactinoma. Endocrinol Diabetes Metab Case Rep. 2018 Jul 21;2018:18-0078. doi: 10.1530/EDM-18-0078. PMID: 30087776; PMCID: PMC6063986.Lifshitz E, Zancisbergs S. Pediatric Endocrinology. New York, 1985:3-36Lifshitz E, Zancisbergs S. // Pediatric Endocrinology. — New York, 1985. - P. 3-36.Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer. 2015;22(5):745-57. doi: https://doi.org/10.1530/ERC-15-0320Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, Holdaway I, Kranenburg-van Klaveren DJ, Chiara Zatelli M, Palacios N, Nozieres C, Zacharin M, Ebeling T, Ojaniemi M, Rozhinskaya L, Verrua E, Jaffrain-Rea ML, Filipponi S, Gusakova D, Pronin V, Bertherat J, Belaya Z, Ilovayskaya I, Sahnoun-Fathallah M, Sievers C, Stalla GK, Castermans E, Caberg JH, Sorkina E, Auriemma RS, Mittal S, Kareva M, Lysy PA, Emy P, De Menis E, Choong CS, Mantovani G, Bours V, De Herder W, Brue T, Barlier A, Neggers SJ, Zacharieva S, Chanson P, Shah NS, Stratakis CA, Naves LA, Beckers A. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer. 2015 Oct;22(5):745-57. doi: 10.1530/ERC-15-0320. Epub 2015 Jul 17. PMID: 26187128; PMCID: PMC6533620.Sada V, Puliani G, Feola T, Pirchio R, Pofi R, et al; TALENT group. Tall stature and gigantism in transition age: clinical and genetic aspects-a literature review and recommendations. J Endocrinol Invest. 2024;47(4):777-793. doi: https://doi.org/10.1007/s40618-023-02223-zSada V, Puliani G, Feola T, Pirchio R, Pofi R, Sesti F, De Alcubierre D, Amodeo ME, D'Aniello F, Vincenzi L, Gianfrilli D, Isidori AM, Grossman AB, Sbardella E; TALENT group. Tall stature and gigantism in transition age: clinical and genetic aspects-a literature review and recommendations. J Endocrinol Invest. 2024 Apr;47(4):777-793. doi: 10.1007/s40618-023-02223-z. Epub 2023 Oct 27. PMID: 37891382; PMCID: PMC10965707.Gadelha MR, Kasuki L, Korbonits M. The genetic background of acromegaly. Pituitary. 2017;20(1):10-21. doi: https://doi.org/10.1007/s11102-017-0789-7Gadelha MR, Kasuki L, Korbonits M. The genetic background of acromegaly. Pituitary. 2017;20(1):10-21. https://doi.org/10.1007/s11102-017-0789-7Personnier C, Cazabat L, Bertherat J, Gaillard S, Souberbielle JC, et al. Clinical features and treatment of pediatric somatotropinoma: case study of an aggressive tumor due to a new AIP mutation and extensive literature review. Horm Res Paediatr. 2011;75(6):392-402. doi: https://doi.org/10.1159/000327831Personnier C, Cazabat L, Bertherat J, Gaillard S, Souberbielle JC, Habrand JL, Dufour C, Clauser E, SainteRose C, Polak M. Clinical features and treatment of pediatric somatotropinoma: case study of an aggressive tumor due to a new AIP mutation and extensive literature review. Horm Res Paediatr. 2011;75(6):392-402. doi: 10.1159/000327831. Epub 2011 May 6. PMID: 21546764.Nozières C, Berlier P, Dupuis C, Raynaud-Ravni C, Morel Y, Chazot FB, Nicolino M. Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature. Orphanet J Rare Dis. 2011;6:67. doi: https://doi.org/10.1186/1750-1172-6-67Nozières C, Berlier P, Dupuis C, Raynaud-Ravni C, Morel Y, Chazot FB, Nicolino M. Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature. Orphanet J Rare Dis. 2011 Oct 24;6:67. doi: 10.1186/1750-1172-6-67. PMID: 22024364; PMCID: PMC3234180.Bogusławska A, Korbonits M. Genetics of Acromegaly and Gigantism. J Clin Med. 2021;10(7):1377. doi: https://doi.org/10.3390/jcm10071377Bogusławska A, Korbonits M. Genetics of Acromegaly and Gigantism. J Clin Med. 2021 Mar 29;10(7):1377. doi: 10.3390/jcm10071377. PMID: 33805450; PMCID: PMC8036715.Cuny T, Mac TT, Romanet P, Dufour H, Morange I, et al. Acromegaly in Carney complex. Pituitary. 2019;22(5):456-466. doi: https://doi.org/10.1007/s11102-019-00974-8Cuny T, Mac TT, Romanet P, Dufour H, Morange I, Albarel F, Lagarde A, Castinetti F, Graillon T, North MO, Barlier A, Brue T. Acromegaly in Carney complex. Pituitary. 2019 Oct;22(5):456-466. doi: 10.1007/s11102-019-00974-8. PMID: 31264077.Washecka R, Dresner MI, Honda SAA. Testicular tumors in Carney’s complex. The Journal of Urology. 2002;167(3):1299–1302. doi: https://doi.org/10.1016/s0022-5347(05)65285-8WASHECKA, R., DRESNER, M. I., & HONDA, S. A. A. (2002). TESTICULAR TUMORS IN CARNEY’S COMPLEX. The Journal of Urology, 167(3), 1299–1302. doi:10.1016/s0022-5347(05)65285-8Henderson CG, Ahmed AA, Sesterhenn I, Belman AB, Rushton HG. Enucleation for prepubertal leydig cell tumor. J Urol. 2006;176(2):703- 5. doi: https://doi.org/10.1016/j.juro.2006.03.083Henderson CG, Ahmed AA, Sesterhenn I, Belman AB, Rushton HG. Enucleation for prepubertal leydig cell tumor. J Urol. 2006 Aug;176(2):703-5. doi: 10.1016/j.juro.2006.03.083. PMID: 16813923.Gheorghisan-Galateanu AA. Leydig cell tumors of the testis: a case report. BMC Res Notes. 2014;7:656. doi: https://doi.org/10.1186/1756-0500-7-656Gheorghisan-Galateanu AA. Leydig cell tumors of the testis: a case report. BMC Res Notes. 2014 Sep 18;7:656. doi: 10.1186/1756-0500-7-656. PMID: 25230718; PMCID: PMC4175283.Hoekstra AS, Bayley JP. The role of complex II in disease. Biochim Biophys Acta. 2013;1827(5):543-551. doi: https://doi.org/10.1016/j.bbabio.2012.11.005Hoekstra AS, Bayley JP. The role of complex II in disease. Biochim Biophys Acta. 2013;1827(5):543-551. doi: 10.1016/j.bbabio.2012.11.005.Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015;100(5):E710-9. doi: https://doi.org/10.1210/jc.2014-4297Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, Mastorakos P, Wassif CA, Raygada M, Rentia N, Dye L, Cougnoux A, Koziol D, Sierra Mde L, Lyssikatos C, Belyavskaya E, Malchoff C, Moline J, Eng C, Maher LJ 3rd, Pacak K, Lodish M, Stratakis CA. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015 May;100(5):E710-9. doi: 10.1210/jc.2014-4297. Epub 2015 Feb 19. PMID: 25695889; PMCID: PMC4422891.Freda PU. The acromegaly lipodystrophy. Front Endocrinol (Lausanne). 2022;13:933039. doi: https://doi.org/10.3389/fendo.2022.933039Freda PU. The acromegaly lipodystrophy. Front Endocrinol (Lausanne). 2022 Sep 13;13:933039. doi: 10.3389/fendo.2022.933039. PMID: 36176462; PMCID: PMC9513226.Giustina A, Arnaldi G, Bogazzi F, Cannavò S, Colao A, et al. Pegvisomant in acromegaly: an update. J Endocrinol Invest. 2017;40(6):577-589. doi: https://doi.org/10.1007/s40618-017-0614-1. Erratum in: J Endocrinol Invest. 2018;41(2):267. doi: https://doi.org/10.1007/s40618-017-0800-1Giustina A, Arnaldi G, Bogazzi F, Cannavò S, Colao A, De Marinis L, De Menis E, Degli Uberti E, Giorgino F, Grottoli S, Lania AG, Maffei P, Pivonello R, Ghigo E. Pegvisomant in acromegaly: an update. J Endocrinol Invest. 2017 Jun;40(6):577-589. doi: 10.1007/s40618-017-0614-1. Epub 2017 Feb 7. Erratum in: J Endocrinol Invest. 2018 Feb;41(2):267. doi: 10.1007/s40618-017-0800-1. PMID: 28176221; PMCID: PMC5443862.Michalaki MA, Gkotsina MI, Mamali I, Markantes GK, Faltaka A, et al. Impaired pharmacokinetics of levothyroxine in severely obese volunteers. Thyroid. 2011;21(5):477-81. doi: https://doi.org/10.1089/thy.2010.0149Michalaki MA, Gkotsina MI, Mamali I, Markantes GK, Faltaka A, Kalfarentzos F, Vagenakis AG, Markou KB. Impaired pharmacokinetics of levothyroxine in severely obese volunteers. Thyroid. 2011 May;21(5):477-81. doi: 10.1089/thy.2010.0149. Epub 2011 Mar 21. PMID: 21417917.

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