Современные подходы к ведению детей с синдромом Алажилля

Синдром Алажилля — заболевание с преимущественно аутосомно-доминантным типом наследования, характеризующееся мультисистемным поражением, обусловленным мутациями в генах JAG1 и NOTCH2. Наиболее частыми проявлениями данного синдрома служат внутрипеченочный холестаз вследствие недоразвития желчных протоков, пороки развития сердца, челюстно-лицевой дисморфизм, патология позвонков, рентгенологически проявляющаяся как «позвонкибабочки», офтальмологические нарушения, сосудистые аномалии и патология почек. Кроме вышеперечисленного, значимыми являются нарушение нервно-психического и физического развития. Использование высокотехнологичных способов диагностики при наблюдении таких детей позволяет выявлять редко встречаемые нарушения, требующие не менее пристального наблюдения врачей мультидисциплинарной команды. Представленная статья посвящена современным подходам к ведению детей с синдромом Алажилля с акцентированием особого внимания на вариабельности клинических проявлений, особенностям диагностики и новым методам, в частности, таргетным препаратам для лечения пациентов с данным заболеванием. 

1. Ayoub M.D., Kamath B.M. Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management. Clin Liver Dis. 2022; 26(3): 355–370. DOI: 10.1016/j.cld.2022.03.002

2. Diaz-Frias J., Kondamudi N.P. Alagille Syndrome. 2023 Aug 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. PMID: 29939604

3. Semenova N., Kamenets E., Annenkova E., Marakhonov A., Gusarova E., Demina N., et al. Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease. Int J Mol Sci. 2023; 24(14): 11758. DOI: 10.3390/ijms241411758

4. Rizvanullah, Saad M., Ahmad KT., Gul A., Ali K. Alajille syndrome in infants: a rare case. J.D.D. Hepatol, 2022; 6: 176. DOI: 10.29011/2574–3511.100076

5. Eiamkulbutr S., Tubjareon C., Sanpavat A., Phewplung T., Srisan N., Sintusek P. Diseases of bile duct in children. World J Gastroenterol. 2024; 30(9): 1043–1072. DOI: 10.3748/wjg.v30.i9.1043

6. Alagille D., Odièvre M., Gautier M., Dommergues J.P. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975; 86(1): 63–71. DOI: 10.1016/s0022–3476(75)80706–2

7. Halma J., Lin H.C. Alagille syndrome: understanding the genotype-phenotype relationship and its potential therapeutic impact. Expert Rev Gastroenterol Hepatol. 2023; 17(9): 883–892. DOI: 10.1080/17474124.2023.2255518

8. Назаренко Л.П. Федеральные клинические рекомендации по диагностике и лечению синдрома Алажилля. М., 2015; 25

9. Дегтярева А.В., Докшукина А.А., Готье М.С., Филиппова Е.А., Туманова Е.Л., Захарова Е.Ю., Албегова М.Б. Ранние клинико-лабораторные и инструментальные характеристики синдрома Алажилля. Неонатология: новости, мнения, обучение. 2024; 12(1): 27–36. DOI: 10.33029/2308–2402–2024–12–1–27–36

10. Волынец Г.В., Никитин А.В., Скворцова Т.А. Синдром Алажилля у детей. Российский вестник перинатологии и педиатр 2020; 65:(2): 108–116. DOI: 10.21508/1027–4065–2020–65–2–108–116 DOI: 10.21508/1027–4065–2020–65–2–108–116

11. Karim F., Hiremath G., Samayoa J.C., Said S.M. Complex Pulmonary Artery Rehabilitation in Children with Alagille Syndrome: An Early Single-Center Experience of a Successful Collaborative Work. J Cardiovasc Dev Dis. 2024; 11(8): 232. DOI: 10.3390/jcdd11080232

12. Kohut T.J., Gilbert M.A., Loomes K.M. Alagille Syndrome: A Focused Review on Clinical Features, Genetics, and Treatment. Semin Liver Dis. 2021; 41(4): 525–537. DOI: 10.1055/s-0041–1730951

13. Şafak A., Karakaya E., Varan B., Özçay F., Çekmen N., Yıldırım S., et al. Experience and Results of Liver Transplantation in Patients With Alagille Syndrome at Our Center. Exp Clin Transplant. 2024; 22(Suppl 5): 94–99. DOI: 10.6002/ect.вpedsymp2024.O27

14. Gilbert M.A., Loomes K.M. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. TranslGastroenterol Hepatol. 2021; 6: 22. DOI: 10.21037/tgh-2020–03

15. Chen L., Chen J., Lou J., Yu J. Clinical and genetic characteristics of patients with Alagille syndrome in China: identification of six novel JAG1 and NOTCH2 mutations. Transl Pediatr. 2024; 13(12): 2144–2154. DOI: 10.21037/tp-24–301

16. Morton A., Kumar S. Alagille syndrome and pregnancy. Obstet Med. 2021; 14(1): 39–41. DOI: 10.1177/1753495X19849738

17. Zhou B., Lin W., Long Y., Yang Y., Zhang H., Wu K., et al. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022; 7(1): 95. DOI: 10.1038/s41392–022–00934–y

18. Spinner N.B., Loomes K.M., Krantz I.D., Gilbert M.A. Alagille Syndrome. 2000 May 19 [updated 2024 Jan 4]. In: GeneReviews®[Internet]. Editros: Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A. Seattle (WA): University of Washington, Seattle; 1993–2025

19. Bufler P., Howard R., Quadrado L., Lacey G., TernerRosenthal J., Goldstein A., et al. The burden of Alagille syndrome: uncovering the potential of emerging therapeutics — a comprehensive systematic literature review. J Comp Eff Res. 2025; 14(2):e240188. DOI: 10.57264/cer-2024–0188

20. Lee P.S., Silva Sepulveda J.A., Del Campo M., Leibel S.L., Hildreth A., Marc-Aurele K.L. A neonatal case of vascular ring with Alagille syndrome. SAGE Open Med Case Rep. 2023; 11: 2050313X231197321. DOI: 10.1177/2050313X231197321

21. D’Amico A., Perillo T., Cuocolo R., Ugga L., Di Dato F., Caranci F., et al. Neuroradiological findings in Alagille syndrome. Br J Radiol. 2022; 95(1129): 20201241. DOI: 10.1259/bjr.20201241

22. Гаджимурадов М.Н., Алиева М.Г., Мамашева Г.Д. Синдром Алажиля. Врач. 2020; 31 (8): 64–69. DOI: 10.29296/25877305–2020–08–10

23. Isa H.M., Alahmed F.A. Clinical, Laboratory, Radiological, and Genetic Characteristics of Pediatric Patients with Alagille Syndrome. Adv Biomed Res. 2023; 12: 155. DOI: 10.4103/abr.abr_201_22

24. Xu F., Peng Q., He X., Chen X., Jiang S., Lu X., et al. Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report. Front Pediatr. 2022; 10: 1020536. DOI: 10.3389/fped.2022.1020536

25. Bonnet A.L., Greset V., Davit-Beal T. Oral manifestations of Alagille syndrome. BMJ Case Rep. 2020; 13(5):e234689. DOI: 10.1136/bcr-2020–234689

26. Andersson E.R., Chivukula I.V., Hankeova S., Sjöqvist M., Tsoi Y.L., Ramsköld D., et al. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations. Gastroenterology. 2018; 154(4): 1080–1095. DOI: 10.1053/j.gastro.2017.11.002

27. Sharma A.D., Parihar A., Reddy P., Mandlik R. Oral manifestations of Alagille-2 syndrome: a rare case report. International Journal of Research in Medical Sciences, 2023; 11(9): 3471–3474. DOI: 10.18203/2320–6012.ijrms20232813

28. Zeng H.S., Zhang Z.H., Hu Y., Zheng G.L., Wang J., Zhang J.W., et al. Alagille syndrome associated with total anomalous pulmonary venous connection and severe xanthomas: A case report. World J Clin Cases. 2022; 10(25): 8932–8938. DOI: 10.12998/wjcc.v10.i25.8932

29. Yuan S.M. Pulmonary artery pathologies in Alagille syndrome: a meta-analysis. Postepy Kardiol Interwencyjnej. 2022; 18(2): 111–117. DOI: 10.5114/aic.2022.118526. Epub 2022 Aug 19

30. Wu K.Y., Treece A.L., Russo P.A., Wen J.W. An Atypical Presentation of Alagille Syndrome. Pediatr Dev Pathol. 2018; 21(1): 79–83. DOI: 10.1177/1093526616686902

31. Katsoulos K.F., Kapsala Z., Livir-Rallatos G. Case Report: Alagille Syndrome Presenting with Angioid Streaks. Optom Vis Sci. 2021; 98(2): 109–112. DOI: 10.1097/OPX.0000000000001641

32. Ranchin B., Meaux M.N., Freppel M., Ruiz M., De Mul A. Kidney and vascular involvement in Alagille syndrome. Pediatr Nephrol. 2025; 40(4): 891–899. DOI: 10.1007/s00467–024–06562–8. Epub 2024 Oct 24

33. Cerron-Vela C.R., Tierradentro-García L.O., Rimba Z.L., Andronikou S. Evolution of cerebrovascular imaging and associated clinical findings in children with Alagille syndrome. Neuroradiology. 2024; 66(8): 1325–1334. DOI: 10.1007/s00234–024–03316–z. Epub 2024 Feb 24

34. Guida L., Gardin A., James S., Arnaud E., Toujouse C., Roux J., et al. Craniosynostosis as a cause of intracranial hypertension in Alagille syndrome: a case series of 6 consecutive pediatric patients. Neurosurg Focus. 2025; 58(1):E6. DOI: 10.3171/2024.10.FOCUS24588

35. Gilbert M.A., Keefer-Jacques E., Jadhav T., Antfolk D., Ming Q., Valente N., Shaw G.T., et al. Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation. Am J Hum Genet. 2024; 111(8): 1656–1672. DOI: 10.1016/j.ajhg.2024.06.011

36. Andrews A.R., Putra J. Central Hepatic Regenerative Nodules in Alagille Syndrome: A Clinicopathological Review. Fetal Pediatr Pathol. 2021; 40(1): 69–79. DOI: 10.1080/15513815.2019.1675834. Epub 2019 Oct 14

37. Surapaneni A., Kuo J., Wang M., Ashour R. Epidermoid cyst in a patient with Alagille syndrome: Coincidence or connection? Surg Neurol Int. 2020; 11: 432 DOI: 10.25259/SNI_611_2020

38. Leung D.H., Sorensen L.G., Ye W., Hawthorne K., Ng V.L., Loomes K.M., et al. Childhood Liver Disease Research Network (ChiLDReN). Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver. J Pediatr Gastroenterol Nutr. 2022; 74(1): 96–103. DOI: 10.1097/MPG.0000000000003337

39. Yan J., Huang Y., Cao L., Dong Y., Xu Z., Wang F., et al. Clinical, pathological and genetic characteristics of 17 unrelated children with Alagille Syndrome. BMC Pediatr. 2024; 24(1): 532. DOI: 10.1186/s12887–024–04973–y

40. Неонатология: национальное руководство: в 2 т. Том 1. Под редакцией Володина Н.Н., Дегтярева Д.Н. 2–е изд., перераб. и доп. — Москва: ГЭОТАР-Медиа, 2023; 752 DOI: 10.33029/9704–7828–8–NNG-2023–1–752

41. Kamath B.M., Stein P., Houwen R.H.J., Verkade H.J. Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020; 40(8): 1812–1822. DOI: 10.1111/liv.14553

42. Heinz N., Vittorio J. Treatment of Cholestasis in Infants and Young Children. Curr Gastroenterol Rep. 2023; 25(11): 344–354. DOI: 10.1007/s11894–023–00891–8

43. Gonzales E., Hardikar W., Stormon M., Baker A., Hierro L., Gliwicz D., et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021; 398(10311): 1581–1592. DOI: 10.1016/S0140–6736(21)01256–3

44. Jarasvaraparn C., Rodrigo M., Hartley C., Karnsakul W. Exploring odevixibat’s efficacy in alagille syndrome: insights from recent clinical trials and IBAT inhibitor experiences. Expert Opin Pharmacother. 2024; 25(12): 1647–1655. DOI: 10.1080/14656566.2024.2392873

45. Shirley M. Maralixibat: First Approval. Drugs. 2022; 82(1): 71–76. DOI: 10.1007/s40265–021–01649–0

46. Hansen B.E., Vandriel S.M., Vig P., Garner W., Mogul D.B., Loomes K.M., et al. Global Alliance (GALA) Study Group ALagille. Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA. Hepatology. 2024; 79(6): 1279–1292. DOI: 10.1097/HEP.0000000000000727

47. Vandriel S.M., Li L.T., She H., Wang J.S., Gilbert M.A., Jankowska I., et al. Global ALagille Alliance (GALA) Study Group. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology. 2023; 77(2): 512–529. DOI: 10.1002/hep.32761