Нунан-подобный синдром с выпадением волос в фазе анагена: генетическая и фенотипическая вариабельность, дифференциальная диагностика

В обзоре обобщены сведения о Нунан-подобном синдроме с выпадением волос в фазе анагена (НПСВВФА) из группы RAS-патий. Рассмотрены генетические аспекты синдрома, патогенез, клинические проявления и сопутствующие состояния. Обсуждается дифференциальная диагностика между двумя генетически гетерогенными типами НПСВВФА, вызванными изменениями в генах SHOC2 (НПСВВФА1) и PPP1CB (НПСВВФА2). Представлено описание пациента с подтвержденным НПСВВФА1. Обзор предназначен для повышения осведомленности врачей, в том числе в вопросах генотип-фенотипических корреляций при НПСВВФА. Последнее необходимо для генетического консультирования, диагностики и разработки новых методов лечения и реабилитации.

1. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of RAS/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19(3):230-236. doi: https://doi.org/10.1016/j.gde.2009.04.001

2. Hilal N, Chen Z, Chen MH, Choudhury S. RASopathies and cardiac manifestations. Front Cardiovasc Med. 2023;10:1176828. doi: https://doi.org/10.3389/fcvm.2023.1176828

3. Weiss E-M, Guhathakurta D, Petruskova A, et al. Developmental effect of RASopathy mutations on neuronal network activity on a chip. Front Cell Neurosci. 2024;18:1388409. doi: https://doi.org/10.3389/fncel.2024.1388409

4. Zenker M. Clinical overview on RASopathies. Am J Med Genet C Semin Med Genet. 2022;190(4):414-424. doi: https://doi.org/10.1002/ajmg.c.32015

5. Tosti A, Misciali C, Borrello P, et al. Loose anagen hair in a child with Noonan's syndrome. Dermatologica. 1991;182(4):247-249. doi: https://doi.org/10.1159/000247806

6. Tosti A, Peluso AM, Misciali C, et al. Loose anagen hair. Arch Dermatol. 1997;133(9):1089-1093.

7. Mazzanti L, Cacciari E, Cicognani A, et al. Noonan-like syndrome with loose anagen hair: a new syndrome? Am J Med Genet A. 2003;118A(3):279-286. doi: https://doi.org/10.1002/ajmg.a.10923

8. Hannig V, Jeoung M, Jang ER, et al. A Novel SHOC2 Variant in Rasopathy. Hum Mutat. 2014;35(11):1290-1294. doi: https://doi.org/10.1002/humu.22634

9. Wang Q, Cheng S, Fu Y, Yuan H. Case report: A de novo RASopathy-causing SHOC2 variant in a Chinese girl with noonan syndromelike with loose anagen hair. Front Genet. 2022;13:1040124. doi: https://doi.org/10.3389/fgene.2022.1040124

10. Komatsuzaki S, Aoki Y, Niihori T, et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010;55(12):801-809. doi: https://doi.org/10.1038/jhg.2010.116

11. Gripp KW, Aldinger KA, Bennett JT, et al. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. Am J Med Genet A. 2016;170(9):2237-2247. doi: https://doi.org/10.1002/ajmg.a.37781

12. Zhang JJ, Zeng Y. Prenatal diagnosis of Rasopathies in Ras/MAPK signaling pathway. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020;37(11):1291-1294. doi: https://doi.org/10.3760/cma.j.cn511374-20190717-00354

13. Tamburrino F, Mazzanti L, Scarano E, et al. Lipid profile in Noonan syndrome and related disorders: trend by age, sex and genotype. Front Endocrinol (Lausanne). 2023;14:1209339. doi: https://doi.org/10.3389/fendo.2023.1209339

14. Guo YJ, Pan WW, Liu SB, et al. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19(3):1997-2007. doi: https://doi.org/10.3892/etm.2020.8454

15. Grant AR, Cushman BJ, Cave H, et al. Assessing the genedisease association of 19 genes with the RASopathies using the ClinGen gene curation framework. Hum Mutat. 2018;39(11): 1485-1493. doi: https://doi.org/10.1002/humu.23624

16. Hebron KE, Hernandez ER, Yohe ME. The RASopathies: from pathogenetics to therapeutics. Dis Model Mech. 2022;15(2):dmm049107. doi: https://doi.org/10.1242/dmm.049107

17. Wilson P, Abdelmoti L, Norcross R, et al. The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair. J Cell Sci. 2021;134(21):jcs258922. doi: https://doi.org/10.1242/jcs.258922

18. Cordeddu V, Di Schiavi E, Pennacchio LA, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022-1026. doi: https://doi.org/10.1038/ng.425

19. Jang H, Stevens P, Gao T, Galperin E. The leucine-rich repeat signaling scaffolds Shoc2 and Erbin: cellular mechanism and role in disease. FEBS J. 2021;288(3):721-739. doi: https://doi.org/10.1111/febs.15450

20. Pudewell S, Wittich C, Kazemein Jasemi NS, et al. Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line. Commun Biol. 2021;4(1):696. doi: https://doi.org/10.1038/s42003-021-02149-3

21. Young LC, Hartig N, Boned Del Rfo I, et al. SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. Proc Natl Acad Sci U S A. 2018;115(45):E10576-E10585. doi: https://doi.org/10.1073/pnas.1720352115

22. Norcross RG, Abdelmoti L, Rouchka EC, et al. Shoc2 controls ERK1/2-driven neural crest development by balancing components of the extracellular matrix. Dev Biol. 2022;492:156-171. doi: https://doi.org/10.1016/j.ydbio.2022.10.010

23. Bonsor DA, Simanshu DK. Structural insights into the role of SHOC2-MRAS-PP1C complex in RAF activation. FEBS J. 2023;290(20):4852-4863. doi: https://doi.org/10.1111/febs.16800

24. Motta M, Giancotti A, Mastromoro G, et al. Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy. Hum Mutat. 2019;40(8):1046-1056. doi: https://doi.org/10.1002/humu.23767

25. Motta M, Solman M, Bonnard AA, et al. Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome. Hum Mol Genet. 2022;31(16):2766-2778. doi: https://doi.org/10.1093/hmg/ddac071

26. OMIM #617506. Noonan syndrome-like disorder with loose anagen hair 2; NSLH2. In: OMIM — Online Mendelian Inheritance in Man: Official website. Available online: https://omim.org/entry/617506. Accessed on May 28, 2025.

27. Gene ID: 5500, PPP1CC protein phosphatase 1 catalytic subunit gamma. In: National Center for Biotechnology Information (NCBI): Official website. Available online: https://www.ncbi.nlm.nih.gov/gene/5500. Accessed on May 28, 2025.

28. Signal Transduction Pathways: Phosphatases. Cellular & Molecular Biology, Signal Transduction Processes. Last Updated: March 27, 2025. In: The Medial Biochemistry Page: Official website. Available online: https://themedicalbiochemistrypage.org/signal-transduction-pathways-phosphatases. Accessed on May 28, 2025.

29. Hamdan FF, Srour M, Capo-Chichi JM, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10(10):e1004772. doi: https://doi.org/10.1371/journal.pgen.1004772

30. Ma L, Bayram Y, McLaughlin HM, et al. De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease. Hum Genet. 2016;135(12):1399-1409. doi: https://doi.org/10.1007/s00439-016-1731-1

31. Lin CH, Lin WD, Chou IC, et al. Epileptic spasms in PPP1CB-associated Noonan-like syndrome: a case report with clinical and therapeutic implications. BMC Neurol. 2018;18(1):150. doi: https://doi.org/10.1186/s12883-018-1157-6

32. Huckstadt V, Chinton J, Gomez A, et al. Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported. Am J Med Genet A. 2021;185(4):1256-1260. doi: https://doi.org/10.1002/ajmg.a.62089

33. Bertola D, Yamamoto G, Buscarilli M, et al. The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: broadening the clinical phenotype. Am J Med Genet A. 2017;173(3):824-828. doi: https://doi.org/10.1002/ajmg.a.38070

34. Zambrano RM, Marble M, Chalew SA, et al. Further evidence that variants in PPP1CB cause a rasopathy similar to Noonan syndrome with loose anagen hair. Am J Med Genet A. 2017;173(2):565-567. doi: https://doi.org/10.1002/ajmg.a.38056

35. Maruwaka K, Nakajima Y, Yamada T, et al. Two Japanese patients with Noonan syndrome-like disorder with loose anagen hair 2. Am J Med Genet A. 2022;188(7):2246-2250. doi: https://doi.org/10.1002/ajmg.a.62733

36. He X, Ma X, Wang J, et al. Case report: Identification and clinical phenotypic analysis of novel mutation of the PPP1CB gene in NSLH2 syndrome. Front Behav Neurosci. 2022;16:987259. doi: https://doi.org/10.3389/fnbeh.2022.987259

37. Capalbo D, Scala MG, Melis D, et al. Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation. Ital J Pediatr. 2012;38:48. doi: https://doi.org/10.1186/1824-7288-38-48

38. Gripp KW, Zand DJ, Demmer L, et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013;161A(10):2420-2430. doi: https://doi.org/10.1002/ajmg.a.36098

39. Zmolikova M, Puchmajerova A, Hecht P, et al. Coarctation of the aorta in Noonan-like syndrome with loose anagen hair. Am J Med Genet A. 2014;164A(5):1218-1221. doi: https://doi.org/10.1002/ajmg.a.36404

40. Baldassarre G, Mussa A, Banaudi E, et al. Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. Am J Med Genet A. 2014;164A(12):3120-3125. doi: https://doi.org/10.1002/ajmg.a.36697

41. Журкова Н.В., Казакова К.А., Варичкина М.А. и др. Нунан-подобный синдром с потерей анагена: три клинических случая // Неврологический журнал имени Л.О. Бадаляна. — 2020. — Т. 1. — № 3. — С. 188-196. — doi: https://doi.org/10.17816/2686-8997-2020-1-3-188-196

42. Davico C, D'Alessandro R, Borgogno M, et al. Epilepsy in a cohort of children with Noonan syndrome and related disorders. Eur J Pediatr. 2022;181(8):2919-2926. doi: https://doi.org/10.1007/s00431-022-04497-6

43. Bouayed Abdelmoula N. Behavioral phenotype of Noonan-like syndrome with loose anagen hair. Eur Psychiatry. 2022;65 (Suppl 1):S462. doi: https://doi.org/10.1192/j.eurpsy.2022.1172

44. Zarbo A, Shwayder T. Loose anagen hair syndrome. J Pediatr. 2018;199:282-282. doi: https://doi.org/10.1016/j.jpeds.2018.03.005

45. Rigante D, Leoni C, Onesimo R, et al. Aberrant N-myristoylation as a prelude to autoimmune manifestations in patients with SHOC2 mutations. Autoimmun Rev. 2023;22(11):103462. doi: https://doi.org/10.1016/j.autrev.2023.103462

46. Uehara T, Hosogaya N, Matsuo N, Kosaki K. Systemic lupus erythematosus in a patient with Noonan syndrome-like disorder with loose anagen hair 1: More than a chance association. Am J Med Genet A. 2018;176(7):1662-1666. doi: https://doi.org/10.1002/ajmg.a.38834

47. Quaio CRDC, Carvalho JF, da Silva CA, et al. Autoimmune Disease and multiple autoantibodies in 42 patients with RASopathies. Am J Med Genet Part A. 2012;158A(5):1077-1082. doi: https://doi.org/10.1002/ajmg.a.35290

48. Okazaki T, Saito Y, Sugita K, et al. Recurrent Erythema Nodosum in a Child with a SHOC2 Gene Mutation. Yonago Acta Med. 2019;62(1):159-162. doi: https://doi.org/10.33160/yam.2019.03.022

49. Liu L, Hu C, Chen Z, et al. Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant. Am J Case Rep. 2023;24:e942377. doi: https://doi.org/10.12659/AJCR.942377

50. Choi JH, Oh MY, Yum MS, et al. Moyamoya syndrome in a patient with Noonan-like syndrome with loose anagen hair. Pediatr Neurol. 2015;52(3):352-355. doi: https://doi.org/10.1016/j.pediatrneurol.2014.11.017

51. Lo FS, Wang CJ, Wong MC, Lee NC. Moyamoya disease in two patients with Noonan-like syndrome with loose anagen hair. Am J Med Genet. 2015;167(6):1285-1288. doi: https://doi.org/10.1002/ajmg.a.37053

52. Garavelli L, Cordeddu V, Errico S, et al. Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma. Am J Med Genet A. 2015;167A(8):1902-1907. doi: https://doi.org/10.1002/ajmg.a.37082

53. Avery A, Metcalf JS, Maize JC, Swanson LA. Cutaneous T-cell lymphoma in SHOC2 mutation-associated Noonan-like syndrome with loose anagen hair. JAAD Case Rep. 2022;24:52-55. doi: https://doi.org/10.1016/j.jdcr.2022.04.009

54. Fujishige S, Ogawa Y, Aoyagi H, Okamoto T. M-type phospholipase A2 receptor-associated membranous nephropathy in a patient with Noonan-like syndrome with loose anagen hair. Pediatr Int. 2023;65(1):e15643. doi: https://doi.org/10.1111/ped.15643

55. Couser NL, Keelean-Fuller D, Davenport ML, et al. Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1. Am J Med Genet A. 2018;176(9):2024-2027. doi: https://doi.org/10.1002/ajmg.a.40432

56. Haverfield E, Masood MM, Henin M, Aylsworth AS. Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1. Am J Med Genet A. 2018;176(9): 2024-2027. doi: https://doi.org/10.1002/ajmg.a.40432

57. Ogden CL, Kuczmarski RJ, Flegal KM, et al. Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics. 2002;109(1):45-60. doi: https://doi.org/10.1542/peds.109.1.45

58. Isojima T, Yokoya S. Development of disease-specific growth charts in Turner syndrome and Noonan syndrome. Ann Pediatr Endocrinol Metab. 2017;22(4):240-246. doi: https://doi.org/10.6065/apem.2017.22.4.240