Noonan-Like Syndrome with Loose Anagen Hair: Genetic and Phenotypic Variability, Differential Diagnosis
Svetlana Ya. Volgina,
Yosuman S. Kurbanova,
Aydamir Sh. Abubakarov,
Arip M. Nimatulaev,
Ekaterina A. Nikolaeva,
Rimma G. Gamirova https://doi.org/10.15690/vsp.v24i3.2911
Abstract
The review summarizes the data on Noonan-like syndrome with loose anagen hair (NSLH) from the group of RASopathies. The genetic aspects of the syndrome, its pathogenesis, clinical signs, and comorbitant conditions are considered. Particular attention is paid to the differential diagnosis between two genetically heterogeneous types of NSLH associated with mutations in the SHOC2 gene (NSLH1) and in the PPP1CB gene (NSLH2). Clinical case description of the patient with confirmed NSLH1 is presented. This review is intended to increase physicians’ awareness specifically on NSLH genotype-phenotype correlations. This is crucial for genetic counseling, diagnosis, and development of new management and rehabilitation methods.
About the Authors
Svetlana Ya. Volgina
Kazan State Medical University
Russian Federation
Disclosure of interest:
Russian Federation
Kazan
Disclosure of interest:
None
Yosuman S. Kurbanova
Kazan State Medical University
Russian Federation
Disclosure of interest:
Russian Federation
Kazan
Disclosure of interest:
None
Aydamir Sh. Abubakarov
Pirogov Russian National Research Medical University
Russian Federation
Disclosure of interest:
Russian Federation
Moscow
Disclosure of interest:
None
Arip M. Nimatulaev
People’s Friendship University of Russia
Russian Federation
Disclosure of interest:
Russian Federation
Moscow
Disclosure of interest:
None
Ekaterina A. Nikolaeva
Pirogov Russian National Research Medical University
Russian Federation
Disclosure of interest:
Russian Federation
Moscow
Disclosure of interest:
None
Rimma G. Gamirova
Kazan (Volga Region) Federal University
Russian Federation
Disclosure of interest:
Russian Federation
Kazan
Disclosure of interest:
None
References
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. Zhurkova NV, Kazakova KA, Varichkina MA, et al. Noonan-like syndrome with loose anagen hair: three clinical cases. Nevrologicheskiy Zhurnal imeni L.O. Badalyana = L.O. Badalyan Neurological Journal. 2020;1(3):188-196. (In Russ). 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
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Volgina S.Ya., Kurbanova Y.S., Abubakarov A.Sh., Nimatulaev A.M., Nikolaeva E.A., Gamirova R.G. Noonan-Like Syndrome with Loose Anagen Hair: Genetic and Phenotypic Variability, Differential Diagnosis. Current Pediatrics. 2025;24(3):130-139. (In Russ.) https://doi.org/10.15690/vsp.v24i3.2911
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