Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Frequency and clinical characteristics of distinct etiologies in patients with Silver-Russell syndrome diagnosed based on the Netchine-Harbison clinical scoring system


Silver-Russel syndrome (SRS) is a representative imprinting disorder (ID) characterized by growth failure and diagnosed by clinical features. Recently, international consensus has recommended using the Netchine-Harbison clinical scoring system (NH-CSS) as clinical diagnostic criteria. Loss of methylation of H19/IGF2:intergenic differentially methylated region (H19LOM) and maternal uniparental disomy chromosome 7 (UPD(7)mat) are common etiologies of SRS; however, other IDs, pathogenic variants (PVs) of genes, and pathogenic copy number variants (PCNVs) have been reported in patients meeting NH-CSS. To clarify the frequency and clinical characteristics of each etiology, we conducted (epi)genetic analysis in 173 patients satisfying NH-CSS. H19LOM and UPD(7)mat were identified in 34.1%. PCNVs, other IDs, and PVs were in 15.0%. Patients with all six NH-CSS items were most frequently observed with H19LOM and UPD(7)mat. This study confirmed the suitability of NH-CSS as clinical diagnostic criteria, the (epi)genetic heterogeneity of SRS, and showed the necessity of further discussion regarding the “SRS spectrum”.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. Wakeling EL, Brioude F, Lokulo-Sodipe O, O’Connell SM, Salem J, Bliek J, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105–24.

    CAS  Article  Google Scholar 

  2. Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, et al. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet. 2013;50:823–30.

    CAS  Article  Google Scholar 

  3. Abi Habib W, Brioude F, Edouard T, Bennett JT, Lienhardt-Roussie A, Tixier F, et al. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction. Genet Med. 2018;20:250–8.

    CAS  Article  Google Scholar 

  4. Masunaga Y, Inoue T, Yamoto K, Fujisawa Y, Sato Y, Kawashima-Sonoyama Y, et al. IGF2 mutations: report of five cases, review of the literature, and comparison with H19/IGF2:IG-DMR epimutations. J Clin Endocrinol Metab. 2020;105:116–25.

    Article  Google Scholar 

  5. Inoue T, Nakamura A, Fuke T, Yamazawa K, Sano S, Matsubara K, et al. Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects. Clin Epigenetics. 2017;9:52.

    Article  Google Scholar 

  6. Fuke T, Nakamura A, Inoue T, Kawashima S, Isono Hara K, Matsubara K, et al. Role of imprinting disorders in short children born SGA and Silver-Russell syndrome. J Clin Endocrinol Metab. 2021;106:802–13.

    Article  Google Scholar 

  7. Luk HM, Ivan LoFM, Sano S, Matsubara K, Nakamura A, Ogata T, et al. Silver–Russell syndrome in a patient with somatic mosaicism for upd(11)mat identified by buccal cell analysis. Am J Med Genet A. 2016;170:1938–41.

    Article  Google Scholar 

  8. Matsubara K, Itoh M, Shimizu K, Saito S, Enomoto K, Nakabayashi K, et al. Exploring the unique function of imprinting control centers in the PWS/AS-responsible region: finding from array-based methylation analysis in cases with variously sized microdeletions. Clin Epigenetics. 2019;11:36.

    Article  Google Scholar 

  9. Inoue T, Nakamura A, Iwahashi-Odano M, Tanase-Nakao K, Matsubara K, Nishioka J, et al. Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients. Clin Epigenetics. 2020;12:86.

    CAS  Article  Google Scholar 

  10. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  11. Wakeling EL, Amero SA, Alders M, Bliek J, Forsythe E, Kumar S, et al. Epigenotype-phenotype correlations in Silver-Russell syndrome. J Med Genet. 2010;47:760–8.

    CAS  Article  Google Scholar 

  12. Walenkamp MJE, Robers JML, Wit JM, Zandwijken GRJ, van Duyvenvoorde HA, Oostdijk W, et al. Phenotypic features and response to GH treatment of patients with a molecular defect of the IGF-1 receptor. J Clin Endocrinol Metab. 2019;104:3157–71.

    Article  Google Scholar 

  13. Avila M, Dyment DA, Sagen JV, St-Onge J, Moog U, Chung BHY, et al. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. Clin Genet. 2016;89:501–6.

    CAS  Article  Google Scholar 

  14. Nakashima S, Kato F, Kosho T, Nagasaki K, Kikuchi T, Kagami M, et al. Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C. J Hum Genet. 2015;60:91–5.

    CAS  Article  Google Scholar 

  15. Kagami M, Nagasaki K, Kosaki R, Horikawa R, Naiki Y, Saitoh S, et al. Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients. Genet Med. 2017;19:1356–66.

    Article  Google Scholar 

  16. Kagami M, Yanagisawa A, Ota M, Matsuoka K, Nakamura A, Matsubara K, et al. Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR. Clin Epigenetics. 2019;11:42.

    Article  Google Scholar 

  17. Kawashima S, Nakamura A, Inoue T, Matsubara K, Horikawa R, Wakui K, et al. Maternal uniparental disomy for chromosome 20: physical and endocrinological characteristics of five patients. J Clin Endocrinol Metab. 2018;103:2083–8.

    Article  Google Scholar 

  18. Inoue T, Yagasaki H, Nishioka J, Nakamura A, Matsubara K, Narumi S, et al. Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology. J Med Genet. 2019;56:413–8.

    Article  Google Scholar 

  19. Masunaga Y, Kagami M, Kato F, Usui T, Yonemoto T, Mishima K, et al. Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia. Clin Epigenetics. 2021;13:73.

    CAS  Article  Google Scholar 

Download references


We are grateful to the patients and their families for their cooperation. This work was supported by grants from the Japan Agency for Medical Research and Development (AMED) (20ek0109373h0003), the National Center for Child Health and Development (28-6, 2019B-4), the Foundation for Growth Science, and the Takeda Science Foundation.

Author information

Authors and Affiliations



Conception and design of study: MK. Acquisition of data: TF, AN, TI, SK, KH-I, KM, SS, KY, MF, TO, and MK. Analysis and/or interpretation of data: TF and AN. Drafting the manuscript: TF and MK. Revising the manuscript critically for important intellectual content: TF and MK. Approval of the version of the manuscript to be published (the names of all authors must be listed): TF, AN, TI, SK, KH-I, KM, SS, KY, MF, TO, and MK.

Corresponding author

Correspondence to Masayo Kagami.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fuke, T., Nakamura, A., Inoue, T. et al. Frequency and clinical characteristics of distinct etiologies in patients with Silver-Russell syndrome diagnosed based on the Netchine-Harbison clinical scoring system. J Hum Genet (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links