ArticleThe Journal of clinical endocrinology and metabolism2025
Distinguishing Genetic Alterations Versus (Epi)Mutations in Silver-Russell Syndrome and Focus on the IGF1R Gene.
Article in The Journal of clinical endocrinology and metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Diagnosis and management of Silver-Russell syndrome: second international consensus statement.Nature reviews. Endocrinology · 2026Review
- Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.Clinical epigenetics · 2025Article
- PEG10 loss of function causes Silver-Russell syndrome: a familial case with paternal deletion.Scientific reports · 2025Article
- Hypomethylation of the MEG8:Int2-DMR in patients with pathogenic PLAG1 variants suggests new role of the chr14q32 imprinting cluster in Silver-Russell syndrome.Clinical epigenetics · 2025Article
- Maternal uniparental disomy of chromosome 7: how chromosome 7-encoded imprinted genes contribute to the Silver-Russell phenotype.Clinical epigenetics · 2025Article
Corrections and comments
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- Erratum issued
Authors and funding
24 authors.
Funding
Abstract
contextSilver-Russell Syndrome (SRS) is a growth retardation disorder characterized by pre- and postnatal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry, and feeding difficulties. The main molecular mechanisms are imprinting alterations at multiple loci, though a small number of pathogenic variants have been reported in the SRS genes IGF2-PLAG1-HMGA2 and CDKN1C. However, around 40% of clinically suspected SRS cases do not achieve a molecular diagnosis, highlighting the necessity to uncover the underlying mechanism in unsolved cases.
objectiveEvaluate the frequency of genetic variants in undiagnosed SRS patients [Netchine-Harbison Clinical Scoring System (NH-CSS) ≥ 4], and investigate whether (epi)genetic patients may be distinguished from genetic patients.
methodsOne hundred thirty-two clinically SRS patients without (epi)genetic deregulations were investigated by whole-exome (n = 15) and targeted (n = 117) Sequencing. Clinical data from our cohort and from an extensive revision of the literature were compared.
resultsPathogenic variants were identified in 9.1% of this cohort: 3% in IGF2, PLAG1, and HMGA2 genes and 3% in the IGF1R gene, associated with IGF-1 resistance (IGF1RES), an SRS differential diagnosis. Overall, IGF2-PLAG1-HMGA2 and IGF1R account for 3.6% of SRS with NH-CSS score ≥ 4. A clinical cross-comparison of (epi)genetic vs genetic SRS underlined (epi)genotype-phenotype correlation highlighted the prevalence of body asymmetry and relative macrocephaly in mosaic (epi)genetic SRS and recurrence of genetic familial cases. Furthermore, overlapping features were evidenced in (epi)genetic SRS and IGF1RES patients.
conclusionOur study explores the frequency of genetic SRS, underscores body asymmetry as a distinctive phenotype in (epi)genetic SRS and suggests IGF1R sequencing in a SRS diagnostic flowchart.
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