ArticleClinical epigenetics2025
Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
Article in Clinical epigenetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.Clinical epigenetics · 2025Article
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6 authors.
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Abstract
contextSilver-Russell syndrome (SRS) is a complex multisystem condition requiring timely diagnosis for appropriate management. A clinical diagnosis is made in individuals scoring ≥ 4 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria, with (epi)genetic investigations undertaken in those with NH-CSS ≥ 3 and strong clinical suspicion. Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS. The frequency of associated phenotypes is unclear.
objectiveWe evaluated the suitability of SRS as an umbrella term for these (epi)genotypes by identifying key clinical features and assessing the validity of NH-CSS.
methodsAn extensive literature search identified 22 IGF2, 18 HMGA2, 11 CDKN1C and 11 PLAG1 published reports.
main outcome measureClinical phenotypes including the NH-CSS criteria were interrogated to assess (dis)similarity between the molecular subgroups of SRS.
resultsStrict adherence to the NH-CSS identified clinical SRS in 91% IGF2, 82% CDKN1C, 78% HMGA2 and 45% PLAG1 affected individuals. Relative macrocephaly was observed in 82% IGF2, 82% CDKN1C, 44% HMGA2, and 27% PLAG1 affected individuals. Prominent forehead was reported in 100% CDKN1C, 91% IGF2, 72% HMGA2, and 64% PLAG1 and body asymmetry in 23% IGF2 and 11% HMGA2 affected individuals. Clinical features not typically associated with SRS included: microcephaly, challenging behaviour, cardiac abnormalities, cleft palate, and asthma.
conclusionsThe NH-CSS missed 9-55% of monogenic SRS. The diverse phenotypes of PLAG1, CDKN1C, HMGA2 and IGF2 variants may hinder a clinical diagnosis of SRS. These rarer (epi)genotypes could be considered as distinct entities.
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