Scholarlink

Context <p>Silver-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 (<i>CDKN1C</i> and <i>IGF2</i>) and non-imprinted (<i>HMGA2</i> and <i>PLAG1</i>) genes are recognised as rare causes of SRS. The frequency of associated phenotypes is unclear.</p> Objective <p>We 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.</p> Methods <p>An extensive literature search identified 22 <i>IGF2,</i> 18 <i>HMGA2</i>, 11 <i>CDKN1C</i> and 11 <i>PLAG1</i> published reports.</p> Main outcome measure <p>Clinical phenotypes including the NH-CSS criteria were interrogated to assess (dis)similarity between the molecular subgroups of SRS.</p> Results <p>Strict adherence to the NH-CSS identified clinical SRS in 91% <i>IGF2,</i> 82% <i>CDKN1C,</i> 78% <i>HMGA2</i> and 45% <i>PLAG1</i> affected individuals. Relative macrocephaly was observed in 82% <i>IGF2</i>, 82% <i>CDKN1C</i>, 44% <i>HMGA2</i>, and 27% <i>PLAG1</i> affected individuals. Prominent forehead was reported in 100% <i>CDKN1C</i>, 91% <i>IGF2</i>, 72% <i>HMGA2</i>, and 64% <i>PLAG1</i> and body asymmetry in 23% <i>IGF2</i> and 11% <i>HMGA2</i> affected individuals. Clinical features not typically associated with SRS included: microcephaly, challenging behaviour, cardiac abnormalities, cleft palate, and asthma.</p> Conclusions <p>The NH-CSS missed 9–55% of monogenic SRS. The diverse phenotypes of <i>PLAG1, CDKN1C, HMGA2</i> and <i>IGF2</i> variants may hinder a clinical diagnosis of SRS. These rarer (epi)genotypes could be considered as distinct entities.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月22日

查看全文
  • Uttara Kurup,
  • David B. N. Lim,
  • Avinaash V. Maharaj,
  • Miho Ishida,
  • Justin H. Davies,
  • Helen L. Storr

摘要

Context

Silver-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.

Objective

We 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.

Methods

An extensive literature search identified 22 IGF2, 18 HMGA2, 11 CDKN1C and 11 PLAG1 published reports.

Main outcome measure

Clinical phenotypes including the NH-CSS criteria were interrogated to assess (dis)similarity between the molecular subgroups of SRS.

Results

Strict 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.

Conclusions

The 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.