Abstract：
Silver-Russell Syndrome (SRS) is a clinical diagnosis requiring the fulfilment of ≥4/6 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria. A score of ≥4/6 (or ≥3/6 with strong clinical suspicion) NH-CSS warrants (epi)genetic confirmation as an underlying cause can be identified in ∼60% patients. The approach to the investigation and diagnosis of SRS is detailed in the only international consensus guidance, published in 2016. In the intervening years, the clinical, biochemical, and (epi)genetic characteristics of SRS have rapidly expanded, largely attributable to advancing molecular genetic techniques and a greater awareness of related disorders. The commonest etiologies of SRS remain loss of methylation of chromosome 11p15 (11p15LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). Rarer causes of SRS include monogenic pathogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (PLAG1 and HMGA2) genes. Although the age-specific NH-CSS can identify commoner molecular causes of SRS, its use in identifying monogenic causes is unclear. Preliminary data suggest NH-CSS is poor at identifying many of these cases. Additionally, there has been increased recognition of conditions with phenotypes overlapping with SRS that may fulfil NH-CSS criteria but have distinct genetic aetiologies and disease trajectories. This group of conditions is frequently overlooked and under-investigated, leading to no or delayed diagnosis. Like SRS, these conditions are multisystem disorders requiring multidisciplinary care and tailored management strategies. Early identification is crucial to improve outcomes and reduce the major burden of the diagnostic odyssey for patients and families. This article aims to enable clinicians to identify key features of rarer causes of SRS and conditions with overlapping phenotypes, show a logical approach to the molecular investigation and highlight the differences in clinical management strategies.
摘要：
Silver-Russell综合征（SRS）是一种临床诊断，需要满足≥4/6Netchine-Harbison临床评分系统（NH-CSS）标准。≥4/6（或≥3/6，具有强烈的临床怀疑）的NH-CSS保证（epi）遗传确认为潜在原因可以在〜60％的患者中确定。唯一的国际共识指南详细介绍了SRS的调查和诊断方法，发表于2016年。在此期间，临床，生物化学，SRS的(epi)遗传特征迅速扩大，主要归因于分子遗传技术的进步和对相关疾病的更多认识。SRS的最常见病因仍然是染色体11p15（11p15LOM）的甲基化丧失和染色体7的母体单亲二体性（upd（7）mat）。SRS的较少原因包括印迹基因(CDKN1C和IGF2)和非印迹基因(PLAG1和HMGA2)中的单基因致病变体。尽管特定年龄的NH-CSS可以识别SRS的普通分子原因，它在识别单基因原因中的用途尚不清楚。初步数据表明，NH-CSS在识别许多此类病例方面表现不佳。此外,对于表型与SRS重叠的病症的认识越来越多,这些病症可能符合NH-CSS标准,但具有不同的遗传病因和疾病轨迹.这组情况经常被忽视和调查不足，导致没有或延迟诊断。像SRS一样,这些疾病是多系统疾病，需要多学科护理和量身定制的管理策略。早期识别对于改善结果和减轻患者和家庭的诊断冒险的主要负担至关重要。本文旨在使临床医生能够识别SRS的罕见原因的关键特征以及具有重叠表型的条件。显示分子研究的逻辑方法，并强调临床管理策略的差异。
