Endocrine Abstracts

Background: Silver-Russell Syndrome (SRS) is a complex multi-system condition and timely diagnosis is important for appropriate management, access to therapy and to reduce the burden of diagnostic uncertainty. A clinical diagnosis is made using the Netchine-Harbison Clinical Scoring System (NH-CSS) with a score ≥4, and (epi)genetic investigation is recommended in those with an NH-CSS ≥3. A molecular defect is identified in ~60% of SRS cases. Monogenic defects in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are increasingly recognised as rare causes of SRS, but genetic testing is reserved for patients with a strong clinical suspicion. We aimed to identify the key presenting features of monogenic SRS and assess the validity of NH-CSS to identify these cases.

Methods: An extensive literature search identified a cohort of monogenic SRS, including CDKN1C (n = 17), IGF2 (n = 21), HMGA2 (n = 17) and PLAG1 (n = 10) gene defects. The associated clinical phenotypes including the NH-CSS criteria were interrogated in all the cases.

Results: A clinical SRS diagnosis (NH-CSS ≥4/6) was noted in 86% IGF2, 65% HMGA2, 53% CDKN1C and 40% PLAG1 cases. Relative macrocephaly (OFC ≥1.5 SDS above birth weight and/or length SDS) was observed in 81% IGF2, 59% CDKN1C, 29% HMGA2, and 20% PLAG1. Prominent forehead was reported in 94% CDKN1C, 86% IGF2, 71% HMGA2, and 60% PLAG1 and body asymmetry in 29% IGF2 and 6% HMGA2. Distinct clinical features (not typically associated with SRS) included: CDKN1C, 6% challenging behaviour, 12% diabetes, and 12% asthma; IGF2, 5% intellectual delay, 43% cardiac abnormalities, 29% cleft palate; HMGA2, 29% microcephaly (OFC >-2 SDS), 12% gastrointestinal manifestations; and PLAG1, 30% microcephaly, 10% learning difficulties, 10% gastrointestinal manifestations.

Conclusions: NH-CSS criteria was poor at identifying monogenic SRS missing the diagnosis in 60% PLAG1, 47% CDKN1C, 35% HMGA2 and 14% IGF2 gene defects. The presence of atypical clinical features, including microcephaly and learning difficulties, should not preclude clinicians from investigating for rarer causes of SRS. This emphasises the need to extend the molecular investigation of apparent and atypical SRS to inform clinical management decisions and enhance outcomes for affected individuals.