6890 The standard clinical diagnostic criteria for Silver-Russell Syndrome poorly identifies monogenic cases

Objectives To assess whether the Netchine-Harbison Clinical Scoring System (NH-CSS) effectively highlights monogenic causes of Silver-Russell Syndrome (SRS), namely variants in HMGA2, CDKN1C, IGF2 and PLAG1. To describe the phenotypic features that may guide in diagnosing rarer causes of SRS and improve the diagnostic odyssey that patients experience thereby ensuring prompt access to bespoke management. Methods An extensive literature search was conducted to identify clinical details of SRS patients with variants in the following genes: HMGA2 (n=17), CDKN1C (n=18), IGF2 (n=23), and PLAG1 (n=10). Only cases with a confirmed molecular diagnosis were included. Clinical details were revised based, not only on NH-CSS clinical criteria but any additional phenotypic features of interest. The NH-CSS results were interpreted based on consensus thresholds which suggest a clinical diagnosis of SRS is likely if ≥4/6 NH-CSS features are present. For individuals with scores below 4/6, confirmatory (epi)genetic investigations are further required. Results Based on NH-CSS criteria, for individuals with defects in HMGA2; 12% scored <3/6, 23% 3/6 and 65% ≥4/6. CDKN1C; 11% scored 3/6, 78% ≥4/6 whilst 11% could not be calculated. IGF2; 4% scored <3/6, 9% 3/6 and 87% ≥4/6. PLAG1; 10% scored <3/6, 50% 3/6 and 40% ≥4/6. Relative macrocephaly (head circumference (HC) at birth ≥1.5SDS above birth weight and/or length SDS) was not observed in 71% HMGA2 (29% microcephaly, HC ≤-2SDS), 17% CDKN1C, 9% IGF2 and 70% PLAG1 (30% microcephaly) cases. Body asymmetry was infrequent, observed in 6% HMGA2, 11% CDKN1C and 30% IGF2 cases. Other clinical features included the following: HMGA2 (gastroesophageal reflux and delayed bone age); CDKN1C (motor and/or speech delay, learning disabilities, challenging behaviour/inattention, diabetes, adrenal insufficiency, asthma); IGF2 (speech/motor/developmental delay, learning disabilities, cardiac abnormalities, cleft palate, male genital abnormalities, and placental hypoplasia) and PLAG1 (speech/motor/developmental delay and gastrointestinal manifestations). Conclusion NH-CSS does not identify 12% HMGA2, 4% IGF2 and 10% PLAG1 variants. The presence of microcephaly, lack of a protruding forehead and the presence of clinical features such as learning disabilities, should not preclude clinicians from investigating rarer causes of SRS.