Endocrine Abstracts

Background: A diagnosis Silver–Russell Syndrome (SRS) is important for early institution of appropriate management, access to therapy and reduces the burden of diagnostic uncertainty. SRS is molecularly heterogeneous and 11p15 LOM/upd(7)mat account for ~60% cases. Monogenic causes include variants in HMGA2, CDKN1C, IGF-2, PLAG1 and contribute to 5% cases. Clinical SRS diagnosis requires the fulfilment of ≥4/6 Netchine–Harbison Clinical Scoring System (NH-CSS) criteria whereas a score of 3/6 warrants (epi)genetic investigations. Although the NH-CSS is useful for identifying commoner molecular causes of SRS, its use in identifying monogenic SRS causes is unclear. Phenotypic features of monogenic causes of SRS are not well described.

Methods: An extensive literature search identified clinical cases/details for: HMGA2 (n=17), CDKN1C (n=18), IGF-2 (n=23), and PLAG1 (n=10). We assessed whether NH-CSS criteria highlighted these monogenic SRS causes and the phenotypic features.

Results: NH-CSS for HMGA2: 12% scored <3/6, 23% 3/6 and 65% ≥4/6. CDKN1C: 11% 3/6, 78% ≥4/6, 11% could not be calculated. IGF-2: 4% <3/6, 9% 3/6 and 87% ≥4/6. PLAG1: 10% <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% had microcephaly, HC ≤−2SDS), 17% CDKN1C, 9% IGF-2 and 70% PLAG1 (30% microcephaly). Body asymmetry was infrequent: 6% HMGA2, 11% CDKN1C, 30% IGF-2. Other clinical features included: HMGA2 12% gastroesophageal reflux and 12% delayed bone age. CDKN1C: 6% motor and/or speech delay, 6% learning disabilities, 6% challenging behaviour/inattention, 11% diabetes, 11% adrenal insufficiency, 6% asthma. IGF-2: 65% speech/motor/developmental delay, 9% learning disabilities, 39% cardiac abnormalities, 30% cleft palate, 35% male genital abnormalities, 17% placental hypoplasia. PLAG1: 40% speech/motor/developmental delay, 20% gastrointestinal manifestations.

Conclusions: NH-CSS is poor at identifying monogenic SRS causes, missing 12% HMGA2, 4% IGF-2 and 10% PLAG1 cases. The presence of associated clinical features, including microcephaly and learning difficulties, should not preclude clinicians from investigating for rarer causes of SRS.