Endocrine Abstracts

JOINT349

Background: Silver Russell Syndrome (SRS) is a rare syndrome characterized by six clinical features composing the Netchine-Harbison Clinical-Scoring-System (NH-CSS): prenatal and postnatal growth retardation, relative macrocephaly at birth, protruding forehead, body asymmetry, and significant feeding difficulties. SRS diagnosis is suspected if ≥4 of these 6 criteria are present. The first (epi)genetic SRS causes identified include maternal uniparental disomy of chromosome 7 (upd(7)mat) and loss of methylation at H19/IGF2:IG-DMR on chromosome 11 (11p15 LOM). Other molecular anomalies are reported in patients with a suspected SRS.

Objective: Evaluate the NH-CSS on patients with suspected SRS with different molecular causes of SRS and differential diagnoses.

Subjects and Methods: Retrospective analysis of 705 patients, with data for all 6 NH-CSS criteria and molecular screening for upd(7)mat and 11p15 LOM, were recruited through the patient support group, The MAGIC Foundation.

Results: Molecular anomalies identified:

• SRS diagnosis confirmed in 356 patients (50. 5%): 11p15 LOM (n = 222, 62, 4% of SRS patients), and upd(7)mat (n = 109, 30. 6%); Maternal 11p15 duplications (n = 19, 5. 3%); Paternal IGF2 mutations (n = 5, 1. 4%); CDKN1C mutations (n = 1, 0. 3%);

• Temple syndrome (TS) in 36 patients (5. 1%): 14q32 LOM (n = 6, 16. 7% of TS patients); upd(14)mat (n = 25, 69. 4%); and 14q32 pat-del (n = 5, 13. 9%);

• HMGA2 mutations (n = 7, 1. 0%); PLAG1 mutations (n = 6, 0. 9%); upd(20)mat (n = 9, 1. 3%); upd(16)mat (n = 3, 0. 4%);

• Various SRS differential diagnosis were identified (5%), including IGF1R mutations, 3M syndrome, Cornelia de Lange, IMAGe, Mulibrey nanism, Bloom, and Floating-Harbor.

NH-CSS Results NH-CSS≥4 demonstrates high sensitivity of 97. 2% to detect 11p15 LOM and upd(7)mat with good Negative Predictive Value of 89. 0%. NH-CSS was ≥4 for 83. 3% of the patients with a PLAG1 mutation; 85. 7% with a HMGA2 mutation; 88. 9% of upd(20)mat; 89. 5% with a 11p15 maternal duplication; 83. 3% of TS 14q32LOM, and 100% of upd(16)mat and IGF2 mutations. It detected only 40% of IGF1R mutations, 52% of TS upd(14)mat and 20% of 14q32 pat-deletions. Relative macrocephaly is associated with 11p15 LOM and upd(7)mat (P < 0. 05) but not with PLAG1, HMGA2 and upd(20)mat. Specific clinical findings can orient toward other diagnoses, (microcephaly for IGF1R mutations, neonatal hypotonia and/or precocious obesity and puberty for TS).

Conclusion: NH-CSS (if ≥4) is a highly sensitive tool to orient toward 11p15 LOM and upd(7)mat suggesting methylation analysis as the first molecular diagnostic step. It also captures other molecular anomalies overlapping with SRS and less frequently differential diagnoses, suggesting the importance of additional clinical signs to orient broader genetic testing after the methylation analysis.