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Original article
A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome
  1. Salah Azzi1,2,3,4,
  2. Jennifer Salem5,
  3. Nathalie Thibaud1,2,3,
  4. Sandra Chantot-Bastaraud6,
  5. Eli Lieber7,
  6. Irène Netchine1,2,3,
  7. Madeleine D Harbison8
  1. 1INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France
  2. 2Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France
  3. 3Department of Pediatric Endocrinology, APHP, Armand Trousseau Hospital, Paris, France
  4. 4Epigenetics Programme, The Babraham Institute, Cambridge, UK
  5. 5MAGIC Foundation, RSS/SGA Research & Education Fund, Oak Park, Illinois, USA
  6. 6AP-HP, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, Paris, France
  7. 7Department of Psychiatry and Biobehavioral Sciences, Semel Institute, University of California, Los Angeles, California, USA
  8. 8Department of Pediatrics, Ichan School of Medicine at Mount Sinai, New York, New York, USA
  1. Correspondence to Dr Irène Netchine, Explorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Pierre & Marie Curie School of Medicine, INSERM UMR-S938, 26 Av du Dr Arnold Netter, Paris 75012, France; irene.netchine{at}trs.aphp.fr

Abstract

Background Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype.

Subjects and methods Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤−2SDS, (2) postnatal growth retardation (height ≤−2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤−2SDS in toddlers; (6) protruding forehead at the age of 1–3 years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data.

Results The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion.

Conclusions This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.

  • Russell Silver Syndrome
  • Silver Russell Spectrum
  • Clinical scoring system
  • ICR1 11p15 hypomethylation and mUPD7
  • phenotypic-genotypic correlation

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