title: 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations.
abstract: BACKGROUND
  Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, dysmorphic features, and frequent body asymmetry, spares cranial growth. Maternal uniparental disomy for chromosome 7 (mUPD7) is found in 5-10% of cases. We identified loss of methylation (LOM) of 11p15 Imprinting Center Region 1 (ICR1) domain (including IGF-II) as a mechanism leading to RSS.
  
  
  OBJECTIVE
  The aim was to screen for 11p15 epimutation and mUPD7 in RSS and non-RSS small-for-gestational-age (SGA) patients and identify epigenetic-phenotypic correlations. STUDIED POPULATION AND METHODS: A total of 127 SGA patients were analyzed. Clinical diagnosis of RSS was established when the criterion of being SGA was associated with at least three of five criteria: postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties. Serum IGF-II was evaluated for 82 patients.
  
  
  RESULTS
  Of the 127 SGA patients, 58 were diagnosed with RSS; 37 of these (63.8%) displayed partial LOM of the 11p15 ICR1 domain, and three (5.2%) had mUPD7. No molecular abnormalities were found in the non-RSS SGA group (n = 69). Birth weight, birth length, and postnatal body mass index (BMI) were lower in the abnormal 11p15 RSS group (ab-ICR1-RSS) than in the normal 11p15 RSS group [-3.4 vs.-2.6 SD score (SDS), -4.4 vs.-3.4 SDS, and -2.5 vs.-1.6 SDS, respectively; P < 0.05]. Among RSS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM. All ab-ICR1-RSS patients had at least four of five criteria of the scoring system. Postnatal IGF-II levels were within normal values.
  
  
  CONCLUSIONS
  The 11p15 ICR1 epimutation is a major, specific cause of RSS exhibiting failure to thrive. We propose a clinical scoring system (including a BMI < -2 SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of RSS.
authors.affiliation: Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes, Paris 75012, France. irene.netchine@trs.aphp.fr
authors.forename: Irène
authors.initials: I
authors.lastname: Netchine
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rossignol
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Dufourg
authors.forename: Salah
authors.initials: S
authors.lastname: Azzi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rousseau
authors.forename: Laurence
authors.initials: L
authors.lastname: Perin
authors.forename: Muriel
authors.initials: M
authors.lastname: Houang
authors.forename: Virginie
authors.initials: V
authors.lastname: Steunou
authors.forename: Blandine
authors.initials: B
authors.lastname: Esteva
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thibaud
authors.forename: Marie-Charles Raux
authors.initials: MC
authors.lastname: Demay
authors.forename: Fabienne
authors.initials: F
authors.lastname: Danton
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Petriczko
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bertrand
authors.forename: Claudine
authors.initials: C
authors.lastname: Heinrichs
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Carel
authors.forename: Guy-André
authors.initials: GA
authors.lastname: Loeuille
authors.forename: Graziella
authors.initials: G
authors.lastname: Pinto
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Jacquemont
authors.forename: Christine
authors.initials: C
authors.lastname: Gicquel
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cabrol
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000375:Aging / Q000378:metabolism; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004247:DNA / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D008745:Methylation; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D013577:Syndrome
chemical_list: D007335:Insulin-Like Growth Factor II; D004247:DNA