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.
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.
Netchine
Irène
I
Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes, Paris 75012, France. irene.netchine@trs.aphp.fr
Rossignol
Sylvie
S
Dufourg
Marie-Noëlle
MN
Azzi
Salah
S
Rousseau
Alexandra
A
Perin
Laurence
L
Houang
Muriel
M
Steunou
Virginie
V
Esteva
Blandine
B
Thibaud
Nathalie
N
Demay
Marie-Charles Raux
MC
Danton
Fabienne
F
Petriczko
Elzbieta
E
Bertrand
Anne-Marie
AM
Heinrichs
Claudine
C
Carel
Jean-Claude
JC
Loeuille
Guy-André
GA
Pinto
Graziella
G
Jacquemont
Marie-Line
ML
Gicquel
Christine
C
Cabrol
Sylvie
S
Le Bouc
Yves
Y
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
D007335:Insulin-Like Growth Factor II; D004247:DNA