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Submitted on February 15, 2007
Accepted on May 4, 2007
APHP, Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes, 75012 Paris, France; Université Pierre et Marie Curie-Paris6, Paris, F-75012 France; INSERM U 515, 75012 Paris, France; APHP, Hôpital Saint-Antoine-URCEST, departement of Pharmacology, 75012 Paris, France; Pomeranian Medical University, Pediatric, Szczecin, Poland; Service de Pédiatrie, Centre Hospitalier de Besançon, France; Reine Fabiola Hospital, Pediatric Endocrinology, Brussels, Belgium; Service d'Endocrinologie Pédiatrique, APHP, Hôpital Robert-Debré, Paris, France; Service de Pédiatrie, Centre Hospitalier de Dunkerque, France; Service d'Endocrinologie pédiatrique, APHP, Hôpital Necker, Paris France; Service de génétique, APHP, Hôpital Robert-Debré, Paris, France
* To whom correspondence should be addressed. E-mail: irene.netchine{at}trs.aphp.fr.
Context: Russell-Silver Syndrome (RSS), characterized by intrauterine and postnatal growth retardation, dysmorphic features, 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 ICR1 domain (including IGF-II) as a mechanism leading to RSS.
Objective: Screen for 11p15 epimutation and mUPD7 in RSS and non-RSS SGA patients and identify epigenetic-phenotypic correlations.
Studied population and methods : 127 SGA patients were analyzed. Clinical diagnosis of RSS was established when the criterion of being SGA was associated with at least 3/5 criteria: postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, feeding difficulties. Serum IGF-II was evaluated for 82 patients.
Results: Of the 127 SGA patients, 58 were diagnosed 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, postnatal BMI were lower in the abnormal 11p15 RSS group (ab-ICR1-RSS) than in the normal 11p15 RSS group, (-3.4 vs -2.6 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 4/5 criteria of the scoring system. Postnatal IGF-II levels were within normal values.
Conclusion: 11p15 ICR1 epimutation is a major, specific cause of RSS exhibiting failure-to-thrive. We propose a clinical scoring system (including a BMI< -2SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of RSS.
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