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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

Assistance Publique Hôpitaux de Paris, Hôpital Armand-Trousseau, Explorations Fonctionnelles Endocriniennes (I.N., S.R., M.-N.D., L.P., M.H., B.E., N.T., M.-C.R.D., F.D., C.G., S.C., Y.L.B.), and Hôpital Saint-Antoine-URCEST, Departement of Pharmacology (A.R.); Université Pierre et Marie Curie-Paris 6 (I.N., S.R., M.-N.D., S.A., A.R., C.G., Y.L.B.); Institut National de la Santé et de la Recherche Médicale U 515 (I.N., S.R., M.-N.D., S.A., V.S., C.G., S.C., Y.L.B.), 75012 Paris, France; Pomeranian Medical University, Pediatric (E.P.), 70-204 Szczecin, Poland; Service de Pédiatrie (A.-M.B.), Centre Hospitalier de Besançon, 25030 Besançon, France; Reine Fabiola Hospital, Pediatric Endocrinology (C.H.), 1020 Brussels, Belgium; Service d’Endocrinologie Pédiatrique (J.-C.C.) and Service de Génétique (M.-L.J.), Assistance Publique Hôpitaux de Paris, Hôpital Robert-Debré, 75019 Paris, France; Service de Pédiatrie (G.-A.L.), Centre Hospitalier de Dunkerque, 59385 Dunkerque, France; and Service d’Endocrinologie Pédiatrique (G.P.), Assistance Publique Hôpitaux de Paris, Hôpital Necker, 75743 Paris, France

Address all correspondence and requests for reprints to: Irène Netchine, M.D., Ph.D., Hopital Trousseau, Pediatric Endocrinology, 26 Av du Dr Arnold Netter, Paris 75012, France. E-mail: irene.netchine{at}trs.aphp.fr.

Context: 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.

Conclusion: 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.

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