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BRIEF REPORT |
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.
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Abstract |
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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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Introduction |
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In mammals, various key genes encoding proteins involved in embryonic and fetal growth are imprinted, and paternally expressed genes enhance fetal growth, whereas maternally expressed genes are inhibitory. Epigenetic marks (DNA methylation and histone modifications) control the allelic expression of imprinted genes (4). Human chromosome 11p15 contains a cluster of imprinted genes that play a crucial role in the control of fetal and placental growth. This cluster includes paternally expressed genes (IGF-II and KCNQ1OT1) and maternally expressed genes (such as CDKN1C and H19). The imprinted 11p15 region consists of two imprinted domains, each under the control of its own imprinting center region (ICR): the telomeric ICR1 regulates the expression of IGF-II and H19, and expression of CDKN1C and KCNQ1OT1 is controlled by the centromeric ICR2 (Fig. 1A
) (4). Mouse models lacking either igf-II or kcnq1ot1 genes have fetal growth retardation (5, 6), and ICR1 disruption resulting in biallelic expression of igf-II or transactivation of the igf-II gene in the mouse leads to fetal overgrowth (7, 8). Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is characterized by prenatal and postnatal overgrowth, organomegaly, abdominal wall defects, frequent hemihyperplasia, and an increased risk of childhood tumors. It is caused by genetic or epigenetic alterations in the imprinted 11p15 region leading to the down-regulation of maternally expressed genes and the up-regulation of paternally expressed genes including IGF-II (Fig. 1B) (9, 10, 11). By contrast, chromosome 11p15 duplications of maternal origin have been identified in patients with fetal growth retardation and Russell-Silver syndrome (RSS, OMIM 180860) (12, 13). RSS is a clinically heterogeneous syndrome with pre- and postnatal growth retardation, first described by Silver et al. (14) and Russell (15). Their common findings were short stature without catch-up growth, normal head size for age, a distinctive triangular face with prominent forehead, low-set ears, and clinodactyly of the fifth fingers. Silver noted skeletal asymmetry as a feature of the disorder. Since then, many signs have been added, and they include café-au-lait spots, genital abnormalities, hypoglycemia, excessive sweating, blue sclera, syndactyly of the toes, and severe feeding difficulties (16, 17, 18). However, no consensus definition has yet been established, making the clinical diagnosis difficult (19). Rare cytogenetic abnormalities were found in RSS patients, and 5–10% of these patients display maternal uniparental disomy for chromosome 7 (mUPD7) (17). Recently, our group identified loss of methylation (LOM) of the 11p15 ICR1 telomeric domain (including the H19 and IGF-II genes) as a mechanism leading to RSS (Fig. 1C) (20). Since our initial report, other groups have confirmed this finding in RSS patient series with various frequencies and phenotypes (21, 22, 23, 24).
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Patients and Methods |
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The study population consisted of 127 SGA patients [birth weight and/or length 
–2 SD score (SDS) for gestational age according to the Usher and McLean charts (25)]. These patients were either followed in our clinic (as SGA or RSS) or were referred by other clinical centers for suspicion of RSS and molecular analysis. For some of them, the clinical diagnosis of RSS was excluded according to our scoring system. Patients with a chromosomal abnormality or with a syndrome other than RSS were excluded from this study. Each patient was examined by a geneticist and/or a pediatric endocrinologist. Whether the patient was referred to our Pediatric Endocrinology Unit or had been seen in another clinic, a clinical form including extensive clinical data, growth charts, a detailed phenotypic description, and pictures was completed. The clinical RSS diagnosis was assessed for each of the 127 SGA patients using a scoring system established after a review of the literature; prenatal growth retardation (birth weight and/or length –2 SDS for gestational age) was mandatory for the diagnosis and had to be associated with at least three of the five following criteria: 1) postnatal growth retardation [height –2 SDS according to the Sempé growth charts (26)] at 2 yr of age or at the nearest measure available, 2) relative macrocephaly at birth [i.e. arbitrarily defined when the head circumference at birth is at least 1.5 SDS above the birth weight and/or length according to the Usher and McLean charts (25)], 3) prominent forehead during early childhood, 4) body asymmetry, and 5) feeding difficulties during early childhood (retained when reduced food intake for the age is documented and/or lack of appetite with the necessity of multiple meals of prolonged duration or when enteral feeding is required). Microcephaly at birth was defined as a head circumference lower than –2 SDS according to the Usher and McLean charts (25). Body mass index (BMI) was expressed in SDS according to the Rolland-Cachera charts (27). Target height was calculated as follows: (father’s height + mother’s height)/2 + 6.5 cm for boys and – 6.5 cm for girls. The clinical forms necessary for our scoring system were analyzed by our investigators. Clinical data allowed us to include 127 patients born SGA in the molecular analysis, and they were classified into two groups (RSS and non-RSS SGA patients). For 87 patients, we had exhaustive data concerning conception method, parental age at birth, gestational age, target height, clinodactyly, psychomotor development, café-au-lait spots, hypoglycemia occurrence, and complete growth data allowing their inclusion in the epigenetic-phenotypic correlation part of the study. Informed consent was obtained from all patients (and/or their parents) in accordance with national ethics rules. Informed consent was obtained from the parents for publication of the pictures.
IGF-II assays
Blood samples were collected in the morning for 82 patients, and serum samples were stored at –20 C until assays. Serum IGF-II concentrations were determined by a specific immunoradiometric assay (9100; Diagnostic Systems Laboratories, Webster, TX), including extraction with acid ethanol. Results were compared with those for control children tested in our laboratory and expressed in SDS according to the age and the pubertal stage. The sensitivity threshold was 12 ng/ml, and the intra- and interassay coefficients of variation were 4.3–7.2% and 6.3–10.4%, respectively, for IGF-II concentrations from 70–1500 ng/ml. There was no cross-reactivity with IGF-I or insulin.
DNA analysis
The 127 patients underwent the following molecular investigations in the same molecular biology laboratory.
11p15 epimutation testing. Methyl-sensitive Southern blotting was used to analyze the methylation status of the 11p15 ICR1 centromeric domain (two probes for this region were used) and of the 11p15 ICR2 centromeric domain as previously described (20). The mean ± SDS (range) methylation indexes were 51.6 ± 2.5% (45–56%) for ICR2, 53.3 ± 3.1% (48–60%) for the H19 promoter, and 53.9 ± 2% (49–57%) for ICR1.
mUPD7 testing. mUPD7 was tested by analyzing the methylation status of the imprinted PEG1/MEST region using methyl-sensitive Southern blotting or methyl-specific PCR (MSPCR) after bisulfite treatment of the DNA (28, 29). These two methods distinguish the unmethylated allele from the methylated allele. A mUPD7 is diagnosed when only the methylated band is detected. For each assay, DNA from a patient with confirmed mUPD7 was used as a positive control. These screening methods can detect whole-chromosome UPD7 or segmental UPD7 involving the PEG/MEST locus but not the rare segmental UPD7 involving other loci (30). For patients exhibiting only the methylated band in MSPCR or Southern blotting tests, eight polymorphic markers spanning chromosome 7 (D7S484, D7S483, D7S493, D7S502, D7S530, D7S669, D7S486, and D7S684) were analyzed in each of these patients and their parents to confirm and further document the mUPD7.
Statistical analysis
Eighty-seven patients were eligible for statistical analysis of the phenotype differences between non-RSS SGA and RSS patients. The characteristics of the population are described as percentages for qualitative variables or as SDS, median, and range for continuous variables. Relationships between qualitative variables and the presence of the 11p15 abnormality were assessed with the Pearson 
2 test or Fisher’s exact test as appropriate. The Wilcoxon rank test with normal approximation was used for continuous variables. A P value < 0.05 was considered to indicate statistical significance. All tests were two sided. The SAS V9 System (SAS Institute, Cary, NC) was used for statistical analyses.
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Results |
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Among the 127 SGA patients included in the molecular analysis, 69 were scored as having fewer than three criteria of the clinical RSS scoring system and were consequently classified as non-RSS SGA; 58 were scored as having three to five criteria and were classified as RSS.
Molecular analysis
The 11p15 region methylation status and mUPD7 were assessed in 127 patients. No molecular abnormality at either the 11p15 region or chromosome 7 was identified in any of the 69 non-RSS SGA patients. We identified a molecular abnormality in 69% of the 58 RSS patients (Fig. 2). A partial ICR1 11p15 LOM was identified in 37 (63.8%) patients (methylation indexes from 1–39%, Fig. 2A). By contrast, the methylation status at 11p15 ICR2 was normal (data not shown). A mUPD7 was identified in three (5.2%) patients by Southern blotting and MSPCR (Fig. 2B) and confirmed by polymorphic marker analysis; at least four of the eight markers used were informative and indicated a maternal-only contribution, thereby confirming the maternal disomy (Fig. 2C).
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The 87 patients (48 non-RSS SGA and 39 RSS) eligible for statistical analysis were included in this part of the study. The non-RSS SGA patients were born between 1983 and 2005, and the RSS patients were born between 1985 and 2005. Figure 3 shows pictures of RSS patients displaying ICR1 epimutation or mUPD7.
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Phenotype characteristics of the non-RSS SGA group and the RSS group are detailed in Table 1. Birth weight and length were significantly lower in the RSS group. Postnatal growth retardation was significantly more severe in RSS patients despite a higher target height, and their postnatal BMI was also significantly lower and under –2 SDS in a larger proportion of cases. By contrast, birth head circumference was significantly higher in RSS patients, and microcephaly was less frequent in RSS patients. Each clinical sign included in the scoring system was independently strongly associated with the RSS group. Among other clinical findings that are often reported as RSS features, clinodactyly was indeed significantly more frequent in the RSS group, but café-au-lait spots were not.
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Table 2 shows the characteristics of the RSS patients with (ab-ICR1-RSS) or without (nl-ICR1-RSS) the 11p15 ICR1 LOM. Birth weight and length and postnatal BMI were significantly lower in the ab-ICR1-RSS group. A low postnatal BMI (–2 SDS), a prominent forehead, a body asymmetry, and a relative macrocephaly were significantly more frequent in the ab-ICR1-RSS group. Parental age, especially paternal age, was not different in the two groups. All the ab-ICR1-RSS patients exhibited at least four criteria of the scoring system vs. 35.7% of the nl-ICR1-RSS. Three patients were born after the use of assisted reproductive technology: one in the ab-ICR1-RSS group and two in the nl-ICR1-RSS group. The three mUPD7 patients were included in the nl-ICR1-RSS group; they fulfilled the scoring criteria for the diagnosis of RSS, because two of them had three of five criteria, whereas the third patient had five of five criteria. These three patients had postnatal growth retardation, feeding difficulties, a BMI less than –2 SDS, and a prominent forehead. One of them also had a relative macrocephaly and body asymmetry.
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Postnatal serum IGF-II levels were within the normal range for most patients (Fig. 4). The mean values, expressed in SDS, were 0.15 ± 1.30 for the non-RSS SGA group (n = 51), 0.21 ± 1.4 for the ab-ICR1-RSS group (n = 17), and –0.24 ± 1.26 for the nl-ICR1-RSS group (n = 14).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In this cohort, 11p15 epimutation of the ICR1 telomeric domain was a frequent (63.8%) and specific cause of RSS because it was not found in any of the non-RSS SGA patients. Maternal UPD7 was also observed in the RSS group only but at a much lower (5.2%) frequency than ICR1 epimutation. We did not identify any abnormality in the 11p15 ICR2 centromeric domain in the 58 analyzed RSS patients. However, a recent report identified a maternal duplication of the region limited to the ICR2 centromeric domain in an RSS patient with a marked developmental delay (31). Therefore, as for BWS, abnormalities of either the 11p15 ICR2 centromeric or the ICR1 telomeric domain can cause RSS. In BWS, ICR2 abnormalities are more frequent than ICR1 abnormalities (11), and thus the opposite may be true for RSS. Since our initial report (20), other groups have confirmed the finding of ICR1 epimutation in RSS patients but with a lower (20–40%) frequency than in our series (21, 22, 23, 24). It should be noted that at least one of these series included patients with an RSS-like phenotype (23). Another group also identified this anomaly in patients with typical RSS or, by contrast, with isolated hemihypotrophy. However, some of the patients described as having isolated hemihypotrophy were born SGA or had postnatal growth retardation, feeding difficulties, or other signs of RSS (21). These various reports illustrate the difficulties associated with establishing the diagnosis of RSS; it can be diagnosed too frequently or underestimated, especially in retrospective studies in which clinical data were collected by different investigators. A consensus for a clinical score system defining RSS would be helpful for future studies.
Diagnosis of RSS, although fairly easy to recognize in extreme cases, can be difficult in more subtle situations, especially in the absence of body asymmetry. There have been numerous reports outlining certain similarities of characteristics between patients with RSS. Not all authors agree on the cardinal manifestations of RSS to help in establishing a diagnosis (17, 32, 33, 34). After reviewing the published data (14, 15, 16, 17, 18, 19, 24, 32, 33, 34, 35, 36), we propose a clinical scoring system for the diagnosis of RSS; the patient must be born SGA and also present at least three of the five following criteria: postnatal growth retardation, relative macrocephaly, body asymmetry, prominent forehead, and feeding difficulties during early childhood. Although this scoring is very similar to that used by other groups (17, 24, 33), we have included feeding difficulties as one of the criteria because they are reported to be particularly frequent and severe in RSS during infancy and early childhood. This manifestation can be associated with frequent gastrointestinal disorders, such as constipation, gut dysmobility, and gastroesophageal reflux disease (18). We have retained the prominent forehead as the main characteristic of facial dysmorphy, but it should be assessed before 3 yr of age because the characteristic facial features of the RSS seem to change and are not as marked in late childhood and adulthood (35). The RSS patients identified according to our scoring system had more severe fetal growth restriction and failure to thrive than non-RSS SGA patients. A recent report comparing the clinical data for a group of RSS with the data for a group of non-RSS SGA also found that a low BMI was significantly associated with the diagnosis of RSS (24). Because feeding difficulties can be difficult to assess and quantify in young children, we would therefore suggest including the item feeding difficulties and/or low postnatal BMI (<–2 SDS) when considering the diagnosis of RSS. Among RSS patients, ab-ICR1-RSS have a more severe phenotype (fetal growth restriction and failure to thrive) and some clinical signs included in the scoring system (i.e. relative macrocephaly, prominent forehead, and body asymmetry) were strongly associated with 11p15 ICR1 LOM.
We have previously shown that two RSS patients displaying the ICR1 epimutation had low levels of IGF-II gene expression in tissues (cultured skin fibroblasts) (20). It was therefore important to assess serum IGF-II levels in such patients. Here, we report postnatal IGF-II serum levels in non-RSS SGA patients and RSS patients with or without 11p15 ICR1 epimutation. We found that most values were similar to control values. Recently, four other RSS patients with 11p15 ICR1 LOM were shown to have serum IGF-II levels within the normal range (24). IGF-II gene expression is regulated in a developmental-dependent and tissue-specific manner depending on its active promoters. In humans, IGF-II has a critical role during fetal growth and has a predominantly monoallelic paternal expression. After birth, serum IGF-II, principally of hepatic origin, results from biallelic IGF-II expression. However, IGF-II remains imprinted and its expression monoallelic in some tissues (37, 38). In ab-ICR1-RSS patients, normal IGF-II serum levels do not therefore necessary reflect the abnormal levels of IGF-II in tissues. In addition, IGF-II serum levels are stabilized in the IGF/IGF-binding protein 3/acid-labile subunit ternary complex which is GH dependent after birth. Most probably, in the case of 11p15 ICR1 LOM, IGF-II production is abnormally low in certain tissues (depending also on the mosaicism pattern of the epimutation), thereby leading, like during fetal development, to a diminished autoparacrine action.
The precise mechanism responsible for the loss of paternal methylation at 11p15 ICR1 in RSS patients remains to be elucidated. Theoretically, the epigenetic defect might concern a factor involved in the establishment (in the paternal germ line) or maintenance (after fertilization) of imprints (4). A more advanced paternal age may have consequences for methylation in the male germ cells, but we did not observe a significant difference in paternal age between ab-ICR1-RSS and nl-ICR1-RSS groups.
Additional studies are necessary to identify the molecular abnormality leading to RSS in the subgroup of patients with a normal 11p15 region.
In summary, the scoring system we used to assess the diagnosis of RSS is strongly associated with the identification of a molecular defect; 63.8% of the patients classified as RSS according to this score displayed 11p15 ICR1 LOM, and 5.2% had a mUPD7. Moreover, we demonstrated that 11p15 ICR1 LOM is also a specific cause of RSS.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online May 15, 2007
1 I.N. and S.R. made an equal contribution. 
Abbreviations: BMI, Body mass index; BWS, Beckwith-Wiedemann syndrome; ICR, imprinting center region; LOM, loss of methylation; MSPCR, methyl-specific PCR; mUPD7, maternal uniparental disomy for chromosome 7; RSS, Russell-Silver syndrome; SDS, SD score; SGA, small for gestational age.
Received February 15, 2007.
Accepted May 4, 2007.
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