This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Binder, G. Articles by Ranke, M. B. Search for Related Content PubMed PubMed Citation Articles by Binder, G. Articles by Ranke, M. B. Related Collections Pediatric Endocrinology

The Endocrine Phenotype in Silver-Russell Syndrome Is Defined by the Underlying Epigenetic Alteration

University Children’s Hospital Tübingen (G.B., A.-K.S., D.D.M., R.S., C.P.S., H.A.W., M.B.R.), 72076 Tübingen, Germany; and Institute of Human Genetics (T.E.), Rheinisch-Westfälische Technische Hochschule Aachen, 52074 Aachen, Germany

Address all correspondence and requests for reprints to: PD Dr. Gerhard Binder, Pediatric Endocrinology Section, University-Children’s Hospital, Hoppe-Seyler-Str.1, 72076 Tübingen, Germany. E-mail: gerhard.binder{at}med.uni-tuebingen.de.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Around 50% of children with Silver-Russell syndrome (SRS) carry a hypomethylation of the imprinting control region 1 at the IGF2/H19 locus on 11p15, the functional significance of which is unknown.

Objective: We aimed to compare the genotype in SRS with the endocrine phenotype.

Design: The retrospective study included all SRS children who were treated during the last 18 yr at our hospital and for comparison a cohort of GH treated nonsyndromic short children born small for gestational age (SGA).

Patients: The 61 patients with SRS included were defined by the presence of intrauterine growth retardation, lack of catch-up growth, and at least two of the criteria: typical face, relative macrocephaly, and skeletal asymmetry. Routine karyotype and GH secretion was normal in all children studied. A subgroup of 53 patients was treated with GH.

Materials and Methods: Genomic DNA was available from 44 children. Multiplex ligation probe-dependent amplification analysis was performed to detect hypomethylation at the imprinting control region 1 on 11p15. Uniparental disomy of chromosome 7 (UPD7) was analyzed by short tandem repeats typing. Serum levels of GH, IGF-I, and IGF-binding protein (IGFBP)-3 were measured by RIA.

Results: Epimutations at 11p15 were found in 19 of 44, UPD7 in five of 44, and small structural aberrations of the short arm of chromosome 11 in two of 44 children. Of 44 cases, 18 were negative for any genetic defect known (41%). The most severe phenotype was found in children with 11p15-SRS. Children with UPD7-SRS had a significantly higher birth length (P < 0.004) but lost height SD score (SDS) postpartum, whereas children with 11p15-SRS showed no change in height SDS. IGF-I and IGFBP-3 serum levels were inadequately high in 11p15-SRS at –0.02 SDS (1.07, SD) and +1.38 SDS (1.01), compared with the low levels in UPD7-SRS and in the cohort of 58 nonsyndromic SGA children (P < 0.0009). During GH therapy, IGFBP-3 serum levels increased above normal values in 11p15-SRS (P < 10^–4), whereas IGF-I increase was moderate. There was a trend toward more height gain in children with UPD7 than in those with 11p15 epimutation under GH therapy (+2.5 vs. +1.9 height SDS after 3 yr) (P = 0.08).

Conclusions: Children with SRS and an 11p15 epimutation have IGFBP-3 excess and show endocrine characteristics suggesting IGF-I insensitivity, whereas children with SRS and UPD7 were not different from nonsyndromic short children born SGA. This phenotype-genotype correlation implicates divergent endocrine mechanisms of growth failure in SRS.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical diagnosis of Silver-Russell syndrome (SRS) (OMIM no. 180860) is based on the presence of intrauterine growth retardation with the lack of catch-up after birth and a normal head circumference that is in overt contrast to the rest of the body (1). The resulting triangular appearance of the face with a large prominent forehead and a very small chin is especially evident in infants and young children. Body asymmetry is frequent, but not obligatory for the diagnosis. The growth failure in SRS is frequently associated with failure to thrive and with a very low body mass index (BMI) (2). Mean final height in SRS is around –4.2 SD score (SDS) (3). Some other characteristics are known to be unspecific and/or infrequent (i.e. clinodactyly V and dysplastic ears) (3, 4, 5). Recombinant GH is nowadays an accepted growth-promoting drug for children born small for gestational age (SGA), including children with SRS (6). However, reports on the effectiveness of GH therapy in SRS are scarce.

With the advent of epigenetics in SRS, around 60% of the clinical diagnoses can now be confirmed genetically. Around 10% of children with SRS have a uniparental disomy of chromosome 7 (UPD7) whose functional role is unclear (7). Recently, maternal duplications of 11p15 (8) as well as demethylation of the imprinting control region 1 (ICR1) locus on 11p15 (9, 10, 11) were described in children with SRS with high frequency (up to 50%). These genetic defects are specific for SRS and for patients with SRS-like features but absent in children with idiopathic intrauterine growth retardation (12). In respect to the severe growth failure and dystrophy in SRS, the functional meaning of these epimutations, which may affect expression of IGF-II (9), is still far from being understood.

The aim of our study was to correlate the genotype with the endocrine phenotype with special respect to the IGF-I-GH axis in a large group of children with SRS.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Individuals

The children studied are patients of the Pediatric Endocrinology Section Tuebingen and have been followed longitudinally. The initial diagnosis was made between 1987 and 2006. For this study we defined SRS by the presence of intrauterine growth retardation (birth weight or length below the third percentile), lack of postnatal catch-up growth, and at least two of the following three criteria: typical face, relative macrocephaly, and skeletal asymmetry (13). The majority received GH therapy (n = 53). Height was measured using an electronic stadiometer and expressed in height SDS according to Prader et al. (14). Birth length, birth weight, and head circumference were expressed in SDS according to Niklasson et al. (15). Mean parental height ± 6.5 cm (boys/girls) was taken as the midparental height. SDS values for the BMI were calculated according to Cole et al. (16). Clinical data were collected from 61 children with SRS (Table 1). Genomic DNA was available from 44 children, 41 of which were treated with GH. Molecular results of a minority of these patients have been published previously (17, 18). The study was approved by the ethical committees of the University Hospitals in Tuebingen and Aachen.

Hypomethylation of the ICR1 in 11p15 as well as genomic imbalances in 11p15 were analyzed by a commercially available methylation sensitive multiplex ligation probe-dependent amplification (MLPA) test (assay ME030BWS/RSS; MRC Holland, Amsterdam, The Netherlands) (17). This MLPA assay allows the detection of abnormal methylation in 11p15 as well as of altered copy numbers for the different genes. Briefly, 200 ng DNA was denatured and hybridized overnight at 60 C with the MLPA probe mix. After ligation only and ligation with HhaI restriction, respectively, PCR amplification was performed with the specific SALSA FAM PCR primers. Amplification products were run on an ABI 3130 automatic sequencing system (Applied Biosystems, Foster City, CA) equipped with a 36-cm capillary using POP7 as polymer. Electrophoretic data were analyzed with an appropriate Gene Mapper file (Applied Biosystems). Calculation of copy numbers and degree of methylation was performed using a modified Excel spreadsheet (Microsoft Corp., Redmond, WA) originally developed for BRCA2 MLPA analysis from the Clinical Molecular Genetics Laboratory at the University Hospital Leeds/United Kingdom. For the detection of UPD7, DNA was analyzed by typing with chromosome 7 short tandem repeat markers (18).

Hormone measurements

Serum levels of IGF-I and IGF-binding protein (IGFBP)-3 were measured by RIA as described by Blum et al. (19). The mean interassay and intraassay coefficients of the IGF-I and the IGFBP-3 assays were lower than 10%. Data were transformed into age-related SDS values on the basis of a reference population of healthy German and Danish children with normal height (19). Human GH levels in serum were measured by a polyclonal in-house RIA and were calibrated against the World Health Organization International Reference Preparation 88/624 (1 mg = 3 IU). The lower detection limit was 0.1 µg/liter. The mean intraassay coefficient of variation was 6.9%, and the mean interassay coefficient was 9.5%.

Statistical analysis

After a one-way ANOVA, the Tukey-Kramer honestly significant difference test was applied for post hoc comparison of all pairs. For descriptive purposes, individual P values were calculated. The global level of significance was set at 5%. Results are expressed as means (±SD) unless stated otherwise.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Out of 61 SRS children studied, genotyping was performed in a subgroup of 44 individuals available. Epimutations at 11p15 were found in 19 of 44 children (43%), UPD7 in five of 44 (11%), and structural aberrations of the short arm of chromosome 11 in two of 44 children (5%). Of 44 cases, 18 were negative for any genetic defect known (41%). This group of children was named idiopathic SRS (idio-SRS). The clinical characteristics of the groups at birth are shown in Table 1. The two children with structural aberrations carried a maternally inherited duplication in 11p14 (8) and a balanced inversion 11p13p15.3, respectively. Both were not incorporated into the 11p15 subgroup because the consequences of these aberrations are not clearly predictable at the moment.

Gestational age, weight, and head circumference SDS at birth and midparental height were comparable. Birth length SDSs were significantly higher in SRS children with UPD7 in comparison to those with 11p15-SRS (P < 0.003). In consequence, relative macrocephaly was absent at birth in the five children with UPD7 (Table 1).

Height SDS of the children with UPD7-SRS decreased significantly during early childhood; this was not the case in children with 11p15-SRS, who maintained their length/height SDS. At the start of GH therapy, both groups had the same mean height SDS. Body asymmetry and the typical face were more frequent in 11p15-SRS than in UPD7-SRS or idio-SRS. Treatment with GH was started in 53 children at a mean age of 6.7 yr.

The main endocrine findings were significantly elevated serum levels of IGF-I and IGFBP-3 in the group of 11p15-SRS in comparison to the nonsyndromic SGA group, which was the ideal reference in regard to the extreme shortness and leanness of the SRS children examined. IGF-I serum levels were inadequately high with a mean of –0.02 SDS (1.07) when compared with serum levels present in the group of 58 nonsyndromic short children born SGA with a mean serum IGF-I level of –1.79 SDS (1.22) (P < 1.0^–4) (Table 2 and Fig. 1). Furthermore, the IGFBP-3 serum levels of 11p15-SRS children were extraordinarily high, with a mean of +1.38 SDS (1.01), again much higher than in the nonsyndromic SGA group, who had a mean IGFBP-3 of –1.12 SDS (1.06) (P < 1.0^–4). In contrast, IGF-I and IGFBP-3 serum levels were similar in UPD7-SRS and in nonsyndromic children born SGA (Table 2 and Fig. 1). The idio-SRS group had IGF-I and IGFBP-3 serum levels in between the two SRS groups with a definite genotype and significantly higher than the SGA group. No child with SRS had GH deficiency, and stimulated GH peaks were not significantly different between the two groups genotyped (Table 2).

View larger version (46K): [in this window] [in a new window]   FIG. 1. Individual serum levels of IGF-I and IGFBP-3 at the start and after 12 months of GH therapy given as age-related SDS-values in SRS children with UPD7 (UPD7 SRS), with 11p15 epimutation (11p15 SRS) and in idio-SRS compared with a cohort of nonsyndromic children born SGA. ns, Not significant.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Children with SRS comprise a subgroup of syndromic children born SGA who do not catch up after birth. Using molecular genetics, we found defects at the epigenetic level in 54% of the affected (epimutation at 11p15 in 43%, and UPD7 in 11%). In addition, 5% carried a structural aberration of chromosome 11, which may also account for an epigenetic defect. This characterization at the epigenetic level enabled us to perform a genotype-phenotype correlation, including the GH-IGF-I axis. We found inadequately high IGF-I serum levels and very high IGFBP-3 serum levels in prepubertal children with SRS and 11p15 epimutations, whereas IGF-I was low in the SRS subgroup with UPD7 and in a cohort of nonsyndromic children born SGA who were used for comparison.

We could confirm previously reported characteristics in auxology and syndromic presentation (2). SRS children with 11p15 epimutations were shorter, leaner, and body asymmetry was more frequent than in those with no genetic alteration detected at all. In addition, we found no change in height SDS from birth to first presentation at the mean age of 6 yr in SRS children with 11p15 epimutations. In clear contrast, there was a significant decrease in height SDS documented during the same time period in the five SRS children with UPD7 who were as short as the children with 11p15 epimutation at the start of GH therapy but significantly taller at birth with a mean length SDS of –1.59. Because of the normal mean birth length, these children were not macrocephalic at birth, but due to postpartum growth failure, they developed relative macrocephaly in early childhood. Dystrophy was milder in children with UPD7 in comparison to those with 11p15 epimutations at any age. These different features of growth failure paralleled the different levels of IGF-I and IGFBP-3 described here. The biometrical characteristics of the group of SRS children whose genetic origin was idiopathic were in between the two characterized groups.

The mechanism of growth retardation in SRS is still obscure. The finding of demethylation at the IGF2/H19 locus on 11p15 is suggestive of a decreased expression of IGF2 as a major mechanism of intrauterine growth restriction. In line with this speculation is that IGF2 expression was decreased in patients’ fibroblast in culture (9). In contrast, IGF-II serum levels were found to be normal in SRS by us and others (2, 13). Here, we demonstrate normal IGF-I serum levels in SRS children with 11p15 epimutations in relation to age, but in relation to their short stature and very low body weight, these levels have to be considered inadequately high, suggesting a form of IGF-I insensitivity. This was apparent in the comparison to our cohort of nonsyndromic short children born SGA, who had low to very low IGF-I serum levels. The latter finding was in accordance with reports on short SGA children in the literature (20, 21, 22). Moreover, children with 11p15-SRS had serum IGFBP-3 levels even exceeding age-related norms and higher than expected from the IGF-I levels. In contrast, children with UPD7-SRS had IGF-I and IGFBP-3 serum levels as low as the nonsyndromic SGA cohort. This is a clear indication that SRS is not only heterogeneous at the genetic and clinical level, but also at the level of hormonal regulation. Our search of the literature indicated that the IGF-I/IGFBP-3 system has not been studied systematically in children with SRS, so far.

To date, congenital IGF-I resistance has been described in children with heterozygous deletion of the IGF-I receptor due to structural aberrations of chromosome 15 and in two cases in the presence of point mutations of the IGF-I receptor gene (one compound-heterozygote and one heterozygote) (23, 24). The phenotype includes intrauterine growth restriction, no catch-up growth after birth, microcephaly, some syndromatic signs, but no body asymmetry. In these instances, IGF-I serum levels were normal or mildly elevated, and resistance was explained by reduced density of normal IGF-I receptors or decreased activity of receptors with normal density. Interestingly, some of these children responded well to GH therapy.

In the absence of IGF-I receptor defects (25), another mechanism of IGF-I insensitivity must be present in SRS. IGF-II deficiency at the cellular level, if present, may account for a change in the interaction between IGFs and insulin with their respective receptors and their binding proteins. In this context, it is of interest that the IGFBP-3 increase in children with 11p15-SRS to GH therapy was more pronounced than the increase of IGF-I, indicating a disordered coregulation of the growth factor and its major binding protein. Such a discordance of serum IGF-I and IGFBP-3 levels is new and has not been reported in the literature before.

In a time when short children born SGA are studied as a single diagnostic and single prognostic group, the here described discovery of significant differences in a distinct subgroup of these children, in SRS, elucidates how heterogeneous these children are. Further research should focus more on strictly defined subgroups than on big numbers of short children. SRS is a prototypical disorder for the study of the epigenetic regulation of prenatal and postnatal endocrine growth regulation.

	Acknowledgments

 
We thank K. Weber and C. Urban for excellent technical assistance, and K. Dietz, Department of Medical Biometry Tuebingen, for support in the statistical analysis of the data.

	Footnotes

 
Disclosure Statement: G.B. received lecture fees from Pfizer, Novo Nordisk, and Eli Lilly and Co. A.-K.S., R.S., C.P.S., and T.E. have nothing to declare. D.D.M. received lecture fees from Novo Nordisk. H.A.W. is employed by Pfizer Co. M.B.R. has served as an expert witness for Tercica Inc., and received lecture fees from Pfizer, Novo Nordisk, and Eli Lilly and Co.

First Published Online January 29, 2008

Abbreviations: BMI, Body mass index; ICR1, imprinting control region 1; idio-SRS, idiopathic Silver-Russell syndrome; IGFBP, IGF-binding protein; MLPA, multiplex ligation probe-dependent amplification; SDS, SD score; SGA, small for gestational age; SRS, Silver-Russell syndrome; UPD7, uniparental disomy of chromosome 7.

Received August 23, 2007.

Accepted January 18, 2008.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Patton MA 1988 Russell-Silver syndrome. J Med Genet 25:557–560[Free Full Text]
2. Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, Houang M, Steunou V, Esteva B, Thibaud N, Raux Demay MC, Danton F, Petriczko E, Bertrand AM, Heinrichs C, Carel JC, Loeuille GA, Pinto G, Jacquemont ML, Gicquel C, Cabrol S, Le Bouc Y 2007 11p15 ICR1 loss of methylation is a common and specific cause of typical Russell-Silver Syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 92:3148–3154[Abstract/Free Full Text]
3. Wollmann HA, Kirchner T, Enders H, Preece MA, Ranke MB 1995 Growth and symptoms in Silver-Russell syndrome: review on the basis of 386 patients. Eur J Pediatr 154:958–968[CrossRef][Medline]
4. Escobar V, Gleiser S, Weaver DD 1978 Phenotypic and genetic analysis of Silver-Russell syndrome. Clin Genet 13:278–288[Medline]
5. Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC 1999 The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet 36:837–842[Abstract/Free Full Text]
6. Clayton PE, Cianfarani S, Czernichow P, Johannsson P, Rapaport R, Rogol A 2007 Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 92:804–810[Abstract/Free Full Text]
7. Kotzot D, Utermann G 2005 Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated. Am J Med Genet A 136:287–305[Medline]
8. Eggermann T, Meyer E, Obermann C, Heil I, Schuler H, Ranke MB, Eggermann K, Wollmann HA 2005 Is maternal duplication of 11p15 associated with Silver-Russell syndrome? J Med Genet 42:e26
9. Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y 2005 Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 37:1003–1007[CrossRef][Medline]
10. Eggermann T, Schonherr N, Meyer E, Obermann C, Mavany M, Eggermann K, Ranke MB, Wollmann HA 2006 Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. J Med Genet 43:615–616[Abstract/Free Full Text]
11. Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, van der Smagt J, Kroes H, Mannens M 2006 Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also asymmetry or an SRS-like phenotype. Am J Hum Genet 78:604–614[CrossRef][Medline]
12. Schönherr N, Meyer E, Eggermann K, Ranke MB, Wollmann HA, Eggermann T 2006 (Epi)mutations in 11p15 significantly contribute to Silver-Russell syndrome: but are they generally involved in growth retardation? Eur J Med Genet 49:414–418[CrossRef][Medline]
13. Binder G, Seidel A-K, Weber K, Haase M, Wollmann HA, Ranke MB, Eggermann T 2006 IGF-II serum levels are normal in children with Silver-Russell syndrome who frequently carry epimutations at the IGF2 locus. J Clin Endocrinol Metab 91:4709–4712[Abstract/Free Full Text]
14. Prader A, Largo RH, Molinari L, Issler C 1989 Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development. Helv Paediatr Acta Suppl 52:1–125[Medline]
15. Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P 1991 An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977–1981). Acta Paediatr Scand 80:756–762[Medline]
16. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH 2000 Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320:1240–1245[Abstract/Free Full Text]
17. Eggermann T, Schönherr N, Eggermann K, Buiting K, Ranke MB, Wollmann HA, Binder G 2008 Use of multiplex ligation-dependent probe amplification increases the detection rate for 11p15 epigenetic alterations in Silver-Russell syndrome. Clin Genet 73:79–84[Medline]
18. Eggermann T, Wollmann HA, Kuner R, Eggermann K, Enders H, Kaiser P, Ranke MB 1997 Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet 100:415–419[CrossRef][Medline]
19. Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB 1993 Serum levels of insulin-like growth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 76:1610–1616[Abstract]
20. Leger J, Noel M, Limal JM, Chernichow P 1996 Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR. Pediatr Res 40:101–107[Medline]
21. de Wall WJ, Hokken-Koelega, Stijnen T, de Muinck Keizer-Schrama SM, Drop SL 1994 Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone. Clin Endocrinol (Oxf) 41:621–630[Medline]
22. Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland K 1996 Changes in serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. J Clin Endocrinol Metab 81:3902–3908[Abstract/Free Full Text]
23. Jain S, Golde DW, Bailey R, Geffner ME 1998 Insulin-like growth factor-I resistance. Endocr Rev 19:625–646[Abstract/Free Full Text]
24. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfäffle R, Raile K, Seidel B, Smith RJ, Chenrnausek SD, Intrauterine Growth Retardation (IUGR) Study Group 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211–2222[Abstract/Free Full Text]
25. Binder G, Mavridou K, Wollmann HA, Eggermann T, Ranke MB 2002 Screening for insulin-like growth factor-I receptor mutations in patients with Silver-Russell syndrome. J Pediatr Endocrinol Metab 15:1167–1171[Medline]

This article has been cited by other articles:

				T. Eggermann, D. Gonzalez, S. Spengler, M. Arslan-Kirchner, G. Binder, and N. Schonherr Broad Clinical Spectrum in Silver-Russell Syndrome and Consequences for Genetic Testing in Growth Retardation Pediatrics, May 1, 2009; 123(5): e929 - e931. [Abstract] [Full Text] [PDF]

				H. Shiura, K. Nakamura, T. Hikichi, T. Hino, K. Oda, R. Suzuki-Migishima, T. Kohda, T. Kaneko-Ishino, and F. Ishino Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation Hum. Mol. Genet., April 15, 2009; 18(8): 1424 - 1438. [Abstract] [Full Text] [PDF]

				S. Bruce, K. Hannula-Jouppi, J. Peltonen, J. Kere, and M. Lipsanen-Nyman Clinically Distinct Epigenetic Subgroups in Silver-Russell Syndrome: The Degree of H19 Hypomethylation Associates with Phenotype Severity and Genital and Skeletal Anomalies J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 579 - 587. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Binder, G. Articles by Ranke, M. B. Search for Related Content PubMed PubMed Citation Articles by Binder, G. Articles by Ranke, M. B. Related Collections Pediatric Endocrinology