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Fetal growth restriction (FGR) can result from multiple causes, such as genetic, epigenetic, environment, hormonal regulation, or vascular troubles and their potential interaction. The physiopathology of FGR is not yet fully elucidated, but the insulin-like growth factor system is known to play a central role. Specific clinical features can lead to the identification of genetic syndromes in some patients. FGR leads to multiple global health concerns, from the perinatal period, with higher morbidity/mortality, through infancy, with neurodevelopmental, growth, and metabolic issues, to the onset of puberty and later in life, with subfertility and elevated risks of cardiovascular and kidney diseases. Adequate follow-up and therapeutics should be offered to these patients. We first review the main molecular etiologies leading to FGR and their specificities. We then highlight the main issues that FGR can raise later in life before concluding with the proposed management of these children.

International audience; Purpose: Fetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver–Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.Methods: Whole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.Results: We report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.Conclusion: Genetic defects of the HMGA2–PLAG1–IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.

Twin pairs with the imprinting disorder Silver-Russell syndrome (SRS) have rarely been reported. All six monozygotic (MZ) twin pairs described so far were clinically discordant. In two of the four SRS twin pairs with molecularly proven 11p15.5 epimutation, the healthy twin also showed the molecular alteration in blood cells, but not in the other tested tissues. The clinical discordance is a well-known but poorly understood observation because MZ twins derive from the same zygote. For the second 11p15.5-associated imprinting disorder, Beckwith-Wiedemann syndrome, a larger number of twins has been described, here the majority of pairs are MZ but clinically discordant as well. Interestingly, there is a considerable preponderance of females among the MZ twins with BWS, and a functional link between altered imprinting and X chromosome inactivation has been suggested. We now describe two further MZ SRS twins with H19/IGF2:IG-DMR hypomethylation, including the first clinically concordant pair. By summarizing the existing data, an excess of females in MZ twins with SRS is observed, thus confirming the hypothesis that X-chromosome inactivation might trigger the inaccurate methylation of imprinted loci at least in female twin conceptions. The occurrence of a MZ concordant SRS twin pair is exceptional. The detailed molecular characterization of both siblings of a twin pair enables a reliable diagnosis, furthermore it allows insights in the etiology of twinning in association with (aberrant) imprinting marking.

ResumenIntroducciónEl síndrome de Silver-Russell presenta restricción del crecimiento intrauterino y posnatal, macrocefalia relativa y asimetría, entre otras características. Es causado por mecanismos genéticos y epigenéticos en el cromosoma 11p15.5 en el 40% de los casos y por disomía uniparental materna del cromosoma 7 en el 10%.MétodosSe identificaron los pacientes con diagnóstico de síndrome de Silver-Russell del Hospital Infantil de México Federico Gómez atendidos de 1998 a 2012; se reevaluaron 20 pacientes según los criterios clínicos internacionales, y se confirmó el diagnóstico en nueve sujetos.ResultadosTodos los pacientes presentaron restricción del crecimiento intrauterino y talla baja, ambos criterios diagnósticos mayores. La macrocefalia relativa estuvo presente en el 78% y la asimetría corporal solo en el 33%. Otras características, como la acidosis tubular renal, estuvieron presentes en más del 50%.ConclusionesEl diagnóstico del síndrome de Silver-Russell es complejo, por lo que contar con criterios clínicos adecuados es fundamental. Dado que la talla baja es la principal solicitud de atención médica en este síndrome, es relevante establecer diagnósticos diferenciales y valorar el crecimiento y desarrollo de todos los pacientes para identificar a aquellos en quienes la talla baja forma parte de una entidad sindrómica y que serían candidatos para realizar estudios moleculares. Este abordaje tendrá implicaciones para su manejo, pronóstico y asesoramiento genético.AbstractBackgroundPatients with Silver-Russell syndrome suffer from severe intrauterine and postnatal growth retardation, relative macrocephaly and body asymmetry, among other characteristics. It is caused by several genetic and epigenetic mechanisms in 11p15.5 in 40% of the cases and maternal uniparental disomy of chromosome 7 in 10%.MethodsTwenty patients with a diagnosis of Silver-Russell syndrome who were seen at the HIMFG from 1998 to 2012, were evaluated according to international clinical criteria confirming the diagnosis in nine of the subjects.ResultsAll patients showed intrauterine and postnatal growth retardation and short stature, both considered as major criteria of Silver-Russell syndrome. Relative macrocephaly was present in 78% of the patients and asymmetry in 33%. Other characteristics such as renal tubular acidosis were present > 50% of the cases.ConclusionsThe clinical diagnosis of Silver-Russell syndrome is complex. Short stature is the main reason for seeking medical attention and is helpful in the identification of a differential diagnosis. This situation underlines the importance of growth and development evaluation of all patients and particularly in those with short stature to identify those cases that may require molecular studies, with implications in management, prognosis and genetic counseling.

Silver–Russell syndrome (SRS) is a heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features. In 5–10% of SRS patients, a maternal uniparental disomy of chromosome 7 (UPD7) can be detected. We describe a 4.5-y old boy. Physical examination at the age of 4.5 y was remarkable for small stature, relatively big head, triangular face, broad forehead, pointed chin and clinodactyly. He had hypopigmented macules on his back with no evidence of asymmetry/hemihypertrophy. Clinical diagnosis of Silver–Russell syndrome was made. Maternal UPD of chromosome 7 was found, confirming the diagnosis. Along with the clinical findings that are described in this syndrome he had moderate developmental delay which is not commonly found in these patients and underwent an autistic regression around the age of 2 years. This association has only once been described before in this syndrome. A possible explanation is that the autism is not a part of SRS but is due to the UPD. Our case suggests an association of autistic regression with a locus on chromosome 7.

International audience; Fetal growth is a complex process. Its restriction is associated with morbidity and long-term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders with opposite fetal growth disturbance. SRS is leading to severe fetal and postnatal growth retardation with severe feeding difficulties during early childhood and long-term metabolic consequences and BWS is an overgrowth syndrome with an enhanced risk of tumors during childhood. Epigenetic (abnormal methylation at the imprinting center regions) or genetic (mutations, duplications, uniparental disomy [UPD]) including defects of imprinted genes on chromosome 11 (BWS and SRS), 7 (SRS) and more recently 14 (SRS) have been identified in these two syndromes. In humans, the 11p15 region contains genes important for the regulation of fetal and postnatal growth. This region includes two imprinted domains: the IGF2/H19 domain regulated by imprinting center region 1 (ICR1 or H19/IGF2:IG-DMR) and the CDKN1C/KCNQ1OT1 domain regulated by ICR2 (or KCNQ1OT1: TSS DMR).

The Silver-Russell syndrome (SRS) is a sporadic clinically and genetically heterogeneous disorder. Diagnosis is based on the variable combination of the following characteristics: intrauterine growth retardation, short stature because of lack of catch-up growth, underweight, relative macrocephaly, typical triangular face, body asymmetry and several minor anomalies including clinodactyly V. Different diagnostic scores have been proposed. The main genetic defects detected are at the epigenetic level: hypomethylation of the imprinting control region 1 (ICR1) on 11p15 in around 44% of cases and maternal uniparental disomy of chromosome 7 (UPD(7)mat) in 5-10% of cases. Severe phenotype is frequently associated with hypomethylation of ICR1 while mild phenotype is more often seen in combination with UPD(7)mat. Origins and biological consequences of these epimutations are still obscure. For genetic testing, we recommend a methylation-specific PCR-approach for both 7p and 7q loci (confirmed by microsatellite typing) for the detection of UPD(7)mat, and the methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) approach for methylation analysis of the 11p15 loci. Short stature in SRS can be treated by use of pharmacological doses of recombinant GH resulting in good short-term catch-up; sufficient information on the therapeutic effect in terms of final height is still missing.

Epigenetic alterations at several maternal loci have been associated with imprinting disorders in children conceived using assisted reproductive technologies. To date, epimutations at paternal loci have been observed in the spermatozoa of infertile men, but there is little evidence of paternal epimutations in babies conceived using assisted reproductive treatment. This is a report of a female infant with classic Russell–Silver Syndrome (RSS) who was conceived using intracytoplasmic injection of spermatozoa obtained from testicular aspiration. Methylation studies revealed hypomethylation of the paternally derived H19 / IGF2 locus. As far as is known, this is the second assisted reproduction treatment-conceived patient with classic RSS and this epigenotype. This case provides further evidence that epimutations affecting paternal alleles might be associated with assisted reproductive treatment.

There is a large group of disorders characterized by non-cranial vascular malformations and a dysregulated growth, of which the prototype may be Klippel-Trenaunay syndrome (KTS). The aetiology of KTS and vascular malformations-dysregulated growth (VM-DG) syndromes resembling KTS is obscure, but polygenic paradominant inheritance involving mutations or polymorphisms in two or more genes simultaneously, of which one (or more) are involved in (lymph) angiogenesis and the other(s) in growth regulation has been proposed for KTS and related VM-DG entities. This provides an explanation for the variability of the VM-DG syndromes through the numerous possible combinations of mutated genes involved. We report on three monozygotic female twins who are discordant for a VM-DG syndrome resembling KTS. We suggest that our observation is consistent with the concept of polygenic paradominant inheritance involving two or more genes. We discuss the published observations in twins discordant for other disorders associated with disturbed growth regulation such as Beckwith-Wiedemann syndrome and Silver-Russell syndrome, and the occurrence in cousins with KTS and Beckwith-Wiedemann syndrome, which are best explained by an imprinting disturbance. We propose that, similarly, disturbed imprinting plays a role in the pathogenesis of VM-DG syndromes in general, and suggest the same may hold for KTS in sensu strictu or Proteus syndrome. Further studies to investigate imprinting status in VM-DG syndromes, including KTS and Proteus syndrome, are warranted. (C) 2009 Elsevier Masson SAS. All rights reserved

(Epi)mutations affecting chromosome 11p15 are meanwhile well known to be associated with growth disturbances. The finding of 11p15 mutations in the overgrowth disease Beckwith–Wiedemann syndrome (BWS) led to the identification of imprinted growth-promoting genes which are expressed paternally and of imprinted growth-suppressing genes in the same region that are expressed maternally. Recently, the opposite (epi)mutations of the same region have been reported to result in growth retardation: maternal duplications of 11p15 as well as hypomethylation of the telomeric 11p15 imprinting domain (ICR1) could be identified in patients with Silver–Russell syndrome (SRS), a disease which is in particular characterised by intrauterine and postnatal growth retardation. To elucidate whether 11p15 mutations are generally involved in growth retardation we screened 125 growth retarded patients, among them 47 patients with SRS-like features and 20 with isolated growth retardation. Additional 58 patients were presented with clinical signs not consistent with SRS. We excluded 11p15 duplications in all 123 families by short tandem repeat typing. ICR1 hypomethylation was investigated by Southern-blot analyses and was therefore restricted to samples with a large amount of DNA. We identified ICR1 hypomethylation in 20% of the patients with SRS-like features (n = 25). No further cases were detectable in the other two subgroups with isolated growth retardation (n = 20) and with clinical signs not consistent with SRS (n = 23), respectively. Our data show that 11p15 duplications are rare in growth retardation in general and that they seem to be restricted to patients with SRS features. Furthermore, testing for the ICR1 hypomethylation should also be focused on patients with SRS features. While the ICR1 epimutation is detectable with a significant frequency only in SRS patients, its role for isolated growth retardation remains to be elucidated.

Tensin family is a group of focal adhesion proteins that interact with integrins, actin, and phosphotyrosine-containing proteins. To explore the in vivo functions of a new member of the family, tensin3, we have generated mutant mice with a disrupted tensin3 gene. Inactivation of tensin3 resulted in growth retardation and postnatal lethality in one third of the homozygous mutants. Histological analysis of those mutants showed incomplete development of the small intestine, lung, and bone. Villus formation in the small intestine was affected and cells migrated slower in the runt mutants. Their lungs also displayed enlarged air space suggesting defects in alveogenesis. In addition, the resting zone was thicker and fewer proliferating cells were present in the growth plates of tensin3−/− tibiae. These observations indicate that tensin3 is essential for normal development and functions of the small intestine, lung, and bone. These phenotypes of the runt tensin3−/− mice are similar to some clinical features of Silver–Russell syndrome (SRS) which is a genetically inherited defect. About 10% of SRS cases have been linked to abnormality in chromosome 7p11.2–13, where human tensin3 gene is located, suggesting a potential link between tensin3 and SRS.

Silver-Russell syndrome (SRS) is a heterogeneous syndrome with evidence for a substantial role of genetic factors in its etiology. Apart from other specific clinical features, severe intrauterine and postnatal growth retardation are the dominant characteristics of SRS. Therefore, studies on the genetic basis of the disease focus on genes involved in growth and its regulation. Another key for the identification of (a) SRS gene(s) is the finding of chromosomal disturbances in SRS patients: recently, four growth retarded patients carrying duplications in 11p15 of maternal origin have been described, two of these cases presented SRS-like features. The same region includes IGF2 and CDKN1C and is well known to harbour alterations in patients suffering from Beckwith-Wiedemann syndrome. We therefore decided to perform an extensive search for variants in the IGF2 and CDKN1C genes; mutations in these genes cause growth disturbances. More than 40 SRS patients were screened for mutations by different detection strategies, allele frequencies were compared between patients and controls. In both genes, we did not detect any obvious pathogenic mutation. In case of IGF2, slight differences in the allelic distribution of specific polymorphisms between SRS patients and controls were observed. In CDKN1C, several variants could be identified in both cohorts with similar frequencies, but only one patient showed a so far unknown variant not detectable in controls.

Summary Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth failure and other dysmorphic features. The syndrome is genetically heterogenous, but maternal uniparental disomy of chromosome 7 has been demonstrated in ∼7% of cases. This suggests that at least one gene on chromosome 7 is imprinted and involved in the pathogenesis of SRS. We have identified a de novo duplication of 7p11.2-p13 in a proband with features characteristic of SRS. FISH confirmed the presence of a tandem duplication encompassing the genes for growth factor receptor–binding protein 10 ( GRB10 ) and insulin-like growth factor–binding proteins 1 and 3 ( IGFBP1 and - 3 ) but not that for epidermal growth factor–receptor ( EGFR ). Microsatellite markers showed that the duplication was of maternal origin. These findings provide the first evidence that SRS may result from overexpression of a maternally expressed imprinted gene, rather than from absent expression of a paternally expressed gene. GRB10 lies within the duplicated region and is a strong candidate, since it is a known growth supressor. Futhermore, the mouse homologue ( Grb10/Meg1 ) is reported to be maternally expressed and maps to the imprinted region of proximal mouse chromosome 11 that demonstrates prenatal growth failure when it is maternally disomic. We have demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting. An additional 36 SRS probands were investigated for duplication of GRB10 , but none were found. However, it remains possible that GRB10 and/or other genes within 7p11.2-p13 are responsible for some cases of SRS.

Imprinting defects have meanwhile been described in nearly all human imprinting disorders among them Silver-Russell syndrome (SRS). In this disorder, 11p15 epimutations and maternal Uniparental Disomy of chromosome 7 (UPD7) are detectable in approximately 50% of patients. To find out whether isolated imprinting defects on chromosome 7 play a role in the aetiology of SRS we screened a cohort of 54 SRS patients without 11p15 epimutations. Methylation-specific PCR was carried out for the PEG1/MEST locus in 7q31. This test detects all known segmental and complete UPD7 cases. The exclusion of isolated imprinting defects in our study population shows that this type of epimutation at the PEG1/MEST locus in 7q31 does not play a relevant role in SRS. However, the role of imprinting disturbances in other genes cannot be excluded.

Silver-Russell syndrome (SRS) is a sporadic and heterogeneous disease that is mainly associated with intrauterine and postnatal growth retardation. The most frequent known aberration in SRS patients is a hypomethylation of the imprinting control region 1 (ICR1) in 11p15 ( approximately 38%). Up to now the basic mechanisms leading to this imprinting defect are unknown. Based on the recent findings that a reduced level of the methyl-CpG binding protein 3 (Mbd3) in mice results in a specific hypomethylation of the ICR1 and in a smaller size of embryos we hypothesized that mutations in the genomic sequence of the human MBD3 gene might cause SRS. We carried out mutation analysis of MBD3 in 20 SRS patients with hypomethylation of the ICR1 but did not detect any pathogenic variant in the coding region. Thus we assume that genomic mutations of MBD3 are not relevant for the aetiology of the ICR1 hypomethylation and therefore for SRS.

Silver-Russell syndrome (SRS) describes a uniform malformation syndrome characterized by intrauterine and postnatal growth restriction and morphological abnormalities including a small triangular face, relative macrocephaly, asymmetry of the head and limbs, and clinodactyly V. In >38% of SRS cases a hypomethylation of the H19/IGF2 DMR in 11p15 can be detected. Recently, ZFP57 mutations have been identified as a cause of hypomethylation of multiple imprinted loci. To determine whether ZFP57 mutations influence the H19/IGF2 DMR we screened 30 SRS patients with 11p15-hypomethylation for mutations within the coding region of this gene. Thereby homozygosity for a novel variant in exon 6 of ZFP57 was detected in one patient. Heterozygosity for this variant was found in the patients' parents as well as in 2.5% of healthy controls. Except this new and probably apathogenic polymorphism and some registered SNPs no further variants were detected. In conclusion, this study does not provide evidence that ZFP57 mutations are the cause of 11p15-hypomethylation in SRS patients and contribute to the aetiology of SRS.

Objective To determine the contribution of submicroscopic chromosomal imbalances to the etiology of Silver-Russell syndrome (SRS) and SRS-like phenotypes. Study design We performed molecular karyotyping in 41 patients with SRS or SRS-like features without known chromosome 7 and 11 defects using the Affymetrix SNP Array 6.0 system (Affymetrix, High Wycombe, United Kingdom). Results In 8 patients, pathogenic copy number variations with sizes ranging from 672 kb to 9.158 Mb were identified. The deletions in 1q21, 15q26, 17p13, and 22q11 were associated with known microdeletion syndromes with overlapping features with SRS. The duplications in 22q13 and Xq25q27 represent unique novel copy number variations but have an obvious influence on the phenotype. In 5 additional patients, the pathogenetic relevance of the detected variants remained unclear. Conclusion Pathogenic submicroscopic imbalances were detectable in a significant proportion of patients with short stature and features reminiscent of SRS. Therefore, molecular karyotyping should be implemented in routine diagnostics for growth-retarded patients with even slight dysmorphisms suggestive for SRS.

Intrauterine growth retardation is a symptom-complex of varied etiology. One distinct group is the “bird-headed” dwarf described by Seckel; such a patient is described here. Chromosomal studies did not reveal any abnormalities.