Clinical and Molecular Heterogeneity of Silver-Russell Syndrome and Therapeutic Challenges: A Systematic Review.

BACKGROUND: Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases. MATERIAL AND METHODS: To have a better understanding of the SRS clinical presentation and mutation/ epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature. RESULTS: 156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort. CONCLUSION: SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations.

Prenatal correction of IGF2 to rescue the growth phenotypes in mouse models of Beckwith-Wiedemann and Silver-Russell syndromes.

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are imprinting disorders manifesting as aberrant fetal growth and severe postnatal-growth-related complications. Based on the insulator model, one-third of BWS cases and two-thirds of SRS cases are consistent with misexpression of insulin-like growth factor 2 (IGF2), an important facilitator of fetal growth. We propose that the IGF2-dependent BWS and SRS cases can be identified by prenatal diagnosis and can be prevented by prenatal intervention targeting IGF2. We test this hypothesis using our mouse models of IGF2-dependent BWS and SRS. We find that genetically normalizing IGF2 levels in a double rescue experiment corrects the fetal overgrowth phenotype in the BWS model and the growth retardation in the SRS model. In addition, we pharmacologically rescue the BWS growth phenotype by reducing IGF2 signaling during late gestation. This animal study encourages clinical investigations to target IGF2 for prenatal diagnosis and prenatal prevention in human BWS and SRS.

Síndrome de Silver-Russell. Aspectos clínicos y etiopatológicos de una entidad ejemplo de impronta genómica / Silver-Russell syndrome. Clinical and etiopathological aspects of a model genomic imprinting entity

El síndrome de Silver-Russell se caracteriza por retraso del crecimiento intrauterino asimétrico, con circunferencia craneal normal, barbilla pequeña y puntiaguda, que proporciona un aspecto de rostro triangular. Puede, además, presentar asimetría corporal, entre otros. Tiene una incidencia mundial estimada de 1 en 30 000-100 000 nacimientos, aunque este número es, probablemente, subestimado. En alrededor del 60 % de los casos, se puede identificar una causa molecular y la principal es la hipometilación del alelo paterno en la región de control de impresión 1 localizado en 11p15.5-p15.4. Realizar el diagnóstico de esta entidad, excluir los diagnósticos diferenciales y conocer las correlaciones (epi)genotipo-fenotipo son necesarios para realizar el adecuado seguimiento, brindar las opciones terapéuticas disponibles y el oportuno asesoramiento genético familiar. El objetivo del presente artículo es mostrar el estado actual del síndrome de Silver-Russell, un ejemplo de trastorno de impronta genómica.

Silver-Russell syndrome is characterized by asymmetrical intrauterine growth retardation, with normal head circumference and small, pointed chin, which results in a triangular face. It can also include body asymmetry, among other characteristics. Its global incidence is estimated at 1 in 30 000-100 000 births, even though this figure may be underestimated. In approximately 60 % of cases, a molecular cause can be identified, and the main one is hypomethylation of the paternal allele at the imprinting control region 1 located at 11p15.5-p15.4. It is necessary to make the diagnosis of this entity, exclude differential diagnoses, and know (epi)genotype-phenotype correlations in order to ensure an adequate follow-up, provide available therapeutic options, and offer a timely family genetic counseling. The objective of this article is to describe the current status of the Silver-Russell syndrome, a model of genomic imprinting disorder.

Silver-Russell syndrome. Clinical and etiopathological aspects of a model genomic imprinting entity. / Síndrome de Silver-Russell. Aspectos clínicos y etiopatológicos de una entidad ejemplo de impronta genómica.

Silver-Russell syndrome is characterized by asymmetrical intrauterine growth retardation, with normal head circumference and small, pointed chin, which results in a triangular face. It can also include body asymmetry, among other characteristics. Its global incidence is estimated at 1 in 30 000-100 000 births, even though this figure may be underestimated. In approximately 60 % of cases, a molecular cause can be identified, and the main one is hypomethylation of the paternal allele at the imprinting control region 1 located at 11p15.5-p15.4. It is necessary to make the diagnosis of this entity, exclude differential diagnoses, and know (epi)genotype-phenotype correlations in order to ensure an adequate follow-up, provide available therapeutic options, and offer a timely family genetic counseling. The objective of this article is to describe the current status of the Silver-Russell syndrome, a model of genomic imprinting disorder.

El síndrome de Silver-Russell se caracteriza por retraso del crecimiento intrauterino asimétrico, con circunferencia craneal normal, barbilla pequeña y puntiaguda, que proporciona un aspecto de rostro triangular. Puede, además, presentar asimetría corporal, entre otros. Tiene una incidencia mundial estimada de 1 en 30 000- 100 000 nacimientos, aunque este número es, probablemente, subestimado. En alrededor del 60 % de los casos, se puede identificar una causa molecular y la principal es la hipometilación del alelo paterno en la región de control de impresión 1 localizado en 11p15.5-p15.4. Realizar el diagnóstico de esta entidad, excluir los diagnósticos diferenciales y conocer las correlaciones (epi)genotipo-fenotipo son necesarios para realizar el adecuado seguimiento, brindar las opciones terapéuticas disponibles y el oportuno asesoramiento genético familiar. El objetivo del presente artículo es mostrar el estado actual del síndrome de Silver-Russell, un ejemplo de trastorno de impronta genómica.

Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management.

Silver-Russell and Beckwith-Wiedemann syndromes (SRS, BWS) are rare congenital human disorders characterized by opposite growth disturbances. With the increasing knowledge on the molecular basis of SRS and BWS, it has become obvious that the disorders mirror opposite alterations at the same genomic loci in 11p15.5. In fact, these changes directly or indirectly affect the expression of IGF2 and CDKN1C and their associated pathways, and thereby, cause growth disturbances as key features of both diseases. The increase of knowledge has become possible with the development and implementation of new and comprehensive assays. Whereas, in the beginning molecular testing was restricted to single chromosomal loci, many tests now address numerous loci in the same run, and the diagnostic implementation of (epi)genome wide assays is only a question of time. These high-throughput approaches will be complemented by the analysis of other omic datasets (e.g., transcriptome, metabolome, proteome), and it can be expected that the integration of these data will massively improve the understanding of the pathobiology of imprinting disorders and their diagnostics. Especially long-read sequencing methods, e.g., nanopore sequencing, allowing direct detection of native DNA modification, will strongly contribute to a better understanding of genomic imprinting in the near future. Thereby, new genomic loci and types of pathogenic variants will be identified, resulting in more precise discrimination into different molecular subgroups. These subgroups serve as the basis for (epi)genotype-phenotype correlations, allowing a more directed prognosis, counseling, and therapy. By deciphering the pathophysiological consequences of SRS and BWS and their molecular disturbances, future therapies will be available targeting the basic cause of the disease and respective pathomechanisms and will complement conventional therapeutic strategies.

A spontaneous pregnancy and successful delivery in a Chinese female with Silver-Russell syndrome accompanied by gestational diabetes mellitus.

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features including body asymmetry, relative macrocephaly, protruding forehead, and feeding difficulties. Previous descriptions of SRS focus on the management of specific issues in children. Herein, we present clinical and metabolic characteristics of an adult woman with SRS accompanied by gestational diabetes mellitus (GDM). Given the rare circumstances presented in our case, the emerging questions concerning the management of metabolic issues and fertility potential in adult SRS patient deserve more attention. Further, long-term follow up is essential to gain future insights into the natural history and optimal management in adulthood.

Silver-Russell Syndrome: A Review.

Silver-Russell syndrome (SRS) is a rare congenital imprinting disorder. The genetic findings in SRS patients are heterogeneous and often sporadic. However, chromosomes 7, 11, and 17 are consistently involved in all individuals who meet the strict diagnostic criteria of SRS. There are many clinical features characteristic of SRS; the most common are low birth weight, short stature, triangular face, clinodactyly, relative macrocephaly, ear anomalies, and skeletal asymmetry.

[Rare diseases with clinical relevance-the Silver-Russell syndrome]. / Seltene Erkrankungen mit klinischer Relevanz ­ das Silver-Russell-Syndrom.

The Silver-Russell syndrome (SRS) is a rare imprinting disease associated with pre- and postnatal growth retardation, craniofacial features, and asymmetry. Genitourinary abnormalities are seen in up to 20% of affected individuals. Apart from structural renal anomalies, cryptorchidism and hypospadias occur frequently in boys, while girls often have anomalies similar to those in Mayer-Rokitansky-Küster-Hauser syndrome with congenital hypoplasia or aplasia of the uterus and upper part of the vagina. Frequently hypospadias repair and orchiopexy are difficult because of lack of buccal mucosa due to facial dysmorphism and intraabdominal position of the testicles, respectively. Anesthetic problems with SRS children can be profound and mostly concern a difficult airway due to facial dysmorphism. Especially the young, very thin SRS patients are prone to hypoglycemia and hypothermia and require close perioperative monitoring. Children with SRS and their families face challenges from birth to adulthood. In case of urogenital abnormalities, they should receive multidisciplinary care by pediatric urologists/surgeons and pediatric anesthesiologists in a center of expertise in rare diseases.

Diagnosis and management of Silver-Russell syndrome: first international consensus statement.

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

The degree of H19 hypomethylation in children with Silver-Russel syndrome (SRS) is not associated with the severity of phenotype and the clinical severity score (CSS).

BACKGROUND: Hypomethylation of the imprinting control region 1 (ICR 1) at the IGF2/H19 locus on 11p15 is linked to Silver-Russel syndrome (SRS). METHODS AND RESULTS: We tested the hypothesis that the severity of the phenotype in SRS patients is dependent on the clinical severity score (CSS) (1). Three SRS patients were clinically scored and their scores ranged between 12, 13 and 13. Two of the three SRS patients (66%) had hypomethylation of one allele. CONCLUSION: All three patients had high CSS. Nevertheless, only two of them had hypomethylation of one H19 allele. Interestingly, two of them had ventricular septal defects, but only one had H19 hypomethylation. All children had low birth length and weight, a classic facial phenotype, haemihypertrophy (>2.5 cm thinner left arm/leg in comparison to the right one), shorter leg, and striking thinness (BMI of >16.0). One child was operated for cryptorchidismus, and the same child had elbow contracture. Two children had scoliosis. All three children were short (-3 to 5.5 SD), and treatment with GH resulted in growth on the third percentile. Since one child had no hypomethylation and two had a lower degree of hypomethylation, the higher CSS (12, 13 and 13) was not followed by a higher degree of hypomethylation of the IGF2/H19 locus.

Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face, asymmetry and feeding difficulties. As many of these features are non-specific, clinical diagnosis of SRS remains difficult. Hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 and maternal uniparental disomy (mUPD) for chromosome 7 are found in up to 60% and around 5-10% of patients with SRS, respectively. Patients with ICR1 hypomethylation are more likely to have classical features of SRS, including asymmetry; patients with mUPD7 are more likely to have learning difficulties, particularly speech problems, although these are usually mild. As features vary widely in severity, clinicians should have a low threshold for genetic investigation of patients with features suggestive of SRS.