Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.

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Novel Variant in PLAG1 in a Familial Case with Silver–Russell Syndrome Suspicion

Genes ◽

10.3390/genes11121461 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1461

Author(s):

Yerai Vado ◽

Arrate Pereda ◽

Isabel Llano-Rivas ◽

Nerea Gorria-Redondo ◽

Ignacio Díez ◽

...

Keyword(s):

Growth Retardation ◽

Genetic Disorder ◽

Panel Study ◽

Uniparental Disomy ◽

Postnatal Growth ◽

Triangular Face ◽

Chromosome 11P15 ◽

Postnatal Growth Retardation ◽

Feeding Difficulties ◽

Silver Russell Syndrome

Silver–Russell syndrome (SRS) is a rare growth-related genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Molecular causes are not clear in all cases, the most common ones being loss of methylation on chromosome 11p15 (≈50%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (≈10%). However, pathogenic variants in genes such as CDKN1C, HMGA2, IGF2, or PLAG1 have also been described. Previously, two families and one sporadic case have been reported with PLAG1 alterations. Here, we present a case of a female with clinical suspicion of SRS (i.e., intrauterine and postnatal growth retardation, triangular face, psychomotor delay, speech delay, feeding difficulties). No alterations in methylation or copy number were detected at chromosomes 11p15 and 7 using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The custom panel study by next-generation sequencing (NGS) revealed a frameshift variant in the PLAG1 gene (NM_002655.3:c.551delA; p.(Lys184Serfs *45)). Familial studies confirmed that the variant was inherited from the mother and it was also present in other family members. New evidence of pathogenic alterations in the HMGA2-PLAG1-IGF2 pathway suggest the importance of studying and taking into account these genes as alternative molecular causes of Silver–Russell syndrome.

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Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106561 ◽

2020 ◽

Vol 57 (10) ◽

pp. 683-691 ◽

Cited By ~ 1

Author(s):

Oluwakemi Lokulo-Sodipe ◽

Lisa Ballard ◽

Jenny Child ◽

Hazel M Inskip ◽

Christopher D Byrne ◽

...

Keyword(s):

Quality Of Life ◽

Uniparental Disomy ◽

Scoring Systems ◽

Hormone Treatment ◽

Diagnostic Features ◽

Maternal Uniparental Disomy ◽

Feeding Difficulties ◽

Adult Growth ◽

Silver Russell Syndrome

BackgroundSilver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%–10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.MethodsA retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.ResultsThe median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤−2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.ConclusionHistorical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.

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Neonato piccolo, ipotonico, con difficoltà di alimentazione: pensiamo anche alla sindrome di Temple

Medico e Bambino pagine elettr ◽

10.53126/mebxxiv138 ◽

2021 ◽

Vol 24 (5) ◽

pp. 138-140

Author(s):

Sara Dal Bo ◽

Claudia Muratori ◽

Chiara Nardini ◽

Ilaria Donati ◽

Anna Maria Magistà ◽

...

Keyword(s):

Growth Retardation ◽

Uniparental Disomy ◽

Final Diagnosis ◽

Early Puberty ◽

Maternal Uniparental Disomy ◽

Feeding Difficulties ◽

Intrauterine Growth ◽

Imprinting Disorder ◽

Development Delay ◽

Temple Syndrome

Temple syndrome is a rare imprinting disorder mainly due to maternal uniparental disomy of the chromosome 14. It represents the main differential diagnosis of Silver-Russell and Prader-Willi syndrome. This syndrome is characterized by growth retardation, hypotonia, difficult feeding, development delay and precocious puberty. The absence of congenital pathognomonic malformations and universally recognized screening methodologies make this pathology be underdiagnosed, so the analysis of 14q32 should be evaluated in all cases of intrauterine growth restriction, hypotonia and neonatal feeding difficulties. It should also be considered in cases of unexplained early puberty associated with poor stature growth. The paper presents the case of a girl with the final diagnosis of Temple syndrome, with an initial picture of intrauterine growth retardation, axial hypotonia and feeding difficulties. The initial diagnostic suspicion was a Silver-Russell syndrome.

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Multiple Segmental Uniparental Disomy Associated with Abnormal DNA Methylation of Imprinted Loci in Silver-Russell Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-1980 ◽

2012 ◽

Vol 97 (11) ◽

pp. E2188-E2193 ◽

Cited By ~ 11

Author(s):

Renuka P. Dias ◽

Irina Bogdarina ◽

Jean-Baptiste Cazier ◽

Charles Buchanan ◽

Malcolm C. Donaldson ◽

...

Keyword(s):

Dna Methylation ◽

Mrna Expression ◽

Single Nucleotide Polymorphism Array ◽

Uniparental Disomy ◽

Postnatal Growth ◽

Chromosome 7 ◽

Imprinted Genes ◽

Methylation Array ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

Background: Silver-Russell syndrome (SRS; online inheritance in man 180860) is a low-birth-weight syndrome characterized by postnatal growth restriction and variable dysmorphic features. Although maternal uniparental disomy (UPD) of chromosome 7 and hypomethylation of H19 have been reported in up to 50% of all cases, no unifying mechanism is apparent. Subjects and Methods: Ten patients and their parents were studied using the Illumina GoldenGate methylation array and the Illumina 370K HumHap single-nucleotide polymorphism array to identify aberrations in DNA methylation as well as genomic changes including copy number changes and uniparental disomy events. Results: We found evidence of UPD events outside chromosome 7 in all patients. In up to 30% of patients with SRS, DNA methylation changes occur in imprinted gene loci outside 11p15.5 (PEG3, PLAGL1, and GRB10), not previously consistently linked with SRS. Furthermore, hypermethylation of GRB10 was associated with increased mRNA expression. In addition, 20% of patients appear to have DNA methylation abnormalities within multiple loci. Not all the imprinted loci with methylation defects were affected directly by UPD. Conclusions: The association of widespread UPD associated with abnormal methylation and mRNA expression in imprinted genes in SRS is consistent with the concept of UPD as an initial genomic abnormality leading to unstable DNA methylation within the regulatory network of imprinted genes. Furthermore, disruption of any one of these genes may contribute to the heterogeneous clinical spectrum of SRS.

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Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105463 ◽

2018 ◽

Vol 56 (6) ◽

pp. 413-418 ◽

Cited By ~ 8

Author(s):

Takanobu Inoue ◽

Hideaki Yagasaki ◽

Junko Nishioka ◽

Akie Nakamura ◽

Keiko Matsubara ◽

...

Keyword(s):

Snp Array ◽

Uniparental Disomy ◽

Gene Mutations ◽

Growth Failure ◽

Postnatal Growth ◽

Differentially Methylated Region ◽

Unknown Aetiology ◽

Chromosome 16 ◽

Maternal Uniparental Disomy ◽

Silver Russell Syndrome

BackgroundRecently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.ObjectiveTo clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.MethodsWe studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR.ResultsWe identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.ConclusionWe suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.

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Silver Russell syndrome in a preterm girl with 8q12.1 deletion encompassing PLAG1.

10.22541/au.160507814.44110683/v2 ◽

2021 ◽

Author(s):

José Ramón Fernández-Fructuoso ◽

Cristina De la Torre-Sandoval ◽

Madeleine Harbison ◽

Sandra Chantot-bastaraud ◽

I. Temple ◽

...

Keyword(s):

Clinical Features ◽

Growth Retardation ◽

Intrauterine Growth Retardation ◽

De Novo ◽

Postnatal Growth ◽

Postnatal Growth Retardation ◽

Feeding Difficulties ◽

Intrauterine Growth ◽

Molecular Features ◽

Silver Russell Syndrome

Silver Russell syndrome (SRS) is a congenital disorder characterised by intrauterine growth retardation (IUGR), feeding difficulties and postnatal growth retardation. In a small number of cases PLAG1 variants have been described (OMIM #618907). PLAG1 haploinsufficiency decreases IGF2 expression and produces a Silver Russell syndrome like phenotype. Here, we describe the phenotype and molecular features of a 26 months girl with clinical features of SRS and a de novo 2.1 Mb deletion encompassing PLAG1 is reported in association with clinical features suggestive of SRS.

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The Diagnostic Value of IGF-2 and the IGF/IGFBP-3 System in Silver-Russell Syndrome

Hormone Research in Paediatrics ◽

10.1159/000477666 ◽

2017 ◽

Vol 88 (3-4) ◽

pp. 201-207 ◽

Cited By ~ 4

Author(s):

Gerhard Binder ◽

Thomas Eggermann ◽

Karin Weber ◽

Nawfel Ferrand ◽

Roland Schweizer

Keyword(s):

Uniparental Disomy ◽

Clinical Signs ◽

Growth Failure ◽

Postnatal Growth ◽

Diagnostic Value ◽

Maternal Uniparental Disomy ◽

Short Children ◽

Postnatal Growth Failure ◽

Silver Russell Syndrome ◽

Igfbp 3

Background/Aims: Recently, we have described a family of 4 members presenting with intrauterine and postnatal growth failure, low IGF-2 levels, and signs of Silver-Russell syndrome (SRS) who carried a genomic IGF2 mutation. Here, we assess the value of IGF-2 in relation to SRS. Methods: We collected data from 48 SRS children and 48 short children born small for gestational age (SGA) seen at our center. The SRS children were 4.6 ± 2.0 years of age, and the SGA children were 4.8 ± 1.8 years of age. All patients were prepubertal and growth hormone naive. An 11p15 ICR1 loss of methylation (11p15LOM) was present in 22, maternal uniparental disomy of chromosome 7 (upd(7)mat) in 7, and IGF2 genomic mutation (IGF2mut) in 3 patients. Growth factors were measured by in-house radioimmunoassays. Results: The median IGF-2 standard deviation scores (SDSs) were: IGF2mut –1.75, upd(7)mat –1.69, nonsyndromic SGA –1.52, 11p15LOM –0.61, and clinical (tested negative) –0.55. The median IGF-2:IGF-1 concentration ratio was 2.57 in IGF2mut compared to 5.44 in 11p15LOM (p = 0.036), 7.84 in clinical, and 7.98 in upd(7)mat. Upd(7)mat patients had significantly lower IGF-1 and IGFBP-3 SDSs than patients with 11p15LOM (p ≤ 0.002). Conclusion: Serum IGF-2 in combination with IGF-1 and IGFBP-3 can add to the clinical signs of SRS patients and help to perform targeted genetic testing. Further studies are needed.

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Prevalence and management of gastrointestinal manifestations in Silver–Russell syndrome

Archives of Disease in Childhood ◽

10.1136/archdischild-2013-305864 ◽

2014 ◽

Vol 100 (4) ◽

pp. 353-358 ◽

Cited By ~ 12

Author(s):

Céline Marsaud ◽

Sylvie Rossignol ◽

Patrick Tounian ◽

Irène Netchine ◽

Béatrice Dubern

Keyword(s):

Growth Hormone ◽

Nutritional Status ◽

Hormone Therapy ◽

Growth Hormone Therapy ◽

Uniparental Disomy ◽

Failure To Thrive ◽

Maternal Uniparental Disomy ◽

Feeding Difficulties ◽

Facial Phenotype ◽

Silver Russell Syndrome

ObjectivesSilver–Russell syndrome (SRS) is an imprinted disorder characterised by intrauterine growth retardation, relative macrocephaly, failure to thrive, typical facial phenotype and frequent body asymmetry. Feeding difficulties are frequently noted, but no study described evolution of gastrointestinal signs during infancy and their management in SRS. The aim of this study was to describe these abnormalities in a large cohort of children with SRS.DesignWe included 75 patients (median age 24.3 months (5.1–135.2)) in the study. We retrospectively analysed nutritional status before growth hormone therapy, the frequency of gastrointestinal signs, such as gastroesophageal reflux (GER), vomiting, constipation and feeding difficulties, and nutritional management.ResultsMaternal uniparental disomy for chromosome 7 was found in 10 patients and 11p15 hypomethylation in 65 patients. Malnutrition (defined as a weight/expected weight for height ratio <80%) was detected in 70% of the children. Gastrointestinal signs were found in 77%, including severe vomiting before the age of 1 year in 50% of cases, persistent vomiting from the age of 1 year in 29% of cases and constipation in 20% of cases. Severe GER was diagnosed in 55% of children by 24 h oesophageal pH-metry. Feeding difficulties were described in 65% of cases, with indications for dietary enrichment in 49%. Enteral nutrition by gastrostomy was indicated in 22% of cases.ConclusionsDigestive signs (GER, constipation) and malnutrition are frequent in children with SRS. The systematic exploration and management of these signs are crucial to improve the nutritional status of these children before initiating growth hormone therapy.

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Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome

Journal of Personalized Medicine ◽

10.3390/jpm11111197 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1197

Author(s):

Hsiang-Yu Lin ◽

Chung-Lin Lee ◽

Sisca Fran ◽

Ru-Yi Tu ◽

Ya-Hui Chang ◽

...

Keyword(s):

Clinical Diagnosis ◽

Growth Characteristic ◽

Diagnostic Testing ◽

Uniparental Disomy ◽

Clinical Manifestations ◽

Postnatal Growth ◽

Maternal Uniparental Disomy ◽

Diagnosis Rate ◽

Copy Number Changes ◽

Silver Russell Syndrome

Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. Methods: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the “IC1 hypomethylation” and “mUPD7” groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). Conclusions: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

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