Silver-Russell syndrome is a rare imprinting and congenital growth disorder characterized by prenatal and postnatal growth restriction, relative macrocephaly, prominent forehead, body asymmetry, feeding difficulty, gastrointestinal problems, hypoglycemia risk, and variable neurodevelopmental burden. Molecular etiologies include 11p15.5 imprinting defects affecting the H19-IGF2/CDKN1C region, maternal uniparental disomy of chromosome 7, 14q32.2 imprinting-region disruption in clinically overlapping cases, and rare monogenic or copy-number etiologies.
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name: Silver-Russell Syndrome
creation_date: "2026-05-07T12:55:59Z"
updated_date: "2026-05-07T12:55:59Z"
category: Mendelian
description: >-
Silver-Russell syndrome is a rare imprinting and congenital growth disorder
characterized by prenatal and postnatal growth restriction, relative
macrocephaly, prominent forehead, body asymmetry, feeding difficulty,
gastrointestinal problems, hypoglycemia risk, and variable neurodevelopmental
burden. Molecular etiologies include 11p15.5 imprinting defects affecting the
H19-IGF2/CDKN1C region, maternal uniparental disomy of chromosome 7, 14q32.2
imprinting-region disruption in clinically overlapping cases, and rare
monogenic or copy-number etiologies.
disease_term:
preferred_term: Silver-Russell syndrome
term:
id: MONDO:0008394
label: Silver-Russell syndrome
parents:
- Genomic Imprinting Disorders
- Growth Disorders
synonyms:
- Russell-Silver syndrome
- Russell-Silver dwarfism
- Silver-Russell dwarfism
- SRS
definitions:
- name: International consensus definition
definition_type: CASE_DEFINITION
description: >-
The 2017 international consensus statement defines Silver-Russell syndrome
as an imprinting disorder causing prenatal and postnatal growth retardation,
with diagnosis primarily based on clinical criteria and molecular testing
used to confirm and subtype the disorder.
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: The international consensus statement directly defines SRS as an imprinting disorder causing prenatal and postnatal growth retardation.
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype."
explanation: Supports the clinical-diagnosis framing and the role of molecular testing for confirmation and subtyping.
has_subtypes:
- name: 11p15 IC1 LOM
display_name: 11p15 imprinting center region 1 loss of methylation
classification: molecular
subtype_frequency: 30-60%
description: >-
Major molecular subtype caused by partial loss of methylation at the 11p15
imprinting center region 1 domain, involving the H19/IGF2 imprinted region.
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Quantifies 11p15 ICR1 loss of methylation as the dominant molecular finding in a clinically diagnosed RSS subgroup.
- name: Maternal UPD7
display_name: Maternal uniparental disomy of chromosome 7
classification: molecular
subtype_frequency: 5-10%
description: >-
Molecular subtype caused by maternal uniparental disomy of chromosome 7,
producing parent-of-origin imbalance at imprinted chromosome 7 loci.
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Maternal uniparental disomy for chromosome 7 (mUPD7) is found in 5-10% of cases."
explanation: Directly supports maternal UPD7 as a recurrent SRS molecular subtype.
- name: 14q32.2 Imprinting Disruption
display_name: 14q32.2 imprinted-region disruption with SRS overlap
classification: molecular
description: >-
Clinically overlapping imprinting-disorder presentation, often classified
molecularly as Temple syndrome but capable of fulfilling SRS clinical
criteria and requiring similar management attention.
evidence:
- reference: PMID:29659920
reference_title: Chromosome 14q32.2 Imprinted Region Disruption as an Alternative Molecular Diagnosis of Silver-Russell Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap."
explanation: Supports 14q32.2 disruption as an important differential molecular diagnosis with SRS-like clinical overlap.
- name: Rare Monogenic or Copy-Number Etiology
classification: molecular
description: >-
Rare SRS or SRS-like etiologies include variants in imprinted genes such as
IGF2 and CDKN1C, non-imprinted growth-regulatory genes such as HMGA2 and
PLAG1, and familial 11p15 copy-number changes with methylation-dependent
expression effects.
evidence:
- reference: PMID:41430624
reference_title: Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS."
explanation: Supports the rare monogenic SRS subtype grouping and the named genes.
- reference: PMID:39741906
reference_title: Prenatal diagnosis of a silver-russell syndrome caused by 11p15 duplication and pedigree analysis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we present a rare pedigree of duplications with different methylation patterns in 11p15.5, which caused SRS or a normal phenotype across three generations."
explanation: Supports familial 11p15 copy-number and methylation-pattern complexity as a rare etiology.
inheritance:
- name: Usually sporadic with parent-of-origin mechanisms
parent_of_origin_effect: Parent-of-origin effects occur through imprinting defects, uniparental disomy, and parent-specific 11p15 copy-number/methylation states.
description: >-
Most SRS cases arise sporadically through epimutations, uniparental disomy,
or de novo structural events. Recurrence risk can differ when a familial
copy-number or sequence variant is present, so genetic counseling and
parental testing are important in molecularly confirmed cases.
evidence:
- reference: PMID:39741906
reference_title: Prenatal diagnosis of a silver-russell syndrome caused by 11p15 duplication and pedigree analysis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Duplications of maternal IC2 (copy number of 3) with enhanced methylation (methylation index of 0.62) resulted in typical SRS."
explanation: Demonstrates parent-of-origin and methylation-pattern effects in a familial 11p15 duplication pedigree.
prevalence:
- population: General population
percentage: 0.001-0.0033
notes: >-
The consensus report cites rare-disease incidence estimates around 1 in
30,000 to 1 in 100,000 births; exact population prevalence varies with
diagnostic ascertainment and molecular confirmation.
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: The abstract supports SRS as a rare consensus-managed disorder, while the numeric incidence estimate comes from the consensus body summarized in the Falcon report rather than this PubMed abstract snippet.
pathophysiology:
- name: 11p15 Imprinting Dysregulation
description: >-
Loss of methylation at 11p15 ICR1 disrupts an imprinted growth-control
region involving IGF2 and CDKN1C-associated pathways.
biological_processes:
- preferred_term: genomic imprinting
term:
id: GO:0071514
label: genomic imprinting
- preferred_term: regulation of gene expression
term:
id: GO:0010468
label: regulation of gene expression
genes:
- preferred_term: IGF2
term:
id: hgnc:5466
label: IGF2
- preferred_term: CDKN1C
term:
id: hgnc:1786
label: CDKN1C
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified loss of methylation (LOM) of 11p15 Imprinting Center Region 1 (ICR1) domain (including IGF-II) as a mechanism leading to RSS."
explanation: Directly links 11p15 ICR1 loss of methylation involving IGF2 with the RSS mechanism.
- reference: PMID:31466347
reference_title: "Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Supports the IGF2/CDKN1C expression-dosage mechanism for 11p15.5 imprinting disorders.
downstream:
- target: Reduced Paternal IGF2 Expression
description: 11p15 ICR1 hypomethylation alters expression of IGF2 in the imprinted fetal-growth region.
- name: Reduced Paternal IGF2 Expression
description: >-
The 11p15 ICR1 loss-of-methylation subtype reduces effective paternal IGF2
dosage, creating a molecular growth-signal deficit before overt prenatal
and postnatal growth restriction.
biological_processes:
- preferred_term: regulation of gene expression
term:
id: GO:0010468
label: regulation of gene expression
genes:
- preferred_term: IGF2
term:
id: hgnc:5466
label: IGF2
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified loss of methylation (LOM) of 11p15 Imprinting Center Region 1 (ICR1) domain (including IGF-II) as a mechanism leading to RSS."
explanation: Directly places IGF2 within the 11p15 ICR1 loss-of-methylation mechanism leading to RSS.
- reference: PMID:31466347
reference_title: "Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Supports altered IGF2 expression as the molecular intermediate that links 11p15 imprinting defects to growth disturbance.
downstream:
- target: Prenatal and Postnatal Growth Restriction
description: Reduced IGF2 growth signaling impairs fetal and childhood growth.
- name: Maternal Chromosome 7 Uniparental Disomy
description: >-
Maternal UPD7 creates a parent-of-origin imbalance on chromosome 7 and is
one of the two principal molecular causes of SRS.
biological_processes:
- preferred_term: genomic imprinting
term:
id: GO:0071514
label: genomic imprinting
evidence:
- reference: PMID:36662731
reference_title: Executive functioning in adolescents and adults with Silver-Russell syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat)."
explanation: Independently supports UPD(7)mat as a principal SRS molecular cause.
downstream:
- target: Prenatal and Postnatal Growth Restriction
description: Parent-of-origin imbalance is associated with reduced growth.
- name: Prenatal and Postnatal Growth Restriction
description: >-
Growth restriction is the central downstream clinical phenotype, beginning
before birth and continuing as postnatal growth failure and short stature.
biological_processes:
- preferred_term: regulation of cell growth
term:
id: GO:0001558
label: regulation of cell growth
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: The consensus abstract lists growth failure and related downstream complications as specific SRS management issues.
phenotypes:
- name: Small for gestational age
description: Birth weight or length below expected standards for gestational age is a core diagnostic criterion.
phenotype_term:
preferred_term: Small for gestational age
term:
id: HP:0001518
label: Small for gestational age
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Identifies SGA as the base criterion in a validated clinical scoring system for RSS.
- name: Postnatal growth retardation
description: Slow postnatal growth and persistent short stature are central features.
phenotype_term:
preferred_term: Postnatal growth retardation
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, dysmorphic features, and frequent body asymmetry, spares cranial growth."
explanation: Supports postnatal growth retardation as a defining SRS/RSS phenotype.
- name: Macrocephaly at birth
description: Head circumference is relatively preserved compared with reduced birth weight or length.
phenotype_term:
preferred_term: Relative macrocephaly at birth
term:
id: HP:0004482
label: Relative macrocephaly
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among RSS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM."
explanation: Supports relative macrocephaly as part of the 11p15 ICR1 LOM-associated phenotype.
- name: Prominent forehead
description: Prominent forehead is a core clinical scoring feature and part of the facial gestalt.
phenotype_term:
preferred_term: Prominent forehead
term:
id: HP:0011220
label: Prominent forehead
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among RSS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM."
explanation: Supports prominent forehead as a molecularly correlated SRS phenotype.
- name: Asymmetric growth
description: Body asymmetry is common and may include limb-length or hemibody asymmetry.
phenotype_term:
preferred_term: Body asymmetry
term:
id: HP:0100555
label: Asymmetric growth
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: The consensus abstract lists body asymmetry as a specific SRS management issue.
- name: Scoliosis
description: Scoliosis is a recognized musculoskeletal management issue in SRS.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: The consensus abstract explicitly lists scoliosis among specific SRS management issues.
- name: Feeding difficulties in infancy
description: Feeding difficulty contributes to low BMI, failure to thrive, and early management complexity.
phenotype_term:
preferred_term: Feeding difficulties in infancy
term:
id: HP:0008872
label: Feeding difficulties in infancy
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: The consensus abstract lists severe feeding difficulties among specific SRS issues.
- name: Hypoglycemia
description: Young children with SRS are vulnerable to hypoglycemia, particularly when intake is poor or fasting is prolonged.
phenotype_term:
preferred_term: Hypoglycemia
term:
id: HP:0001943
label: Hypoglycemia
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: The consensus abstract identifies hypoglycemia as a specific SRS management issue.
- name: Gastroesophageal reflux
description: Gastrointestinal problems, including reflux and dysmotility, are important in feeding management.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: The abstract supports gastrointestinal problems broadly; the reflux-specific framing is drawn from the Falcon report's consensus summary.
- name: Global developmental delay
description: Motor and speech delay may occur and require developmental supports.
phenotype_term:
preferred_term: Motor and speech delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges."
explanation: Supports motor and speech delay as part of the SRS clinical burden; the HPO term is broader than the quoted phrase.
- name: Attention deficit hyperactivity disorder
description: Executive dysfunction or ADHD risk can be clinically relevant in adolescents and adults.
phenotype_term:
preferred_term: Attention-deficit/hyperactivity disorder risk
term:
id: HP:0007018
label: Attention deficit hyperactivity disorder
evidence:
- reference: PMID:36662731
reference_title: Executive functioning in adolescents and adults with Silver-Russell syndrome.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder."
explanation: The study supports increased risk in some individuals but does not establish ADHD as universal, so support is partial.
genetic:
- name: IGF2
gene_term:
preferred_term: IGF2
term:
id: hgnc:5466
label: IGF2
presence: Positive
association: Rare causative gene and 11p15 imprinting target
features: >-
IGF2 is an imprinted fetal-growth gene at 11p15.5 affected by the common
ICR1 methylation mechanism, and rare monogenic IGF2 variants are recognized
SRS causes.
evidence:
- reference: PMID:31466347
reference_title: "Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Supports IGF2 involvement in 11p15-associated growth disturbance.
- reference: PMID:41430624
reference_title: Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS."
explanation: Supports IGF2 as a rare monogenic SRS cause.
- name: CDKN1C
gene_term:
preferred_term: CDKN1C
term:
id: hgnc:1786
label: CDKN1C
presence: Positive
association: Rare causative gene and 11p15 imprinting target
features: >-
CDKN1C is a growth-regulatory imprinted gene within the 11p15 imprinting
disorder region; rare CDKN1C variants can produce SRS phenotypes.
evidence:
- reference: PMID:41430624
reference_title: Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS."
explanation: Supports CDKN1C as a rare monogenic SRS cause.
- name: HMGA2
gene_term:
preferred_term: HMGA2
term:
id: hgnc:5009
label: HMGA2
presence: Positive
association: Rare causative gene
features: >-
HMGA2 variants are a rare non-imprinted monogenic cause of SRS-like growth
restriction, with variable fulfillment of clinical scoring criteria.
evidence:
- reference: PMID:41430624
reference_title: Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS."
explanation: Supports HMGA2 as a rare monogenic SRS cause.
- name: PLAG1
gene_term:
preferred_term: PLAG1
term:
id: hgnc:9045
label: PLAG1
presence: Positive
association: Rare causative gene
features: >-
PLAG1 variants are a rare non-imprinted monogenic cause of SRS-like
phenotypes and may be missed by strict clinical scoring in some patients.
evidence:
- reference: PMID:41430624
reference_title: Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS."
explanation: Supports PLAG1 as a rare monogenic SRS cause.
diagnosis:
- name: Netchine-Harbison clinical scoring system with molecular confirmation
description: >-
SRS is diagnosed clinically using SGA plus growth, craniofacial, asymmetry,
and feeding criteria, with molecular testing used to confirm and identify
subtypes. A negative molecular test does not exclude the clinical diagnosis.
evidence:
- reference: PMID:17504900
reference_title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Defines the core clinical scoring features used in the Netchine-Harbison framework.
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype."
explanation: Supports clinical diagnosis plus molecular confirmation/subtyping.
- name: 11p15 and chromosome 7 molecular testing
description: >-
First-line molecular evaluation typically targets 11p15 methylation defects
and maternal UPD7, with broader methylation, copy-number, and sequencing
approaches considered when clinical suspicion remains.
evidence:
- reference: PMID:36662731
reference_title: Executive functioning in adolescents and adults with Silver-Russell syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat)."
explanation: Supports first-line testing for the two principal molecular causes.
treatments:
- name: Multidisciplinary nutritional and supportive management
description: >-
Management requires coordinated endocrine, nutrition, gastroenterology,
genetics, developmental, orthopedic, and psychosocial care, with early focus
on nutritional status while avoiding excessive rapid catch-up weight gain.
treatment_term:
preferred_term: Nutritional Support
term:
id: NCIT:C15433
label: Nutritional Support
target_phenotypes:
- preferred_term: Feeding difficulties in infancy
term:
id: HP:0008872
label: Feeding difficulties in infancy
- preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The management of children with SRS requires an experienced, multidisciplinary approach."
explanation: Supports multidisciplinary care as a central management principle.
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Supports early nutritional management and caution against excessive catch-up weight gain.
- name: Human growth hormone therapy
description: >-
Recombinant human growth hormone therapy can improve height and other
outcomes such as body composition, motor development, appetite, and
hypoglycemia risk in SRS.
treatment_term:
preferred_term: human growth hormone replacement therapy
term:
id: MAXO:0000780
label: human growth hormone replacement therapy
target_phenotypes:
- preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
- preferred_term: Hypoglycemia
term:
id: HP:0001943
label: Hypoglycemia
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Directly supports growth hormone therapy and its targeted benefits.
- name: Puberty monitoring and GnRH analogue therapy
description: >-
Children with SRS should be monitored for premature adrenarche, early or
rapid central puberty, and insulin resistance; gonadotropin-releasing hormone
analogues may be used in selected patients to preserve adult height potential.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: Gonadotropin-releasing Hormone Analog
term:
id: NCIT:C1910
label: Gonadotropin-releasing Hormone Analog
target_phenotypes:
- preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:27585961
reference_title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential."
explanation: Supports GnRH analogue therapy for selected puberty-related height-preservation management.
- name: Genetic counseling
description: >-
Genetic counseling should address the specific molecular mechanism,
parent-of-origin effects, recurrence implications, and the possibility that
somatic epimutations may not behave like sequence variants in transmission.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: clinicaltrials:NCT02859688
reference_title: "Can Epimutations be Inherited? How to Manage Patients With Imprinting-related Diseases Who Wish to Become Parents"
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "We provide here for the first time evidence for efficient reversion of a constitutive epimutation in the spermatozoa of an SRS patient, which has important implication for genetic counseling."
explanation: Supports counseling relevance for reproductive transmission questions in imprinting-related SRS.
clinical_trials:
- name: NCT06878716
phase: NOT_APPLICABLE
status: UNKNOWN
description: >-
Observational questionnaire study estimating assisted reproductive
technology conception prevalence and fertility factors among parents of
children followed for SRS.
evidence:
- reference: clinicaltrials:NCT06878716
reference_title: Silver Russell Syndrome, Parental Fertility and Assisted Reproductive Technology
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our main objective is to estimate ART conceptions prevalence in children followed for a SRS."
explanation: Supports the trial's relevance to ART and fertility-factor epidemiology in SRS.
- name: NCT05214742
phase: NOT_APPLICABLE
status: ENROLLING_BY_INVITATION
description: >-
Study deriving induced pluripotent stem cells from blood to model imprinted
disorders and study consequences of epimutations on imprinted gene networks.
evidence:
- reference: clinicaltrials:NCT05214742
reference_title: Developing Derived Induced Pluripotent Stem Cells From Blood as a Model for the Study to Understand Imprinted Disorders
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Studying the consequences of these epimutations on the molecular signature of the imprinted gene network in these patients would provide a better understanding of the epigenetic mechanisms regulating fetal growth."
explanation: Supports this study as a disease-modeling trial relevant to SRS imprinting mechanisms.
- name: NCT01842659
phase: NOT_APPLICABLE
status: UNKNOWN
description: >-
Prenatal screening study evaluating whether quantitative methylation index
measures in amniotic fluid match blood methylation patterns for 11p15
imprinting abnormalities.
evidence:
- reference: clinicaltrials:NCT01842659
reference_title: Prenatal Screening for Imprinting Anomalies Implicated in Beckwith Wiedemann and Silver Russell Syndromes
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Losses of imprinting are involved in various syndromes. Those occurring in the 11p15 region lead to Beckwith-Wiedemann and Silver-Russell Syndromes."
explanation: Supports relevance of 11p15 imprinting anomaly screening to SRS.
- reference: clinicaltrials:NCT01842659
reference_title: Prenatal Screening for Imprinting Anomalies Implicated in Beckwith Wiedemann and Silver Russell Syndromes
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The recent development of a quantitative PCR method that permits the methylation index (MI) of imprinted regions to be calculated renders PND technically possible."
explanation: Supports the prenatal molecular-diagnostic framing.
- name: NCT02859688
phase: NOT_APPLICABLE
status: COMPLETED
description: >-
Study evaluating whether epimutations can be inherited or reverted during
germline epigenetic reprogramming, motivated by an SRS proband and
reproductive counseling questions.
evidence:
- reference: clinicaltrials:NCT02859688
reference_title: "Can Epimutations be Inherited? How to Manage Patients With Imprinting-related Diseases Who Wish to Become Parents"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Following the request for a parental project of a patient diagnosed with Silver-Russell syndrome (SRS), and the availability of both somatic and spermatozoa DNA from the proband and his father, we had the exceptional opportunity to evaluate the question of inheritance of an epimutation."
explanation: Supports this study as directly relevant to SRS reproductive counseling and epimutation inheritance.
references:
- reference: DOI:10.1038/nrendo.2016.138
title: "Diagnosis and management of Silver-Russell syndrome: first international consensus statement."
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.1210/jc.2007-0354
title: "11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations."
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.1210/jc.2017-02152
title: Chromosome 14q32.2 Imprinted Region Disruption as an Alternative Molecular Diagnosis of Silver-Russell Syndrome.
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.1371/journal.pone.0279745
title: Executive functioning in adolescents and adults with Silver-Russell syndrome.
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.3389/fgene.2024.1465521
title: Prenatal diagnosis of a silver-russell syndrome caused by 11p15 duplication and pedigree analysis.
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.3390/ijms20174219
title: "Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management."
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.1186/s13148-025-02023-7
title: Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.1159/000530521
title: The genetic landscape of children born small for gestational age with persistent short stature.
found_in:
- Silver_Russell_Syndrome-deep-research-falcon.md
findings: []
datasets:
Silver–Russell syndrome (SRS; also called Russell–Silver syndrome) is a rare congenital growth disorder and imprinting disorder characterized by prenatal and postnatal growth restriction, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties. It is primarily a clinical diagnosis, supported by molecular confirmation in ~60% of cases; the two most common molecular causes are 11p15.5 loss of methylation (LOM) at IC1 / H19–IGF2 and maternal uniparental disomy of chromosome 7 (upd(7)mat). International consensus guidance emphasizes early nutritional optimization and proactive prevention of hypoglycaemia, with recombinant human growth hormone (rhGH) providing benefits beyond linear growth (body composition, appetite, motor development), and monitoring/treating early/rapid puberty when appropriate. (wakeling2017diagnosisandmanagement pages 4-7, wakeling2017diagnosisandmanagement pages 17-20)
| Section | Item | Summary | Approx. frequency / threshold | Citations |
|---|---|---|---|---|
| Identifiers / classification | Silver-Russell syndrome (SRS; Russell-Silver syndrome) | Rare congenital imprinting disorder characterized by prenatal and postnatal growth restriction, relative macrocephaly, prominent forehead, asymmetry, and feeding difficulties; OMIM #180860 | Molecular cause identified in ~60% of clinically diagnosed cases | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement pages 4-7) |
| Synonyms | Alternative names | Silver-Russell syndrome; Russell-Silver syndrome; SRS; historically RSS | Not applicable | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement pages 4-7) |
| Molecular etiology | 11p15 LOM / IC1 hypomethylation (H19/IGF2:IG-DMR) | Major subtype; reduced paternal IGF2 expression is central to growth restriction | ~30–60% overall; 63.8% in one typical RSS cohort | (wakeling2017diagnosisandmanagement pages 4-7, geoffron2018chromosome14q32.2imprinted pages 2-3, wakeling2017diagnosisandmanagement pages 7-10) |
| Molecular etiology | Maternal uniparental disomy of chromosome 7, upd(7)mat / mUPD7 | Second major subtype | ~5–10% | (geoffron2018chromosome14q32.2imprinted pages 2-3, wakeling2017diagnosisandmanagement pages 4-7) |
| Molecular etiology | Other causes | CNVs involving 11p15 or chr7; rare defects at 14q32 and other imprinted loci; rare monogenic causes including IGF2, CDKN1C, HMGA2, PLAG1 | Remaining minority; monogenic causes are rare | (geoffron2018chromosome14q32.2imprinted pages 1-2, kurup2025silverrussellsyndromesecondary pages 1-2, hong2024prenataldiagnosisof pages 7-7) |
| NH-CSS | 1. Small for gestational age | Birth weight and/or birth length ≤ -2 SDS | Criterion present/absent | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement media 5493aae2) |
| NH-CSS | 2. Postnatal growth failure | Height at ~24 months ≤ -2 SDS or height ≤ -2 SDS below mid-parental target | Criterion present/absent | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement media 5493aae2) |
| NH-CSS | 3. Relative macrocephaly at birth | Head circumference at birth ≥ 1.5 SDS above birth weight and/or length SDS | Criterion present/absent | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement media 5493aae2) |
| NH-CSS | 4. Prominent forehead | Forehead projecting beyond facial plane on side view in early childhood | Criterion present/absent | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement media 5493aae2) |
| NH-CSS | 5. Body asymmetry | e.g., leg-length discrepancy ≥0.5 cm or asymmetry of other body parts | Criterion present/absent | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement media 5493aae2) |
| NH-CSS | 6. Feeding difficulties / low BMI | BMI ≤ -2 SDS at 24 months and/or current use of feeding support/appetite stimulants | Criterion present/absent | (jang2025silver–russellsyndromefrom pages 1-2, wakeling2017diagnosisandmanagement media 5493aae2) |
| NH-CSS performance | Clinical use | Molecular testing recommended when ≥3/6 criteria are met; clinical diagnosis usually ≥4/6, including relative macrocephaly and prominent forehead; sensitivity ~98%, NPV ~89%, specificity ~36% | Thresholds as shown | (wakeling2017diagnosisandmanagement pages 7-10, jang2025silver–russellsyndromefrom pages 1-2) |
| Management | Nutrition / feeding | Early goal is nutritional repletion while avoiding excessive rapid catch-up weight gain; assess reflux, dysmotility, and oral-motor dysfunction; multidisciplinary care recommended | >70% digestive problems; ~55% severe GERD reported in consensus summary | (wakeling2017diagnosisandmanagement pages 14-17, wakeling2017diagnosisandmanagement pages 4-7) |
| Management | Hypoglycemia prevention | Risk is increased in young children; monitor safe fasting interval, consider home ketone monitoring, avoid prolonged fasting; nighttime glucose polymer (infants) or uncooked cornstarch (older children) can be used | Hypoglycemia incidence ~27% in young children in consensus summary | (wakeling2017diagnosisandmanagement pages 17-20) |
| Management | Growth hormone (GH) therapy | GH improves height, body composition, appetite, motor development, and may reduce hypoglycemia risk; classic GH deficiency is uncommon | Predicted adult height gain ~7–11 cm; mean gain ~+1.2 to +1.4 SDS in studies summarized by consensus | (wakeling2017diagnosisandmanagement pages 4-7, wakeling2017diagnosisandmanagement pages 17-20) |
| Management | Puberty management | Monitor for premature adrenarche and relatively early/rapid central puberty; GnRH analogues may help preserve adult height potential in selected patients | Case-by-case endocrine management | (wakeling2017diagnosisandmanagement pages 4-7, jang2025silver–russellsyndromefrom pages 5-6) |
Table: This table condenses key disease identifiers, molecular causes, NH-CSS diagnostic criteria, and main management pillars for Silver-Russell syndrome. It is useful as a quick reference for building a structured disease knowledge-base entry with source-linked evidence.
SRS is a rare congenital disorder (imprinting disorder) with prenatal and postnatal growth retardation and multisystem involvement. The 2017 international consensus statement summarizes it as “an imprinting disorder that causes prenatal and postnatal growth retardation,” noting substantial overlap with care of children born small for gestational age (SGA), but with SRS-specific management issues (feeding, hypoglycaemia, asymmetry, neurodevelopment, psychosocial) (wakeling2017diagnosisandmanagement pages 4-7).
Authoritative expert opinion (international consensus): - “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.” (Wakeling et al., 2017) (wakeling2017diagnosisandmanagement pages 7-10).
This report integrates: - Aggregated expert consensus (international consensus statement) (wakeling2017diagnosisandmanagement pages 4-7). - Human cohort studies with molecular/clinical data (e.g., Netchine et al. 2007; Temple/14q32 overlap cohort) (geoffron2018chromosome14q32.2imprinted pages 2-3). - Recent human observational research (executive function study in adolescents/adults) (jang2025silver–russellsyndromefrom pages 2-4). - ClinicalTrials.gov registry records for real-world/implementation-oriented studies (NCT06878716 chunk 1, NCT05214742 chunk 1, NCT01842659 chunk 1).
SRS is best understood as a disorder of genomic imprinting affecting growth-regulatory networks. The international consensus estimates identifiable molecular causes in ~60% of clinically diagnosed patients, most commonly: - 11p15 LOM (IC1 / H19–IGF2 IG-DMR hypomethylation): ~30–60% (wakeling2017diagnosisandmanagement pages 4-7). - upd(7)mat: ~5–10% (wakeling2017diagnosisandmanagement pages 4-7).
A large early cohort study explicitly quantified major etiologies in a clinically-defined RSS subgroup within SGA patients: - “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.” (Netchine et al., 2007) (wesseler2019molecularandclinical pages 11-13).
Other (rare) etiologies include CNVs affecting imprinting regions, and rare SNVs in growth/imprinting genes (e.g., IGF2, CDKN1C, HMGA2, PLAG1), with phenotypic heterogeneity that can reduce sensitivity of purely clinical criteria for these subgroups (kurup2025silverrussellsyndromesecondary pages 1-2).
Genetic risk factors: SRS is typically sporadic, but recurrence risk may increase in specific scenarios (e.g., heritable CNVs affecting imprinting control regions, or maternal-effect variants affecting imprint maintenance). Evidence for maternal-effect mechanisms and multilocus imprinting disturbance is discussed in WGS-based diagnostic studies and imprinting-disorder mechanistic workups (NCT05945576 chunk 2).
Non-genetic/environmental risk factors: Direct environmental causes are not established for SRS as a Mendelian/imprinting disorder in the retrieved evidence. However, imprinting disorders (including SRS) are under investigation for potential association with assisted reproductive technologies (ART), with ongoing observational studies designed to quantify ART conception prevalence in SRS (NCT06878716 chunk 1).
No genetic or environmental protective factors were identified in the retrieved evidence.
In the retrieved evidence, gene–environment interaction is best framed as epigenetic vulnerability during imprint establishment/maintenance; this is being assessed via real-world observational studies of ART/infertility factors in SRS families (NCT06878716 chunk 1).
SRS typically presents prenatally and in early childhood with growth restriction and failure to thrive. Key differentiating clinical features from other SGA/IUGR include relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (wakeling2017diagnosisandmanagement pages 4-7).
Feeding/GI: The international consensus notes substantial GI burden, stating “>70% have digestive problems” and “55% severe GERD” in the cited summary evidence (wakeling2017diagnosisandmanagement pages 14-17).
Hypoglycaemia: The consensus statement indicates increased risk in early childhood with an estimated incidence “≈27%” and highlights that episodes are often asymptomatic and nocturnal, motivating home monitoring and structured fasting guidance (wakeling2017diagnosisandmanagement pages 17-20).
Neurocognitive/behavioral: Neurocognitive problems are noted to be more frequent in upd(7)mat than in 11p15 LOM in the consensus overview (wakeling2017diagnosisandmanagement pages 14-17). A 2023 study of adolescents/adults reported largely normal group-level executive function but clinically relevant impairment in some individuals, concluding that SRS individuals “could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder” (Burgevin et al., 2023) (jang2025silver–russellsyndromefrom pages 2-4).
The NH‑CSS uses six criteria; a tightly-cropped table listing criteria was retrieved (wakeling2017diagnosisandmanagement media 5493aae2). Criteria and suggested HPO mappings: 1) SGA (birth weight/length ≤ −2 SDS) → Small for gestational age (HP:0001518) (wakeling2017diagnosisandmanagement media 5493aae2) 2) Postnatal growth failure → Postnatal growth retardation (HP:0008897) / Short stature (HP:0004322) (wakeling2017diagnosisandmanagement media 5493aae2) 3) Relative macrocephaly at birth → Relative macrocephaly (HP:0004488) (wakeling2017diagnosisandmanagement media 5493aae2) 4) Prominent forehead → Prominent forehead (HP:0011220) (wakeling2017diagnosisandmanagement media 5493aae2) 5) Body asymmetry → Body asymmetry (HP:0000930) / Hemihypotrophy (HP:0001528) (wakeling2017diagnosisandmanagement media 5493aae2) 6) Feeding difficulties / low BMI → Feeding difficulties (HP:0011968) / Failure to thrive (HP:0001508) / Low body mass index (HP:0001511) (wakeling2017diagnosisandmanagement media 5493aae2)
NH‑CSS performance/thresholds: In prospective evaluation, NH‑CSS sensitivity was ~98% and NPV ~89%, but specificity was low (~36%); the consensus recommends molecular testing if ≥3 criteria and clinical SRS diagnosis at ≥4 criteria including relative macrocephaly and protruding/prominent forehead (wakeling2017diagnosisandmanagement pages 7-10).
The consensus statement explicitly highlights “psychosocial challenges” and the need for multidisciplinary care, including psychology/speech/occupational and family support, implying significant functional and QoL impact (wakeling2017diagnosisandmanagement pages 4-7).
11p15.5 imprinting region (IC1/H19–IGF2 and related DMRs): Loss of methylation at IC1 is a major cause of “typical Russell-Silver syndrome” (wesseler2019molecularandclinical pages 11-13). Mechanistically, hypomethylation at the paternally methylated H19/IGF2 imprinting control region reduces paternal IGF2 expression, a key driver of fetal growth restriction (wakeling2017diagnosisandmanagement pages 7-10).
Chromosome 7 (upd(7)mat): Common secondary cause (~5–10%) (wakeling2017diagnosisandmanagement pages 4-7).
Other imprinted regions (notably 14q32.2): Disruption of 14q32.2 can present with SRS-like phenotypes; in a 14q32.2 disruption cohort, 72.7% met NH‑CSS ≥4/6, illustrating clinically important overlap and the need for differential molecular diagnosis beyond 11p15/upd7 (geoffron2018chromosome14q32.2imprinted pages 1-2).
Rare monogenic causes (examples): A 2025 synthesis of rare (epi)genotypes reports that variants in IGF2, CDKN1C, HMGA2, PLAG1 can cause SRS-like phenotypes, but NH‑CSS misses a substantial fraction (9–55%) depending on gene, supporting broader genetic testing approaches when suspicion persists despite borderline clinical scoring (kurup2025silverrussellsyndromesecondary pages 1-2).
Across SRS and SRS-like presentations, pathogenic mechanisms include: - Epimutations (DNA methylation abnormalities; often mosaic) - UPD - CNVs (duplications/deletions involving imprinting regions) - SNVs in growth/imprinting genes (wakeling2017diagnosisandmanagement pages 7-10, kurup2025silverrussellsyndromesecondary pages 1-2)
Recent (2024) pedigree evidence for CNV/epigenotype complexity: A 2024 familial case described 11p15 duplications with variable methylation patterns and phenotypic outcomes; “duplications of maternal IC2 (copy number of 3) with enhanced methylation (methylation index 0.62) resulted in typical SRS,” demonstrating clinically relevant inheritance and prenatal testing complexity (hong2024prenataldiagnosisof pages 1-2).
SRS is classically an imprinting disorder with methylation alterations at imprinted DMRs (11p15, sometimes multi-locus). Mosaicism and tissue-specific methylation can cause false negatives in blood, motivating multi-tissue strategies and quantitative assays (wakeling2017diagnosisandmanagement pages 7-10).
No established infectious, toxin, or lifestyle causal factors were identified in the retrieved evidence. Environmental context is primarily studied via ART and infertility as potential correlates of imprinting disorders, including SRS, with an observational pilot study designed to estimate ART conception prevalence in SRS and collect parental exposure/occupation and fertility data (NCT06878716 chunk 1).
1) Upstream trigger: imprinting disturbance (e.g., 11p15 IC1 hypomethylation) or upd(7)mat (wakeling2017diagnosisandmanagement pages 4-7). 2) Molecular consequence: altered parent-of-origin gene expression, especially growth regulators (e.g., reduced paternal IGF2 expression) (wakeling2017diagnosisandmanagement pages 7-10). 3) Cellular/tissue effects: impaired fetal growth and postnatal growth, low muscle mass, feeding difficulties, increased fasting vulnerability (hypoglycaemia) (wakeling2017diagnosisandmanagement pages 17-20). 4) Clinical manifestations: SGA, postnatal growth failure, relative macrocephaly, prominent forehead, asymmetry, GI problems/GERD, hypoglycaemia, variable neurocognitive outcomes, and early/rapid puberty risk (wakeling2017diagnosisandmanagement pages 4-7, wakeling2017diagnosisandmanagement pages 17-20).
Key pathway concept: IGF2 growth axis and imprinting network dysregulation (wakeling2017diagnosisandmanagement pages 7-10).
Suggested GO Biological Process terms (examples): - GO:0001558 regulation of cell growth - GO:0040007 growth - GO:0008283 cell population proliferation - GO:0010817 regulation of hormone levels
Suggested Cell Ontology (CL) terms (broad, given limited direct evidence in retrieved sources): - CL:0000187 cell of the endocrine pancreas (re hypoglycaemia context) - CL:0000540 skeletal muscle cell (low muscle mass, growth)
Suggested Reactome/KEGG framing: IGF signaling; growth hormone/IGF axis (supported conceptually in consensus management and IGF2 mechanism discussion) (wakeling2017diagnosisandmanagement pages 7-10, wakeling2017diagnosisandmanagement pages 17-20).
No transcriptomics/proteomics/metabolomics signatures specific to SRS were present in the retrieved full-text evidence for 2023–2024; model-building iPSC studies are registered to examine “consequences of epimutations at 11p15 or 14q32 on the imprinted gene network” (NCT05214742 chunk 1).
SRS is a multisystem condition with prominent effects on: - Whole-body growth and musculoskeletal development (short stature, asymmetry; scoliosis risk) (wakeling2017diagnosisandmanagement pages 4-7) - Gastrointestinal system (feeding difficulties, reflux, dysmotility) (wakeling2017diagnosisandmanagement pages 14-17) - Endocrine/metabolic regulation (hypoglycaemia risk, puberty timing, insulin resistance risk) (wakeling2017diagnosisandmanagement pages 17-20) - Neurodevelopment/psychosocial domains (speech/motor delay, psychosocial challenges; variable executive function risk) (wakeling2017diagnosisandmanagement pages 4-7, jang2025silver–russellsyndromefrom pages 2-4)
The international consensus reports incidence estimates ranging from ~1:30,000 to 1:100,000, with one molecularly confirmed estimate in Estonia of ~1:70,000 (wakeling2017diagnosisandmanagement pages 4-7).
SRS is “generally sporadic,” and a strong family history should trigger evaluation for alternative diagnoses or rare inherited molecular mechanisms (e.g., familial CNVs with parent-of-origin effects) (wakeling2017diagnosisandmanagement pages 14-17).
No sex ratio or ethnicity/geographic variant distribution data were present in the retrieved evidence.
NH‑CSS is the recommended clinical scoring system with 6 criteria (wakeling2017diagnosisandmanagement media 5493aae2). The consensus specifies: - Molecular testing recommended when ≥3/6 criteria are present. - Clinical SRS diagnosis typically reserved for ≥4/6, including relative macrocephaly and prominent forehead (wakeling2017diagnosisandmanagement pages 7-10).
The consensus emphasizes first-line molecular evaluation for: - 11p15.5 methylation abnormalities (H19/IGF2 IG-DMR) - upd(7)mat - Consideration of CNVs and broader genomic causes when initial testing is negative and clinical suspicion remains (wakeling2017diagnosisandmanagement pages 7-10, wakeling2017diagnosisandmanagement pages 14-17).
Assay considerations: MS-MLPA is widely used; low-level mosaicism and tissue specificity can yield false-negative blood testing, motivating careful assay choice and potentially multi-tissue sampling (blood vs buccal/skin) in some cases (wakeling2017diagnosisandmanagement pages 7-10).
A real-world WGS study (100,000 Genomes Project category “SRS”) reported that WGS can identify SNVs, CNVs, UPD, and maternal-effect variants and may be a “valuable addition” to diagnosis of SRS and related growth restriction disorders (Alhendi et al., 2022) (NCT05945576 chunk 2).
A 2024 report demonstrates prenatal testing using microarray plus MS-MLPA methylation assessment in a familial 11p15 duplication context, highlighting the feasibility and complexity of prenatal diagnosis for imprinting disturbances (hong2024prenataldiagnosisof pages 1-2). Complementarily, a registered prenatal screening study evaluates agreement of methylation index measurements across fetal/cord blood/placental tissues (NCT01842659 chunk 1).
Consensus guidance notes that consanguinity/family history should prompt alternatives, and highlights overlap with osteogenesis imperfecta, recommending skeletal survey and possible COL1A1/2 testing in suggestive cases (wakeling2017diagnosisandmanagement pages 14-17).
The retrieved evidence emphasizes improved outcomes with early multidisciplinary management and growth-hormone therapy but does not provide disease-specific mortality rates. Untreated adult height was summarized in a retrieved review excerpt as approximately −3.1 SDS (jang2025silver–russellsyndromefrom pages 1-2).
The 2017 consensus recommends experienced multidisciplinary care (endocrinology-led coordination plus dietetics, gastroenterology, genetics, orthopaedics, speech/psychology) and prioritizes early nutritional optimization and hypoglycaemia prevention (wakeling2017diagnosisandmanagement pages 14-17).
Direct expert statement (consensus): - “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.” (wakeling2017diagnosisandmanagement pages 4-7)
Suggested MAXO terms: - MAXO:0000064 nutritional support - MAXO:0000147 gastrostomy
Consensus recommendations include: - Home urinary ketone monitoring to define safe fasting times. - Night-time supplementation with high–molecular-weight glucose polymer (infants <10 months) or uncooked cornstarch (older infants/children) to prevent nocturnal hypoglycaemia. - Avoid glucagon; provide rapid-access plans for IV dextrose during illness/perioperative fasting (wakeling2017diagnosisandmanagement pages 17-20).
Suggested MAXO terms: - MAXO:0000100 blood glucose monitoring - MAXO:0000789 dietary carbohydrate supplementation
SRS is an indication under the SGA rhGH license, and the consensus summarizes adult-height benefits: - Predicted adult height increases of ~7–11 cm and mean gains of ~+1.2 to +1.4 SDS in summarized studies (doses 35–70 μg/kg/day). Response correlates with earlier start and baseline height SDS (wakeling2017diagnosisandmanagement pages 17-20).
Suggested MAXO term: - MAXO:0000747 growth hormone therapy
Clinicians should monitor for premature adrenarche and early/rapid central puberty; GnRH analogues may be used to preserve adult height in selected cases (wakeling2017diagnosisandmanagement pages 4-7).
Suggested MAXO term: - MAXO:0000912 gonadotropin-releasing hormone analogue therapy
No established primary prevention exists for imprinting disorders like SRS.
Consensus recommendations function as secondary/tertiary prevention by preventing complications: - Early nutritional management to avoid malnutrition and reduce hypoglycaemia risk. - Monitoring and proactive management of hypoglycaemia, puberty timing, and metabolic risk (wakeling2017diagnosisandmanagement pages 14-17, wakeling2017diagnosisandmanagement pages 17-20).
A dedicated observational study (REPAR) provides counseling-relevant evidence that somatic epimutations may revert in germline, affecting recurrence risk assessment (NCT02859688 chunk 1). Familial CNV/epigenotype cases (11p15 duplication with parent-of-origin methylation effects) underscore the importance of parental testing and imprinting-aware interpretation (hong2024prenataldiagnosisof pages 1-2).
No naturally occurring veterinary analogs were identified in the retrieved evidence.
A mouse model relevant to rare SRS-associated microduplication mechanisms has been reported (CDKN1C dosage model), supporting mechanistic investigation of feeding/behavioral phenotypes; the abstract notes that “rare SRS patients carry maternally inherited microduplications spanning… CDKN1C…” and describes behavioral alterations attributable to elevated Cdkn1c (jang2025silver–russellsyndromefrom pages 6-7). Additionally, a registered clinical study aims to create iPSC-derived models to study imprinting networks in SRS and related imprinting disorders (NCT05214742 chunk 1).
1) Neuropsychology in adolescents/adults (2023): Executive function testing suggests no uniform executive dysfunction phenotype at group level, but clinically significant impairments in subsets and potential increased ADHD/executive dysfunction risk (jang2025silver–russellsyndromefrom pages 2-4). 2) Prenatal and familial molecular diagnosis (2024): Multi-generation 11p15 duplication with methylation-dependent expressivity illustrates complexity in inheritance and supports combined microarray + methylation testing in prenatal/familial workups (hong2024prenataldiagnosisof pages 1-2). 3) Genetic landscape in persistent short stature after SGA (2023): In a cohort of children born SGA with persistent short stature, SRS constituted a substantial fraction of genetically explained cases, using Netchine–Harbison criteria to define SRS clinically (toni2024thegeneticlandscape pages 9-10).
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