Russell-Silver Syndrome (RSS) is a rare congenital growth disorder characterized by severe growth restriction beginning before birth. It is classified as an imprinting disorder, involving abnormalities in how certain genes are expressed rather than a change in the DNA sequence. RSS is characterized by a wide spectrum of physical and medical challenges, making it genetically complex and clinically variable. Optimal care requires a coordinated approach involving specialists. Early identification and comprehensive intervention are valuable for managing the condition and improving long-term outcomes.
Key Physical Characteristics
RSS is defined by a consistent pattern of physical findings, starting with significant growth failure both prenatally and postnatally. Infants are typically born small for gestational age and remain well below the average growth range throughout childhood. A distinctive physical trait is relative macrocephaly at birth, where the head circumference appears disproportionately large compared to the child’s small body size. Body asymmetry, also known as hemihypertrophy, is a common feature where one side of the body or a limb grows noticeably slower or smaller than the other. Affected children often exhibit unique facial characteristics, including a triangular-shaped face, a prominent forehead (frontal bossing), and a small, narrow chin and jaw (micrognathia). Feeding difficulties are frequent in infancy, contributing to a failure to thrive due to poor appetite, low muscle tone, and chronic acid reflux.
Genetic and Epigenetic Causes
The underlying cause of RSS is rooted in the complex mechanisms of genomic imprinting, an epigenetic process that controls gene expression based on which parent the gene was inherited from. In RSS, this process is set incorrectly for growth-regulating genes, leading to reduced expression of growth factors.
The most frequently identified cause, accounting for about 35% to 67% of cases, is hypomethylation of the Imprinting Control Region 1 (ICR1) on chromosome 11p15.5. This epigenetic alteration affects the regulation of the IGF2 (Insulin-like Growth Factor 2) gene, a potent promoter of growth. The reduced methylation causes the IGF2 gene to be under-expressed, directly inhibiting normal growth.
The second common molecular finding, present in 7% to 10% of individuals, is maternal uniparental disomy of chromosome 7, or UPD(7)mat. This occurs when an individual inherits both copies of chromosome 7 from the mother and none from the father. Since certain genes on chromosome 7 are meant to be expressed only from the paternal copy, having two maternal copies disrupts the balance of gene expression and results in the growth-restricted phenotype. The cause remains unknown in approximately 30% to 40% of clinically diagnosed cases.
Diagnosis and Clinical Criteria
Diagnosis of Russell-Silver Syndrome begins with a detailed clinical assessment of the child’s physical features and growth history. Clinicians frequently use the Netchine-Harbison Clinical Scoring System (NHCSS) to standardize this process. This tool assigns a score based on the presence of six specific clinical criteria, helping to determine the likelihood of an RSS diagnosis.
NHCSS Criteria
The six criteria assessed by the NHCSS include:
- Small for gestational age status
- Postnatal growth failure
- Relative macrocephaly at birth
- A protruding forehead
- Body asymmetry
- Feeding difficulties or low Body Mass Index (BMI)
Meeting at least four of these six criteria strongly suggests an RSS diagnosis and guides the next step: specialized genetic and epigenetic testing. Molecular testing involves DNA methylation analysis to detect hypomethylation at the 11p15 region, and chromosomal analysis to identify maternal uniparental disomy of chromosome 7. Identifying the specific molecular cause can aid in predicting clinical severity and tailoring management strategies. However, a negative molecular test does not rule out the diagnosis if the clinical presentation strongly aligns with the NHCSS criteria.
Long-Term Management Strategies
Management of RSS requires a multidisciplinary team approach to address the varied challenges that arise throughout an individual’s life. A primary focus is on nutritional support, particularly in infancy and early childhood, to combat failure to thrive and prevent recurrent hypoglycemia (low blood sugar). High-calorie diets and specialized feeding techniques are common, and in severe cases, a gastrostomy tube (G-tube) may be utilized to ensure adequate caloric intake.
Growth Hormone (GH) therapy is a standard medical intervention for improving growth and final adult height, typically starting around two to four years of age. GH treatment is also valuable for improving body composition, increasing muscle mass, and reducing the risk of hypoglycemia. Clinicians must closely monitor for signs of premature adrenarche or early puberty, as rapid bone age advancement can compromise the potential for catch-up growth.
Orthopedic issues stemming from body asymmetry, such as scoliosis and limb length discrepancy, require regular monitoring and intervention. Physical, occupational, and speech therapy are often initiated early to support motor skill development, low muscle tone, and any resulting speech delays. Comprehensive management aims to mitigate complications, maximize the child’s growth and functional capabilities, and ensure the best possible quality of life.