Russell-Silver Syndrome (RSS) is a rare, congenital growth disorder that severely affects a child’s size and development both before and after birth. It is classified as an imprinting disorder, involving issues with how certain genes are expressed rather than a change in the DNA sequence itself. RSS occurs in approximately one out of every 50,000 to 100,000 live births. While the condition is clinically heterogeneous, meaning its signs can vary widely, a common set of features guides diagnosis.
Defining Physical Characteristics
The most noticeable sign of RSS is severe growth restriction that begins while the fetus is still in the womb, known as intrauterine growth restriction (IUGR). Infants are typically born small for their gestational age, and this short stature continues after birth with a persistent lack of “catch-up” growth. The average adult height for an untreated person with RSS is significantly below the population mean, often around four feet seven inches for females and four feet eleven inches for males.
Children with RSS often exhibit a distinct set of facial features. These include a triangular face that tapers to a small, pointed chin (micrognathia) and a prominent forehead (frontal bossing), which makes the head appear relatively large compared to the small body. These craniofacial features may become less pronounced as the child grows older.
A hallmark of the syndrome is body asymmetry, or hemidisharmony, where one side of the body grows more slowly than the other, potentially leading to limb length discrepancies. Infants frequently experience significant feeding difficulties, poor appetite, and low muscle tone (hypotonia). These issues, combined with a lack of subcutaneous fat, can result in recurrent low blood sugar (hypoglycemia).
Genetic and Epigenetic Origins
The underlying cause of Russell-Silver Syndrome is a disruption in the regulation of growth-related genes, often involving an epigenetic mechanism rather than a traditional genetic mutation. Epigenetics refers to changes in gene expression that do not involve altering the underlying DNA sequence. In RSS, this typically involves a problem with genomic imprinting, where a gene is expressed differently depending on which parent it was inherited from.
The most common molecular cause (35% to 67% of cases) is hypomethylation of the imprinting control region 1 (ICR1) on chromosome 11p15. This loss of methylation leads to the under-expression of Insulin-like Growth Factor 2 (IGF2), a powerful fetal growth promoter. Another major cause (7% to 10% of cases) is maternal uniparental disomy (UPD) of chromosome 7, meaning the individual inherited both copies of chromosome 7 from their mother and none from their father.
For approximately 40% of individuals, a molecular cause remains unidentified after current testing, leading to a diagnosis based solely on clinical features. This suggests that other genetic or epigenetic factors may also contribute to the syndrome.
Diagnosis and Clinical Confirmation
Diagnosis of Russell-Silver Syndrome is primarily clinical, relying on a healthcare provider’s evaluation of characteristic physical features and growth patterns. Clinicians use the Netchine-Harbison Clinical Scoring System (NH-CSS) to standardize the process and differentiate RSS from other growth disorders. This system assigns points for six specific features:
- Prenatal and postnatal growth delay
- Relative macrocephaly
- Prominent forehead
- Body asymmetry
- Feeding difficulties
A diagnosis of RSS is strongly supported if an individual meets at least four of the six NH-CSS criteria. Following a clinical suspicion, molecular genetic testing is performed to confirm the diagnosis and identify the underlying epigenetic cause. The most common technique for this is methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), which detects hypomethylation on chromosome 11p15.5 and maternal UPD of chromosome 7.
Molecular testing confirms the diagnosis in about 60% of individuals with classic symptoms. However, a negative genetic test result does not rule out RSS, as a significant portion of cases are idiopathic.
Comprehensive Management and Support
Management of Russell-Silver Syndrome requires a coordinated, multidisciplinary approach involving pediatric specialists, including endocrinologists, gastroenterologists, and physical therapists. Early intervention focuses on addressing severe feeding difficulties and low caloric intake common in infancy. Nutritional support, such as high-calorie supplements or, in severe cases, the placement of a gastrostomy feeding tube, is often necessary to ensure adequate weight gain and prevent hypoglycemia.
Growth hormone (GH) therapy is a standard treatment used to improve height and overall body composition. International guidelines recommend starting recombinant human growth hormone treatment as early as two years of age for children with RSS who have not shown adequate catch-up growth. The therapy improves appetite, muscle mass, motor development, and increases the patient’s final adult height.
Individuals with RSS may also experience delays in motor and speech development. These are addressed through early intervention programs, including physical, occupational, and speech therapy. Orthopedic consultation is necessary to monitor body asymmetry, which can lead to scoliosis or significant leg length discrepancies requiring specialized shoe inserts or other interventions. Ongoing monitoring throughout childhood addresses potential complications like early puberty or metabolic issues.