What Is It, Causes, Diagnosis, and More
Author: Lily Guo
Editor: Alyssa Haag
Editor: Ian Mannarino, MD, MBA
Editor: Kelsey LaFayette, DNP
Illustrator: Jessica Reynolds, MS
Copyeditor: David G. Walker
Modified: Mar 04, 2025
What is Russell Silver syndrome?
Russell Silver syndrome (RSS) is a rare genetic condition characterized by several key features, including low birth weight, short stature, and discrepancies in limb length. The underlying genetic defects of Russell Silver syndrome affect the body's ability to produce or utilize growth hormone effectively, thereby having a significant effect on growth and development. Common signs include delays in overall development as well as distinct facial features, such as a triangular face, a prominent forehead, and a small mouth and chin. Individuals with Russell Silver syndrome may also experience feeding difficulties and have musculoskeletal defects and genitourinary anomalies. The exact prevalence of the syndrome is currently unknown, but it is estimated to affect approximately 1 in 30,000 to 1 in 100,000 individuals.
What causes Russell Silver syndrome?
Russell Silver syndrome is primarily caused by genetic mutations. Approximately 35% to 50% of individuals with the syndrome have a specific defect in the methylation process, which regulates gene activation and inactivation. This defect typically occurs in the H19/IGF2 gene on chromosome 11p15.5. The H19 gene serves as a tumor suppressor and controls body growth and development. Hypomethylation of the H19 gene can lead to reduced expression, resulting in improper growth and development, a defining characteristic of Russell Silver syndrome. The IGF2 gene is vital for fetal growth. Normally, its expression is higher on the paternal chromosome. Changes in DNA methylation within the H19/IGF2 region can disrupt the regulation of these genes, leading to decreased growth, development, and other clinical features of Russell Silver syndrome. It's important to note that not all patients with the syndrome have this specific genetic alteration, indicating the involvement of other genetic and epigenetic factors in its development.
In 7% to 10% of cases, Russell Silver syndrome is caused by maternal uniparental disomy (mUPD7), which occurs when an individual inherits both copies of chromosome 7 from their mother, lacking any contribution from their father. As a result, important genes related to growth and development located on the father's chromosome are lost. Additionally, a small number of individuals with Russell Silver syndrome have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or chromosome 7. Lastly, in rare cases, specific variants in genes like
CDKN1C,
IGF2,
PLAG1, and
HMGA2 have been associated with the development of Russell Silver syndrome.
What are the signs and symptoms of Russell Silver syndrome?
The signs and symptoms of Russell Silver syndrome include a prominent forehead, a triangular shaped face, micrognathia (i.e., a small jaw), dental crowding, and down-turned corners of the mouth. Babies with this condition are typically born smaller than average for their gestational age, often with a larger head circumference compared to their body weight and length. After birth, affected individuals generally experience growth failure, which can lead to a progressive discrepancy in limb length and body asymmetry. Feeding difficulties (e.g., poor appetite, fussiness, slow feeding) are also common. Other clinical features of Russell Silver syndrome include a high-pitched voice, diminished muscle mass, shoulder dimples, hypoplastic elbow joints, and clinodactyly of the fifth finger (i.e., curved fifth fingers). Additional symptoms may include scoliosis, excessive sweating, fasting hypoglycemia, speech delay, motor delay, and genitourinary anomalies. The closure of the anterior fontanelle (i.e. the soft spot on a baby's head) may also be delayed.
How is Russell Silver syndrome diagnosed?
Russell Silver syndrome is diagnosed during childhood based on physical and developmental characteristics. A special scoring system called the Netchine-Harbison Clinical Scoring System (NH-CSS) has been created to help clinicians identify the condition accurately and sensitively. To receive a clinical diagnosis, an individual must have other disorders ruled out and meet at least four of the NH-CSS criteria, two of which must be relative macrocephaly at birth and frontal bossing. The criteria for diagnosis include the following six criteria:
Small for gestational age (SGA) (birth weight and/or length ≥ 2 standard deviations below the mean for gestational age)
Postnatal growth failure (length/height ≥ standard deviation below the mean at 24 months)
Relative macrocephaly at birth (head circumference > 1.5 standard deviations above birth weight and/or length)
Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view as a toddler)
Body asymmetry (limb length discrepancy ≥ 0.5 cm, or < 0.5 cm with ≥ 2 other asymmetric body parts)
Feeding difficulties or body mass index ≤ 2 standard deviations at 24 months or current use of a feeding tube or cyproheptadine for appetite stimulation
If an individual meets four of these six criteria, a clinical diagnosis of Russell Silver syndrome is suspected and further testing is necessary for confirmation. In some rare cases, individuals who meet three of the criteria have also tested positive for Russell Silver syndrome. The diagnosis is confirmed when an individual meets four of the six Netchine-Harbison clinical criteria and has genetic testing results consistent with hypomethylation on chromosome 11p15.5 or maternal uniparental disomy (UPD) for chromosome 7. Of note, approximately 40% of individuals who meet the NH-CSS clinical criteria may have negative molecular and/or cytogenetic testing.
How is Russell Silver syndrome treated?
Treatment of Russell Silver syndrome involves addressing the symptoms and providing early childhood intervention to meet their specific needs. One common approach is growth hormone treatment, which helps promote growth and development in affected children. However, nutritional interventions are also important to manage feeding difficulties and ensure proper nutrition, which may include supplements and medication for gastroesophageal reflux. Physical therapy may be beneficial for addressing musculoskeletal issues, such as limb asymmetry. Various therapies, including physical, occupational, speech, and language therapy, are used to address developmental delays. Psychological counseling can provide support for psychosocial and body image concerns. Multidisciplinary care involving specialists (e.g. pediatricians, geneticists, gastroenterologists, and endocrinologists) is essential for managing specific medical issues, such as craniofacial abnormalities or genitourinary anomalies.
Regular medical check-ups and early intervention help improve health outcomes and overall quality of life. Although life expectancy can vary depending on factors such as the severity of the condition and associated medical problems, most individuals with Russell Silver syndrome have a life expectancy similar to the general population. With proper management and support, individuals with Russell Silver syndrome can lead healthy and fulfilling lives.
What are the most important facts to know about Russell Silver syndrome?
Russell Silver syndrome is a rare genetic disorder characterized by significant impacts on growth and development. It presents with low birth weight, short stature, and limb length discrepancies. Genetic defects affecting growth hormone production or utilization contribute to the syndrome. Common signs include developmental delays, distinct facial features, feeding difficulties, and musculoskeletal and genitourinary anomalies. Diagnosis is made using the Netchine-Harbison Clinical Scoring System (NH-CSS) criteria and genetic testing. Treatment involves managing symptoms through growth hormone treatment, nutritional interventions, physical therapy, and multidisciplinary care.
