Silver–Russell syndrome

Overview

Silver–Russell syndrome (SRS), also known as Russell–Silver syndrome, is a rare congenital growth disorder characterized by poor growth before and after birth (intrauterine and postnatal growth retardation), distinctive facial features, limb or body asymmetry, and feeding difficulties. First described independently by Drs. Silver and Russell in the 1950s, the condition varies in severity but commonly presents with short stature and characteristic physical features. Despite growth challenges, cognitive development is typically normal in most cases. SRS is estimated to affect approximately 1 in 30,000 to 100,000 live births and is equally prevalent in both males and females.

Causes

Silver–Russell syndrome is a genetic disorder, but it can result from different types of genetic and epigenetic changes, particularly involving genes that regulate growth. The two most common genetic causes include:

• Loss of methylation at chromosome 11p15 (ICR1 region): Found in about 30–60% of individuals with SRS. This region contains genes (including IGF2 and H19) important for normal growth and development. Hypomethylation here reduces IGF2 activity, a critical growth factor.

• Maternal uniparental disomy of chromosome 7 (mUPD7): Present in about 5–10% of cases. This occurs when a child inherits both copies of chromosome 7 from the mother instead of one from each parent, disrupting gene expression on this chromosome.

Other less common causes include mutations in CDKN1C or other imprinting defects. In many cases, no identifiable genetic abnormality is found.

Symptoms

The symptoms of Silver–Russell syndrome are highly variable, but characteristic features include:

Growth-Related Features:

• Intrauterine growth restriction (low birth weight despite full-term birth)

• Postnatal growth failure (short stature)

• Failure to thrive in infancy

Craniofacial and Physical Characteristics:

• Triangular-shaped face with a broad forehead and narrow chin

• Prominent eyes and downturned mouth corners

• Feeding difficulties, poor appetite, and gastrointestinal reflux

• Clinodactyly (curved fifth finger)

• Body or limb asymmetry (hemihypertrophy)

• Low muscle tone and delayed motor milestones

Other Possible Features:

• Hypoglycemia (low blood sugar), especially in infancy

• Scoliosis or other skeletal abnormalities

• Dental crowding and delayed dental eruption

• Subtle learning difficulties or speech delay in some cases

While intellectual development is usually normal, some individuals may have mild developmental or behavioral issues, particularly if hypoglycemia is not well controlled early in life.

Diagnosis

Diagnosis of Silver–Russell syndrome is based on clinical evaluation supported by genetic and epigenetic testing. The following criteria and steps are used:

Clinical Diagnosis:

• Use of scoring systems such as the Netchine–Harbison Clinical Scoring System (NH-CSS), which assesses key features including growth restriction, facial characteristics, and asymmetry

• Physical examination documenting typical features

• Growth measurements compared to population norms

Genetic Testing:

• DNA methylation studies for 11p15 region (hypomethylation of ICR1)

• Testing for maternal uniparental disomy of chromosome 7 (mUPD7)

• Targeted gene panel testing if initial results are negative

Imaging and Additional Tests:

• Bone age assessment (often delayed in SRS)

• Brain imaging or developmental assessment if neurological concerns are present

• Abdominal ultrasound if asymmetry or kidney anomalies are suspected

Early diagnosis allows for timely intervention to support growth and development and manage complications.

Treatment

There is no cure for Silver–Russell syndrome, but treatment focuses on managing growth, nutrition, and developmental challenges. A multidisciplinary team is often required, including endocrinologists, nutritionists, speech and occupational therapists, and genetic counselors.

Growth Management:

• Growth hormone therapy: Often prescribed to improve height and muscle mass, even if growth hormone levels are normal

• Regular monitoring of growth parameters and bone age

Nutrition and Feeding:

• High-calorie, nutrient-rich diets for infants with poor appetite

• Feeding therapy for swallowing difficulties or oral aversion

• Management of gastroesophageal reflux or constipation

Developmental and Educational Support:

• Early intervention programs for delayed motor or speech development

• Special education services if learning difficulties arise

• Psychological support for social or behavioral concerns

Medical Monitoring and Management:

• Surveillance for hypoglycemia and blood sugar control

• Orthopedic monitoring for scoliosis or limb-length discrepancies

• Regular dental checkups for crowding and malocclusion

Prognosis

The long-term outlook for individuals with Silver–Russell syndrome is generally favorable, especially with early and comprehensive management. Most children grow into adulthood with normal intelligence and can lead independent lives. However:

• Short stature may persist, though growth hormone can improve final height

• Feeding difficulties often resolve with age but may require prolonged support

• Limb asymmetry may require orthopedic intervention or shoe lifts

• Social and psychological support may benefit those with self-esteem issues or mild learning challenges

With multidisciplinary care and family support, individuals with SRS can achieve good functional outcomes and quality of life.