Russell-Silver syndrome is a growth disorder characterized by slow growth before and after birth. Babies with this condition have a low birth weight and often fail to grow and gain weight at the expected rate (failure to thrive). Head growth is normal, however, so the head may appear unusually large compared to the rest of the body. Affected children are thin and have poor appetites, and some develop recurrent episodes of low blood glucose (hypoglycemia) as a result of feeding difficulties. Adults with Russell-Silver syndrome are short; the average height for affected men is about 151 centimeters (4 feet, 11 inches) and the average height for affected women is about 140 centimeters (4 feet, 7 inches).

Many children with Russell-Silver syndrome have a small, triangular face with distinctive facial features including a prominent forehead, a narrow chin, a small jaw, and downturned corners of the mouth. Other features of this disorder can include an unusual curving of the fifth finger (clinodactyly), asymmetric or uneven growth of some parts of the body, and digestive system abnormalities. Russell-Silver syndrome is also associated with an increased risk of delayed development, speech and language problems, and learning disabilities.

The genetic causes of Russell-Silver syndrome are complex. The disorder often results from the abnormal regulation of certain genes that control growth. Research has focused on genes located in particular regions of chromosome 7 and chromosome 11.

People normally inherit one copy of each chromosome from their mother and one copy from their father. For most genes, both copies are expressed, or "turned on," in cells. For some genes, however, only the copy inherited from a person's father (the paternal copy) is expressed. For other genes, only the copy inherited from a person's mother (the maternal copy) is expressed. These parent-specific differences in gene expression are caused by a phenomenon called genomic imprinting. Both chromosome 7 and chromosome 11 contain groups of genes that normally undergo genomic imprinting; some of these genes are active only on the maternal copy of the chromosome, while others are active only on the paternal copy. Abnormalities involving these genes appear to be responsible for many cases of Russell-Silver syndrome.

Researchers suspect that 30 to 50 percent of all cases of Russell-Silver syndrome result from changes in a process called methylation on the short (p) arm of chromosome 11 at position 15 (11p15). Methylation is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. In genes that undergo genomic imprinting, methylation is one way that a gene's parent of origin is marked during the formation of egg and sperm cells. Russell-Silver syndrome has been associated with changes in methylation involving the H19 and IGF2 genes, which are located near one another at 11p15. These genes are thought to be involved in directing normal growth. A loss of methylation disrupts the regulation of these genes, which leads to slow growth and the other characteristic features of this disorder.

Abnormalities involving genes on chromosome 7 can also cause Russell-Silver syndrome. In 7 percent to 10 percent of cases, people inherit both copies of chromosome 7 from their mother instead of one copy from each parent. This phenomenon is called maternal uniparental disomy (UPD). Maternal UPD causes people to have two active copies of some imprinted genes and no active copies of others. An imbalance in certain active paternal and maternal genes on chromosome 7 underlies the signs and symptoms of the disorder.

In about 40 percent of people with Russell-Silver syndrome, the cause of the condition is unknown. It is likely that changes involving imprinted genes on chromosomes other than 7 and 11 play a role. Researchers are working to identify additional genetic changes that underlie this disorder.

Most cases of Russell-Silver syndrome are sporadic, which means they occur in people with no history of the disorder in their family.

Rarely, Russell-Silver syndrome can run in families. In some affected families, the condition appears to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of a genetic change in each cell is sufficient to cause the disorder. In other families, the condition appears to have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of a gene are altered in each cell. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

• Intrauterine growth restriction (poor growth before birth)
• Low birth weight
• Head that appears large in relation to body size (relative macrocephaly)
• Poor appetite and feeding difficulties
• Hypoglycemia
• Poor growth after birth, leading to short stature
• Scoliosis
• Curving of the pinky finger (clinodactyly)
• Characteristic facial features (prominent forehead; small, triangular-shaped face; a small jaw; a narrow chin; and down-turned corners of the mouth)
• Arms and legs of different lengths (body asymmetry)
• Delayed bone age
• Gastroesophageal reflux disease or other digestive problems
• Kidney problems
• Developmental delay and/or learning disabilities
• Psychosocial challenges

Symptoms of several disorders can be similar to those of Russell-Silver syndrome (RSS). For this reason, when RSS is suspected, it may be useful compare the symptoms of these disorders with a person's symptoms to narrow the differential diagnosis. The differential diagnosis of Russell-Silver syndrome (RSS) generally includes any condition that can cause intrauterine growth restriction (IUGR) and short stature.

• IUGR may occur in a number of congenital disorders, including Mulibrey nanism and many chromosome disorders. Chromosome abnormalities to consider in the differential diagnosis of RSS include:
  • mosaic Turner syndrome
  • diploid/triploid mixoploidy (because of limb asymmetry)
  • Yq deletions
  • other chromosome deletions (involving 12p14 , 15q26.3, and a distal deletion of 22q11.2)
  • rearrangements of chromosome 17q25
• Three M syndrome is an extremely rare genetic disorder with features that include low birth weight, short stature, characteristic head and facial features, and distinctive bone abnormalities.
• Disorders of DNA repair (chromosome breakage disorders), including Fanconi anemia, Bloom syndrome, and Nijmegen breakage syndrome, are often associated with IUGR and short stature. In these conditions, additional features such as small head size (microcephaly), limb abnormalities, and abnormal sensitivity to sunlight (photosensitivity), are often evident.
• Fetal alcohol spectrum disorders (FASDs) may be characterized by mental and physical birth defects from maternal use of alcohol during pregnancy. The range and severity of symptoms vary greatly. In some cases, learning delays or intellectual disability occurs without any obvious physical abnormalities.
• IMAGe syndrome is characterized by IUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital abnormalities. A skeletal survey should be performed to exclude a skeletal dysplasia that may mimic RSS.
• One condition that has been confused with RSS is an X-linked disorder of short stature with skin hyperpigmentation. It has sometimes been referred to as X-linked RSS. This condition may be difficult to distinguish from classic RSS in the absence of a positive family history.

The presence of other particular features (especially those atypical for RSS) should prompt consideration of a diagnosis other than RSS. Atypical features may include microcephaly; notable global developmental delay or intellectual disability (without a related explanation); absence of severe feeding difficulties; the presence of additional congenital anomalies; and facial dysmorphism. Disproportionate short stature is suggestive of skeletal dysplasia, and photosensitivity or recurrent respiratory infections may be suggestive of chromosome breakage disorders. Because RSS is generally sporadic (not inherited), a family history of growth failure and/or consanguinity might suggest a different diagnosis.

People with a questions about a possible genetic diagnosis are encouraged to meet with a genetics professional who can provide detailed information and support.

• karyotype and chromosomal microarrays to exclude other disorders
• evaluation of patient and parental blood for uniparental disomy of chromosome 7 and hypomethylation (a form of DNA modification) at chromosome 11p15 by polymerase chain reaction (PCR)
• hand x-ray to determine bone age - findings may include:
  • delayed bone age
  • white or ivory appearance on parts of the fingers (ivory epiphyses of distal phalanges)
  • short middle bone of the pinky (small middle phalanx of the fifth finger), which occurs in 80% of people with RSS
  • extra bone formation at the base of the pointer finger (pseudoepiphyses at base of second metacarpal)

• Metabolic syndrome
• Uterine and vaginal dysgenesis (in females with 11p15-related RSS)
• Gonadal hypofunction or testicular cancer in males
• Low muscle mass or low bone mineral density
• Myoclonus dystonia (in people with chromosome 7-related RSS)

The exact incidence of Russell-Silver syndrome is unknown. Worldwide estimates range from 1 in 30,000 to 1 in 100,000 people.