SRS is estimated to occur in 1:30,000 to 1:100,000 live births.

Most cases of SRS are sporadic, meaning there is no family history of disease, and, in many cases, there is no detectable genetic cause. However, abnormalities of chromosome 7 and 11 have been reported in up to 60% of SRS patients. 

Chromosomes are bundles of genetic material, or DNA, that children inherit from their parents. Typically, each person has 23 pairs of chromosomes, with one of each pair inherited from the mother (maternal copy) and the other inherited from the father (paternal copy). Each chromosome has a long (q) and short (p) arm, along which different genes and gene-regulating elements are located. Most genes are active, or expressed, from both the maternal and paternal chromosomes. However, for some genes, called “imprinted genes,” only one copy is active. For imprinted genes, whether the maternal or paternal copy is active depends on imprinting control regions (ICRs).

Some SRS patients have a chromosomal abnormality called maternal uniparental disomy of chromosome 7, abbreviated matUPD7. In this case, 2 maternal (from the mother) copies of chromosome 7 are inherited rather than one maternal and one paternal. This phenomenon is thought to disrupt the normal balance of gene imprinting, causing excess activation of some genes and not enough activation of others. The exact genes involved have not been determined.

Other genetic causes involve abnormalities on chromosome 11p15 (the 15th band on the short arm of chromosome 11). In a large number of cases, there is an imprinting error caused by dysregulation of imprinting control region 1 (ICR1) on the paternal copy of chromosome 11. This dysregulation leads to reduced activation of the IGF2 gene, or insulin-like growth factor II, which is involved in fetal growth and development and may also affect other gene regulatory regions.

In 3-4% of cases, maternal duplication of ICR1 and/or ICR2 are implicated. Among its many targets, ICR2 controls expression of the maternally expressed genes KCNQ1 and CDKN1C. CDKN1C is involved in growth regulation, while KCNQ1 is a potassium channel affecting heart function. 

In about 1% of cases, patients have a mutation directly affecting the CDKN1C gene.

Growth, birth, and puberty
Decreased fetal growth during pregnancy (intrauterine growth restriction)
Premature birth
Poor growth after birth (weight and length <3rd percentile)
Poor appetite and feeding difficulties
Failure to thrive
Delayed bone maturation
Delayed closing of “soft spot” or anterior fontanelle
Early sexual maturation (premature adrenarche)
Increased risk of early puberty

Muscular, joint, and motor
Muscle and weight loss due to an underlying condition (cachexia)
Decreased muscle mass
Loss of the healthy, baseline tension or stiffness in the muscles (hypotonia)
Motor delay
Involuntary muscle twitches (myoclonus)
Joint pain (arthralgia)

Head and face, orthopedic, dental, and skin
Short stature
Large head size relative to the body (head sparing or relative macrocephaly)
Triangular face shape
Small jaw (micrognathia)
Small mouth with downturned corners
Low-set, posteriorly rotated ears
Prominent forehead
Body asymmetry (hemihypertrophy)
Scoliosis or the abnormal curvature of the pine
Short and in-curving 5th fingers (clinodactyly)
Fingers that cannot be fully straightened (camptodactyly)
Webbing of the second and third toes (syndactyly)
High, narrow palate
Cleft palate
High-pitched voice
Dental abnormalities, including absence of teeth, small teeth (microdontia), or crowding
Blue appearance of the white of the eye during infancy 
Flat, dark patches of skin (Café-au-lait spots)

Endocrine 
Increased risk of low blood sugar and increased ketone levels in the urine  (due to fasting and lack of subcutaneous fat). Urine ketone levels are elevated when the body breaks down fat in the absence of sufficient sugar levels.
Insulin resistance
Excessive sweating
Sleep disturbances

Genitourinary 
Undescended testes (cryptorchidism). Testes normally develop in the abdomen and descend to the scrotum before birth as the baby develops. However, individuals with SRS may have undescended testes, meaning that the testicles remain in the abdomen as opposed to being located inside the scrotum.
Mislocation of male urethral opening (hypospadias)
Decreased testicular size
Structural kidney abnormalities

Gastrointestinal
Inflammation of the esophagus (esophagitis) causing painful swallowing and/or chest pain
Gastroesophageal reflux causing heartburn or indigestion
Constipation
Vomiting or spitting up

Neurodevelopment and Psychology
Psychosocial challenges
Attention deficit disorder (ADD)
Learning difficulties
Autism spectrum disorder

Diagnosis of SRS is based on the Netchine-Harbison clinical scoring system (http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html) which uses the following diagnostic criteria:

1. Small for gestational age

2. Postnatal growth failure

3. Relative macrocephaly (large head size at birth)

4. Protruding forehead

5. Body asymmetry

6. Feeding difficulties

The MAGIC Foundation provides free SRS screening using the above scoring system.

Known genetic causes of SRS only account for about 60% of cases. Therefore, a “negative” genetic test cannot exclude an SRS diagnosis. Testing is conducted on chromosomes 7 and 11. Maternal uniparental disomy (matUPD) of chromosome 7 can lead to a diagnosis of SRS. Additionally, abnormalities of chromosome 11 at band p15 can be involved in SRS in four ways:

1) dysregulation of paternal imprinting control region 1 (ICR1)

2) duplication of ICR1 and ICR2 

3) duplication of ICR2

4) mutation of CDKN1C gene

There is no cure for SRS, and treatment consists primarily of symptom management, including physical, occupational, and speech therapy. Patients should consult an orthopedist for body asymmetry and other skeletal abnormalities and seek out specialists for additional problematic symptoms as necessary.

SRS patients are not typically deficient in growth hormone and, therefore, do not generally respond to growth hormone therapy.

Most individuals affected by SRS are able to live full, productive lives while managing symptoms.

1. https://rarediseases.org/rare-diseases/russell-silver-syndrome/

2. https://medlineplus.gov/genetics/condition/russell-silver-syndrome/#causes

3. https://rarediseases.info.nih.gov/diseases/4870/russell-silver-syndrome 

4. https://omim.org/entry/616186 

5. Silver-Russell Syndrome Global Alliance http://silverrussellsyndrome.org/ 

6. The MAGIC Foundation https://www.magicfoundation.org/

7. https://www.omim.org/entry/600856?search=cdkn1c&highlight=cdkn1c 

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9. Bonaldi A, Mazzeu JF, Costa SS, Honjo RS, Bertola DR, Albano LMJ, Furquim IM, Kim CA, Vianna-Morgante AM. Microduplication of the ICR2 Domain at Chromosome11p15 and Familial Silver–Russell Syndrome. Am J Med Genet. 2011 Sept; Part A 155:2479–2483. https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.34023