We aim to provide helpful information for those affected by and the families of those effected by Growth Conditions.
This simple animation explains what we know about the condition and its features, and how it is diagnosed and treated.
Russell Silver Syndrome (RSS) Intrauterine Growth Restriction (IUGR) Small for Gestational Age (SGA)
The term IUGR probably represents a spectrum of conditions (some of which are described as Silver Russell Syndrome) resulting from abnormal foetal growth. As with any syndrome, not every child will have all the features described. The child who has IUGR, but has not experienced catch-up growth during the early years (before 3 years), will generally remain small for their age. Their final height may be in the region of 157cm (5’2″) for a boy and 144cm (4’9″) for a girl.
Many features of IUGR may require medical help and support, so discuss any concerns with your growth specialist, who can then refer your child to another appropriate specialist if necessary. This may be especially relevant when considering leg asymmetry and the referral to an orthopaedic surgeon with experience in the procedure of limb lengthening (not shortening).
There is no definitive way to help your child put on weight, although this can be very worrying. These children are healthy and active, and confrontation over food should be avoided where possible.
Growth hormone has been shown to be beneficial both in the short term, and the long-term, with final height increased by up at 14cm. As a result, GH is now licensed from 4 years of age for children born SGA who fail to show catch-up growth and who are short, both compared to the normal population and their parents.
Diagnosis – Intrauterine Growth Restriction and Small for Gestational Age
A baby is classed as Small for Gestational Age when they are born with a low birth weight, one which is inappropriately low given the length of the pregnancy. For a baby born at term this would be less than 2.5kg.
The inappropriately low weight indicates that the growth of the baby in the womb has been unsatisfactory – hence the name Intrauterine Growth Restriction.
Most babies born too small for their gestational age catch up over the first two or three years of life. However, in about a third, complete catch-up growth does not occur. These children remain small and don’t reach their genetic potential as defined by their parental heights.
The diagnosis of IUGR is based on comparison of the babies’ weight centile at birth, with standards including the baby’s gestational age. Ideally, infant length should also be taken into account.
How is Silver Russell Syndrome Diagnosed?
Silver Russell Syndrome is very rare; it is very difficult to put a number on this but estimates are in the region of 1 in 50,000 to 1:75,000 births, and little is known about what causes it. In most families, only one child has the condition, but very occasionally more than one affected child is born into the same family.
Molecular Testing: Silver Russell Syndrome can be diagnosed with genetic testing. Currently, genetic testing is available for known causes of SRS involving chromosomes 7 and 11.
Chromosome 7 is involved in the cause of the maternal uniparental disomy of chromosome 7 [MUPD7] type of SRS, which can be either heterodisomy (rare) or isodisomy (most common). MUPD7 is thought to account for less than 10% SRS cases.
Chromosome 11p15 is involved in four different SRS mechanisms representing approximately 44-60% of SRS cases:
A) hypomethylation of the paternal imprinting control region 1 (ICR1) due to an imprinting error in up to 40-55% of cases;
B) duplication of ICR1 and ICR2 in about 2-3% of cases;
C) duplication of ICR2 in about 1% of cases;
D) mutation of CDKN1C gene in about 1% of cases.
In the rare mechanisms B, C & D above, which are chromosomal copy number variations (CNV), there can be a risk of transmission either to the patient’s own children or with the patient’s siblings. Genetic testing of the child’s parents will need to be completed and the results discussed with the geneticist.
There are other chromosomal abnormalities that have overlapping physical characteristics with SRS such as MUPD16, MUPD20 and MUPD14 (Temple Syndrome). As additional research is published in the future, we hope to know if these molecular abnormalities represent additional causes of Silver Russell Syndrome.
The above molecular causes account for only 60-70% of SRS cases; the other 30-40% are “idiopathic”, meaning the cause is unknown. For these children, doctors will generally base their diagnosis on characteristic, clinical findings that make up the RSS phenotype. It is easy to diagnose the “textbook” RSS phenotype; other cases are more difficult to classify and may require a specialist highly experienced in Silver Russell Syndrome to rule out another syndrome or another cause of short stature. The Netchine-Harbison RSS clinical scoring system (Azzi et al, 2015) found that the following six clinical characteristics are statistically correlated with either a positive molecular result or a clinical SRS diagnosis by an experienced specialist:
- Small for gestational age (SGA) in birth for weight and/or length
- Large head size for body size at BIRTH (1.5SDS difference between birth head circumference and birth weight or length)
- Postnatal growth failure (length <-2SDS by 24mos)
- Feeding difficulties and/or low BMI (<-2SDS at 24mos)
- Prominent protruding forehead (age 1-3 years)
- Body asymmetry
Characteristics that occur more frequently in SRS children than SGA/IUGR children (the characteristics that Azzi et al (2015) found to be statistically different between specific molecular SRS groups and SGA-non RSS subjects are marked below with an asterisk*):
- Body asymmetry – LARGE side is the “normal” side*
- Large head size for body size*
- Broad protruding forehead*
- Low-set, posteriorly rotated &/or prominent ears
- Clinodactyly (inward curving) of the 5th finger (pinky)*
- Syndactyly (webbing) of the 2nd and 3rd toes*
- Inadequate catch-up growth in first 2 years
- Persistently low weight-for-height*
- Lack of muscle mass and/or poor muscle tone*
- Hypoplastic (underdeveloped) chin & midface
- Downturned corners of mouth*
- Thin upper lip
- High-arched palate
- Small, crowded teeth
- Unusually high-pitched voice in early years
- Café-au-lait (coffee-with-milk) birth marks
- Dimples in the posterior shoulders and hips*
- Narrow, flat feet
- Scoliosis (curved spine, associated with spinal asymmetry & accentuated by a short leg)
- Prominent heels [mUPD7 primarily] *
- autism [MUPD7 children primarily] *
- Myoclonus dystonia (movement disorder) [MUPD7 primarily]
- Characteristics of both SGA/IUGR and SRS individuals
- Lack of interest in eating
- Fasting hypoglycaemia & mild metabolic acidosis
- Generalized intestinal movement abnormalities:
- Oesophageal reflux resulting in movement of food up from stomach into food tube
- Delayed stomach emptying resulting in vomiting or frequent spitting up
- Slow movement of the small intestine &/or large intestine (constipation)
- Late closure of the anterior fontanel (soft spot)
- Frequent ear infections or chronic fluid in ears
- Congenital absence of the second premolars
- Delay of gross and fine motor development
- Delay of speech and oral motor development
- Kidney abnormalities
- Delayed bone age early, later fast advancement
- Early pubic hair and underarm odour (adrenarche)
- Early puberty
- Classical or neurosecretory growth hormone deficiency
- ADHD and specific learning disabilities
- Blue sclera (bluish tinge in white of eye)
- Hypospadias (abnormal opening of the penis)
- Cryptorchidism (undescended testicles
An infant with SRS is generally born with normal intelligence. Some MUPD7 individuals may have learning difficulties, and it is thought there may be a link to Autistic Spectrum disorders and RSS (MUPD7). We are currently funding a research project looking at SRS and behaviour, entitled “Investigating Behaviour in Russell Silver Syndrome”. (link to information) So hopefully we will have more information soon.
it is unclear whether these problems appear to be increased or are acquired through early malnutrition and hypoglycaemia, both of which are preventable. It is very important to do everything possible to prevent hypoglycaemia from occurring.
Physical Signs of Hypoglycaemia
- Waking to feed at night past early infancy
- Excessive sweating
- Extreme irritability improved by feeding
- Difficulty waking up in the morning or extreme lethargy when ill and not able to eat
- Pallor and shakiness
- Poor coordination or slurred speech
- Ketones in the urine
Typical growth and weight chart for a boy with Russell Silver Syndrome
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