Management of Silver–Russell Syndrome

Case history

A 2-year-old boy, “Mason”, is brought to the Paediatric Endocrine clinic with concerns of short stature.

Birth history

  • Poor growth in utero from 21 weeks
  • Born at 32 weeks’ gestation
  • Birthweight of 1.08 kg (–2.25 SDS) and head circumference of 29 cm (SDS –0.7)
  • Difficulty feeding noted from birth and required prolonged nasogastric feeding
  • No hypoglycaemia episodes
  • No prolonged jaundice

Past medical history

  • Unilateral hydronephrosis with two previous urinary tract infections
  • Gastro-oesophageal reflux
  • Poor weight gain with poor appetite, and is followed up by Gastroenterology and Dieticians
  • Gastrostomy inserted at 9 months of age for supplementation feeding
  • Previous right undescended testis (Right orchidopexy) at 12 months of age
  • Delayed gross motor skills – yet to walk independently
  • Minor speech delay
  • Age-appropriate social and performance skills

Family history

  • Nil of note and no endocrinopathy
  • Heights: Father 181 cm, Mother 160 cm
  • Parental target range for height: 9th to 91st centile

Drug history

  • No known drug allergies
  • Aluminium hydroxide and magnesium trisilicate, ranitidine, domperidone, omeprazole, sodium feredetate, ketotifen, milk bolus feeds
  • Immunisations up to date

Examination

  • Length 74.9 cm (SDS –3.58), weight 10.16 kg (SDS –1.57) and head circumference 46 cm (SDS –1.65)
  • Slightly triangular face
  • Relative macrocephaly
  • No obvious body or limb asymmetry
  • No café au lait pigmentation
  • Bilateral testes in scrotum
  • No hypospadias
  • Muscle tone less than expected for his age
  • Examination unremarkable otherwise

Possible diagnosis: Silver–Russell syndrome (SRS)

Question 1.

Which of the following features are included in the Netchine–Harbison clinical scoring system (NH-CSS) (1) for the diagnosis of Silver–Russell syndrome (SRS)?

  • Small for gestational age (SGA)
  • Postnatal growth failure
  • Relative macrocephaly at birth
  • Protruding forehead
  • Body asymmetry
  • Feeding difficulties
  • Recurrent hypoglycaemia
  • Café au lait pigmentation
  • Triangular face
  • Fifth finger clinodactyly
  • Delayed development
  • Small for gestational age (SGA)
  • Postnatal growth failure
  • Relative macrocephaly at birth
  • Protruding forehead
  • Body asymmetry
  • Feeding difficulties

While all the above options are recognised features of SRS, the six criteria in the NH-CSS (1) are:

  1. SGA: birthweight and/or birth length ≤−2 SDS for gestational age
  2. Postnatal growth failure: height at 24 ± 1 months ≤−2 SDS or height ≤−2 SDS below mid-parental target height
  3. Relative macrocephaly at birth: head circumference at birth ≥1.5 SDS above birth weight and/or length SDS
  4. Protruding forehead: forehead projecting beyond the facial plane on a side view as a toddler (1–3 years)
  5. Body asymmetry: leg length discrepancy (LLD) of ≥0.5 cm or arm asymmetry or LLD <0.5 cm with at least two other asymmetrical body parts (one non-face)
  6. Feeding difficulties and/or low BMI: BMI ≤−2 SDS at 24 months or current use of a feeding tube or cyproheptadine for appetite stimulation
  • The diagnosis of SRS can be either be made clinically, based on a combination of characteristic features, or from genetic testing through which a molecular cause is found.
  • The NH-CSS is the most internationally accepted clinical diagnostic scoring system for SRS.
  • The International Consensus Statement for the diagnosis and management of SRS (1, 2, 3) recommends that clinical diagnosis is first considered if a patient fulfils a minimum of four of the six NH-CSS criteria, and if there then is no molecular cause identified and other differential diagnoses are excluded, patients with at least five of the six criteria, or four of the six criteria including both prominent forehead and relative macrocephaly, should be diagnosed with “clinical SRS”. These two physical characteristics best distinguish SRS from non-SRS SGA.
  • If there is clinical suspicion, with a patient only fulfilling three of the six criteria, molecular testing should also still be performed, as depending on molecular subtype some patients have fewer typical clinical features of SRS than others.
  • The two most common molecular aetiologies for SRS are chromosome 11p15 loss of methylation (LOM) imprinting abnormalities (30–60%) and maternal uniparental disomy of chromosome 7 (UPD(7) mat; up to 10%).

Genetic investigations later demonstrated that Mason had maternal uniparental disomy of chromosome 7 (UPD(7) mat).

Mason’s parents are concerned with episodes of screaming and sweating, especially in the early morning.

Question 2.

What are important differential diagnoses to consider here?

  •  Hypoglycaemic episodes: young children (especially <5 years) with SRS are at increased risk of fasting hypoglycaemia as they have low muscle mass, impaired liver glycogen stores, a relatively large brain-for-body size and may have feeding difficulties.
  • Gut dysmotility: children with SRS are more likely to have gut dysmotility which may manifest as gastro-oesophageal reflux, delayed gastric emptying and constipation. This may contribute to his episodes of apparent distress.
  • Behavioural issues: these are more common in children with SRS, particularly autistic traits, and tend to be more apparent in those with the UPD(7) mat subtype, which Mason has.

Other important points:

  • Mason should have open access to his local hospital due to the risk of hypoglycaemia in SRS, and a plan for admission with iv dextrose treatment should be pre-empted if he is unwell with poor oral intake and has a hypoglycaemic episode.
  • Glucagon is less effective in treating hypoglycaemia in SRS patients as they have limited glycogen stores and less effective gluconeogenesis.
  • Mason’s parents should be educated on the recognition of signs and symptoms of hypoglycaemia and its monitoring and treatments, with provision of an emergency guidance plan for illnesses.
  • The risk of nocturnal hypoglycaemia can be avoided by supplementing the child’s last evening feed with high-molecular-weight glucose polymer or uncooked corn starch.

Mason was electively admitted for a 24-hour period to obtain a blood glucose profile. Blood glucose levels were obtained pre-feeds and 3 hourly overnight, and also measured when he had any of these episodes of distress. The blood glucose levels were all between 4 and 7 mmol/L, with several of these coinciding with these episodes of distress. Hence it was unlikely that these episodes were related to hypoglycaemia.

Mason was also reviewed by the Gastroenterology Team who assessed that these episodes were related to gut dysmotility. Probiotics were trialled.

In the past year Mason’s height has consistently been ≤–3 SDS, weight –1.5 to –2 SDS and BMI +1.5 to +2 SDS. The family has been counselled about weight management.

Question 3.

What statement best describes the goal of weight management and nutritional support for children with SRS?

  • Children with SRS have failure to thrive and feeding difficulties, and hence require feeding supplementation through to adulthood.
  • Children with SRS should be started on human growth hormone (hGH) therapy before 2 years of age to help improve body composition and gain muscle mass.
  • Children with SRS should aim for nutritional repletion in the first years of life, balanced against the risk of rapid postnatal catch-up weight gain leading to subsequent increased metabolic risk.

Children with SRS should aim for nutritional repletion in the first years of life, balanced against the risk of rapid postnatal catch-up weight gain leading to subsequent increased metabolic risk.

  • In the first 2 years of life, the focus should be on nutritional support, hypoglycaemia prevention and recovery of calorie-related growth deficit before commencing hGH therapy. Rapid catch-up weight gain must concurrently be avoided, as this is associated with future increased metabolic and cardiovascular risks.
  • Poor weight gain is common in children with SRS, due to a variety of reasons including feeding difficulties (eg, poor appetite, oro-motor issues) and gastrointestinal anatomical or functional problems (eg, gastro-oesophageal reflux, constipation, delayed gastric emptying). There should be avoidance of a nasogastric/ gastrostomy tube where possible, because this may impede feeding behavioural development.
  • The target for healthy nutritional status is narrow, and even mild over-nourishment can cause a significant increase in relative fat mass.
  • Children aged 2–4 years and preparing for hGH therapy should aim for a weight of 75–85% of the 50th centile weight-for-height and/or BMI 12–14 kg/m2.
  • For children aged >4 years, the optimal BMI depends on muscle mass. Children with 11p15 LOM typically have very low muscle mass and considerable body asymmetry, so a lower BMI of 11–12 kg/mmay suffice. Those with maternal UPD(7) mat who have near normal muscle mass may aim for a slightly higher BMI of 14–15 kg/m2.

What statement best describes the goal of weight management and nutritional support for children with SRS?

Although Mason has evidence of significant catch-up weight gain, this has not been the case with linear growth. hGH therapy was commenced at a dose of 35 µg/kg per day following discussions with the family. GH stimulation testing was not indicated. Treatment with hGH for SRS was under the SGA registered license.

Principles of hGH therapy for SRS

  • The aims of hGH treatment are to improve body composition, psychomotor development and appetite, prevent hypoglycaemia, and enhance linear growth.
  • hGH treatment may be started below the age of 2 years when there is profound fasting hypoglycaemia, as hGH will support gluconeogenesis and increase muscle mass.
  • hGH therapy is continued until height velocity is <2 cm/year over a 6-month period and bone age is >14 years (girls) or >17 years (boys).

In the 9 months after commencement of hGH therapy, Mason’s serial height velocities were between 5.0 and 6.0 cm/year. His serum insulin-like growth factor (IGF)-1 levels were 220–300 nmol/L (normal range 25–169).

Question 4.

Which of the statements is true?

  • Mason’s IGF-1 levels are high despite modest improvement in height velocity, suggesting the possibility of IGF-1 resistance.
  • His IGF-1 levels are high despite modest improvement in height velocity, hence the hGH dose should be increased by at least 10–20%.
  • His IGF-1 levels are high, suggesting GH sensitivity, and the hGH dose should be reduced.

Mason’s IGF-1 levels are high despite modest improvement in height velocity, suggesting the possibility of IGF-1 resistance.

  • Mason’s height velocity remains on the lower side of an effective response range for his age. For most children with SRS, an increase in height velocity of ≥3 cm/year is the lower limit of an effective response range.
  • His high IGF-1 levels suggest that there is a good IGF-1 response to hGH therapy, although this did not directly translate to improvement in height velocity, suggesting the possibility of IGF-1 resistance.
  • The interpretation of IGF-1 levels in response to hGH treatment is challenging. Children with 11p15 LOM typically have higher IGF-1 levels than those with UPD(7) mat and other SGA children, suggesting the possibility of IGF-1 resistance in the former group.
  • Basal IGF-1 levels in children with SRS may be in the upper end or higher than the normal age-related range, and can rise significantly above the reference range on standard hGH doses.
  • Despite Mason’s suboptimal improvement in height velocity, with already elevated IGF-1 levels it is not recommended to keep increasing the hGH dose. The side effects of excess GH have to be balanced against the benefits of hGH therapy in improving linear growth.

Mason is now 6 years old. His parents are concerned about adult-type body odour and the appearance of pubic hair. On examination his Tanner staging is Pubic hair 1–2, Genitalia 1 with testicular volumes of 2 mL.

Blood tests are performed:

Androstenedione <0.2 nmol/L (0–1.0)
DHEA-sulphate 4.0 µmol/L (0.3–1.5)
Testosterone <0.4 nmol/L (0–0.5)
Luteinising hormone (LH) 0.2 IU/L
Follicle-stimulating hormone (FSH) 0.9 IU/L
17-hydroxyprogesterone <0.2 nmol/L (0.2–3.2)

Question 5.

What does this indicate?

  • Premature adrenarche
  • Gonadotrophic-dependent precocious puberty
  • Late-onset congenital adrenal hyperplasia

Premature adrenarche

  • Mason’s testicular volumes are less than 4 mL and low basal LH of 0.2 IU/L indicate no clinical evidence of gonadotrophin-dependent puberty development. Apart from DHEA-sulphate, which is mildly elevated at 4 µmol/L, all other androgens are reassuringly low. This biochemical picture is typical for children with premature adrenarche.
  • Premature adrenarche is seen more frequently in children with SRS (4).
  • In SRS, early hGH therapy is significantly associated with early adrenarche. A high IGF-1 concentration for years from early hGH treatment may stimulate the maturation of the adrenal zona reticularis, leading to early adrenal steroidogenesis.
  • Children with SRS who have premature adrenarche may have an earlier onset of central puberty and faster tempo of puberty. Excessive weight gain leading to increased insulin resistance is a contributory factor.
  • Close monitoring of pubertal progression is indicated.

Mason’s pubertal progression is closely monitored. His testicular volumes remain pre-pubertal at 3 mL over the next 2 years. At a chronological age of 8 years 2 months, his bone age was 9 years.

However, at 9.5 years, there was increase in pubic hair and penile length. His pubertal staging was Pubic hair 2–3, Genitalia 2 with testicular volumes of 4–5 mL. His BMI was 17 kg/m2. His bone age was advanced at 11 years 6 months with a chronological age of 9 years 5 months. His height velocity was 9.3 cm/year.

Blood tests are done:

FSH 7.6 IU/L
LH 8.0 IU/L
Sex hormone binding globulin 58 nmol/L (10–50)
Testosterone 8.5 nmol/L (0–0.5)

Question 6.

What are the issues to be considered here?

  • Mason has entered puberty evidenced by testicular volumes of >4 mL and accelerated height velocity, supported by pubertal levels of gonadotrophins and testosterone. His bone age is also advanced (having been normal before), indicating a rapid tempo of puberty.
  • The option to commence a gonadotrophin-releasing hormone (GnRH) analogue needs to be discussed. The aim is to reduce growth plate exposure to sex steroids, notably oestrogens, to allow hGH treatment to decrease the rate of skeletal maturation and improve final height prognosis.
  • Weight management strategies need to be instituted, as excessive weight gain further drives pubertal progression – the aim for BMI in UPD(7) mat is 14–15 kg/m2.

Following discussion with parents, GnRH analogue (leuprorelin) injections were started from age 9.5 years. Mason tolerated the injections well. At 9.9 years, there was no further acceleration in linear growth. There was a slight reduction of testicular volumes to 4 mL.

Bloods during GnRH analogue therapy are checked again:

LH0.4 IU/L
FSH0.3 IU/L
Testosterone<0.4 nmol/L (0–0.5)

The suppressed gonadotrophins (LH and FSH) and undetectable testosterone levels, together with no further acceleration in linear growth and reduction in testicular volumes, demonstrate the success of GnRH analogue in halting further pubertal progression.

Conclusion

  • The NH-CSS is useful to make a clinical diagnosis of Silver–Russell syndrome (SRS). Molecular diagnosis is possible in 60% of cases.
  • SRS is a multi-system disorder and requires a specialised multi-disciplinary team for optimal management.
  • Nutritional management is a key aspect from diagnosis throughout childhood.
  • Growth hormone therapy is indicated for SRS under the SGA license, usually starting at 2–4 years old to improve height during childhood and final height prognosis.
  • GnRH analogue therapy may be helpful to improve height outcome in those with early puberty and advancing bone age.

Meet the author

David Lim

Specialist Registrar in Paediatric Endocrinology, Southampton Children’s Hospital

With assistance from Dr Justin Davies, Consultant Paediatric Endocrinologist, Southampton Children’s Hospital

David-Lim-150x150
Martin Savage
Programme Director

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