Case history

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

Birth and past medical history

Family and drug history

Examination

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

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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?

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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.
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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.
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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
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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?

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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:

LH 0.4 IU/L
FSH 0.3 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.


Presented by David Lim
Specialist Registrar in Paediatric Endocrinology,
Southampton Children’s Hospital

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

 

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