2 Clinical need and practice

2 Clinical need and practice

2.1 Human growth hormone is produced by the anterior pituitary gland. The synthetic form is called somatropin (recombinant human growth hormone). Human growth hormone is essential for normal growth in children. It increases growth by a direct action on the growth plates and by production of insulin‑like growth factors (especially IGF‑1), mainly in the liver. Human growth hormone also has important effects on the metabolism of proteins, lipids and carbohydrates, not only during childhood, but also throughout adult life. Growth failure in children can be a result of growth hormone deficiency, but also occurs in children with Turner syndrome, chronic renal insufficiency (CRI), short stature homeobox‑containing gene (SHOX) deficiency, and in children born small for gestational age.

2.2 Growth hormone deficiency occurs when the pituitary gland does not produce enough human growth hormone, which is the most common endocrine cause of short stature. Growth hormone deficiency may occur as an isolated hormonal deficiency or in combination with deficiencies in several pituitary hormones arising from hypopituitarism, tumours in the central nervous system, cranial irradiation or other physiological causes. The prevalence of growth hormone deficiency is estimated to be between 1 in 3500 and 1 in 4000 children. In about half of the children with growth hormone deficiency (50%), the cause is unknown (idiopathic growth hormone deficiency).

2.3 Turner syndrome is a chromosomal disorder characterised by the complete or partial lack of one X chromosome in girls. The two most common clinical features are short stature and ovarian failure. Girls with Turner syndrome do not have a deficiency in human growth hormone, although they may have a relative lack of sensitivity to human growth hormone because of haploinsufficiency of the short stature homeobox‑containing gene. Not all girls with Turner syndrome need treatment with somatropin. Turner syndrome occurs in between 1 in 1500 and 1 in 2500 live female births. If untreated, girls with Turner syndrome have a final adult height of 136–147 cm. Adult women with Turner syndrome are on average 20 cm shorter than other adult women.

2.4 Prader–Willi syndrome is a genetic disorder caused by an abnormality of chromosome 15. Common clinical characteristics include hypogonadism, short stature, hypotonia, dysmorphic features, hypoventilation, changes in body composition, obesity and obesity‑related diseases, and behavioural problems. Prader–Willi syndrome occurs in between 1 in 15,000 and 1 in 25,000 live births. Men with Prader–Willi syndrome have a final adult height of about 154 cm; women have a final adult height of 145–159 cm.

2.5 Chronic renal insufficiency (CRI), which may include end‑stage renal disease, is defined as a persistent elevation of serum creatinine and/or urea. It can be caused by a variety of conditions, including congenital disorders, glomerular disorders and infections. Growth failure associated with CRI usually begins when the glomerular filtration rate falls to 50% of normal. Not all people with CRI in childhood will be shorter than average; figures from the UK Renal Registry indicate that 29% of children who undergo renal transplantation and 41% of children on dialysis are below the 2nd percentile for height within their first year and remain so throughout childhood because of more pronounced deceleration in height velocity. Children with congenital disorders leading to CRI (approximately 60% of children with CRI) are of normal length at birth, but are below the 3rd percentile for height within their first year and remain so throughout childhood.

2.6 Various thresholds for height and weight at birth are used to define 'small for gestational age', the three most commonly used being:

  • a height at birth that is 2 standard deviations or more below the population average, or

  • a weight at birth that is 2 standard deviations or more below the population average, or

  • a weight at birth below the 10th percentile.

    In addition to accurate measurements of a newborn's weight, length and head circumference, the diagnosis of small for gestational age requires accurate assessment of gestational age and valid data from a reference population. The international consensus definition of 'small for gestational age' is a length or weight at birth that is 2 standard deviations below ( −2 SD) the population average for birth or weight. The licensed indication for somatropin is for growth disturbance (current height standard deviation score [SDS]  −2.5 and parental adjusted height SDS  −1) in short children born small for gestational age, with a birth weight and/or length below −2 SD, who failed to show catch‑up growth (height velocity SDS less than 0 during the past year) by 4 years of age or later. Children classified as born small for gestational age may have concurrent diagnoses such as familial short stature, Turner syndrome, or growth hormone deficiency. Approximately 10% of children born small for gestational age do not reach the normal height range. Those whose growth has not caught up by 4 years of age are candidates for treatment with growth hormone.

2.7 The short stature homeobox‑containing gene (SHOX) is located on the distal ends of X and Y chromosomes and plays a role in long bone growth. Normal growth requires two functional copies of the gene. Consequently, growth impairment can occur if one copy of the SHOX gene has been inactivated by mutation or deleted (haploinsufficiency). SHOX deficiency can cause short stature in people with conditions such as Turner syndrome, Leri–Weil syndrome and dyschondrosteosis. Based on a small study (26 people with SHOX haploinsufficiency compared with 45 of their unaffected relatives), children with SHOX haploinsufficiency were 3.8 cm shorter (2.1 standard deviations shorter) than their unaffected relatives and this difference persisted throughout their childhood.

2.8 Somatropin (recombinant human growth hormone) is currently the only active treatment option for growth failure in children with growth hormone deficiency, Turner syndrome, CRI, Prader–Willi syndrome, in short children born small for gestational age and in children with SHOX deficiency. The place of somatropin in the treatment pathway depends on the child's particular condition, his or her age at diagnosis and the licensed indications of the seven somatropin preparations that are available for use in UK practice. For girls with Turner syndrome, oxandrolone, an anabolic steroid, may be added to growth hormone treatment. In the UK, conservative strategies for the management of growth failure in children with CRI include advice on diet and nutritional supplementation.

  • National Institute for Health and Care Excellence (NICE)