The importance of monitoring growth and weight in childhood and its progression into adulthood cannot be overemphasised. A record of consecutive accurate heights and weights over time yields more information than isolated measurements.
Short stature has been defined as a height below the 0.4th centile of the 1990 Growth Reference Charts.1 While this group requires an explanation for their short stature, the process can be refined by consideration of their growth rate. Children with an abnormal growth velocity warrant a more detailed assessment for a pathological cause. A simple classification distinguishes short stature into two main categories:
The former includes children with genetic short stature and constitutional delay. The latter includes children who have an hormonal abnormality, a dysmorphic syndrome, intrauterine growth restriction and/or systemic chronic illnesses.
Human GH is a single chain polypeptide of 191 amino acid residues with two disulphide bridges.2 It is secreted by the somatotrophs of the anterior pituitary gland under the control of the hypothalamic peptides GH releasing hormone (GHRH), somatostatin and the recently discovered peptide, Ghrelin.3
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Panel 1: Growth hormone effects
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Growth hormone deficiency (GHD) encompasses a group of different pathologies, all with failure of or a reduction in GH secretion. It may occur singly or in combination with other pituitary hormone deficiencies and may be sporadic or familial. It may be congenital or acquired as a result of trauma, infiltrations (eg, disseminated tuberculosis, sarcoidosis, haemochromatosis) , tumour or radiation therapy. The pathology arises either as a result of abnormalities in the pituitary GH-producing cells or in the hypothalamus, ie, in the GHRH cells. Despite the large number of aetiologies, the majority of GH deficient children have "idiopathic" GH deficiency.
Clinical features Most children with GHD have normal body proportions and features. However certain characteristics, if present, are suggestive of GHD.
Auxological parameters The following auxological parameters are suggestive of GHD.8
Neonatal presentation A characteristic neonatal presentation of GHD would be a newborn baby with unexplained hypoglycaemia, prolonged hyperbilirubinaemia, clinical appearance suggestive of GHD, microphallus and cryptorchidism. A turbulent neonatal course and hyponatraemia may point towards additional pituitary hormone deficiencies.
Developmental abnormality Every child with a midline facial defect should be considered at risk of having pituitary hormone deficiencies. This is because the pituitary gland is derived from midline structures and a defective development of these structures leads to an abnormal pituitary gland itself. GHD is also seen as an association with several other developmental defects.
Post cranial irradiation Initially, all children treated for a neoplastic disease show some growth failure because of both the disease itself and as a result of the radiation and/or chemotherapy. This is followed by a second phase of growth failure due to GHD, as a result of cranial and craniospinal irradiation. This GHD is directly related to the dose of the radiation received.
Failure of pubertal growth Failure of a pubertal growth spurt by mid-puberty is a feature suggestive of GHD
Pituitary abnormalities Evidence of other pituitary hormone abnormalities would suggest GHD.
Some of the developmental defects associated with GHD are shown in Panel 2.
Panel 2: Some developmental defects associated with GHD
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GH deficiency is a difficult diagnosis. It requires a combination of the above clinical and auxological parameters coupled with biochemical investigations.
GH provocation testing In view of the complex nature of pulsatile GH secretion, a single blood sample for GH measurement is not informative. Various pharmacological stimuli such as insulin, glucagon, arginine, clonidine, and GHRH are powerful stimulators of GH secretion and help to evaluate the hypothalamic-pituitary axis. These should only be conducted in specialist centres by experienced personnel. There is considerable variability in the different types of assay used to measure GH so each laboratory needs to set its own threshold for defining GHD. This adds to the difficulty and variability in the diagnosis of GHD worldwide. Finally there are false positive and negative results with any of these tests so that "normal" children with normal growth patterns can have a GH response on pharmacological testing that could support a diagnosis of GHD. Generally, a peak GH response of less than 20 mU/L or less than 5-10mg/L is considered evidence of GHD.9,10
Spontaneous GH secretion Spontaneous GH secretory studies are done by measuring blood samples every 15 to 20 minutes for 24 hours or for 12 hours overnight. Because of the laborious nature of testing, this technique remains primarily a research tool. However, it can be useful in children who have a growth pattern suggestive of GHD but normal results in stimulation studies. In such a situation, measuring GH secretion can identify a subgroup of children with growth hormone neurosecretory dysfunction (GHNSD) who are short, have a poor growth velocity, delayed bone age but normal GH results on provocation testing.11,12
Urinary GH secretion Urinary GH secretion has been found to correlate significantly with IGF-1 levels and growth velocity provided that renal function is not impaired. However, there are wide inter-day variations and difficulties with interpretation.
Other investigations Other investigations that are carried out in the diagnosis of GHD are:
Crude extracts of human growth hormone were first used to treat GHD nearly 40 years ago. With the emergence of commercially produced recombinant GH therapy (rhGH), there have been major improvements in the treatment of short children. On the other hand, there has also been an increased awareness of the need for careful evaluation of the effect and benefit of GH usage in non-GH deficient children.
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Panel 3: Current licensed indications for GH therapy in Europe
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Effects Early treatment of GHD with daily subcutaneous injections of an adequate dose of GH can, in most instances, normalise growth and will achieve an adult height within the predicted target height. The key to success is early diagnosis. Treatment commenced within the first two years of life will normalise height in the short and long term and allow the child to reach its genetic height potential. In the short term, GH therapy can restore lean body mass, reduce excess and abnormal body fat and prevent hypoglycaemia.14,15
GHD in adulthood causes increased obesity, reduces muscle tone and strength, causes low self esteem and increases the risk of cardiovascular mortality and osteoporosis. The increased cardiovascular mortality stems from an increased body fat mass, increased abdominal fat, elevated free fatty acids and elevated total and low density lipoprotein cholesterol.16,17 Recombinant GH has also made replacement therapy in these adults a feasible, albeit, in some people's eyes, a controversial option.
Dosage and method of administration There continues to be marked variability in the dosage calculation and expression worldwide. In some countries, the dosage is calculated per kg body weight, while other countries use body surface area. To complicate the situation further, the dose calculated may be expressed as either international units (IU) or as milligrams (mg). The WHO and European Pharmacopeia have implemented a change in this dosage expression from IU to mg. This change will be fully implemented by mid 2001 (3IU=1mg).
Data from previous studies indicate that a daily dosage of 0.67mg/m2 (2IU/m2) or 0.024mg/kg (0.071IU/kg) provide satisfactory catch-up and an adult height SDS (standard deviation score) between -0.5 and -1.9,10,18 The dose is administered subcutaneously and given at bedtime to mimic normal peak GH physiology.
Evening GH injections have been shown to have greater peak levels than morning administration.19
Side effects of treatment GH treatment with rhGH is essentially safe.20 There is no risk of CJD, as seen with the previous crude pituitary extracts. Benign intracranial hypertension, salt and water retention and a few cases of acute pancreatitis have been reported.21,22 A common hip disorder, slipped capital femoral epiphysis, can occur in adolescence (see Panel 4).
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Panel 4: Potential side effects of GH treatment
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Response and monitoring The response to growth hormone treatment is influenced by:
Since height at puberty also influences final height, normalisation of growth prior to the onset of puberty is important.
Careful measurements and growth velocity need to be monitored on each visit. Bone age evaluation shows an improvement in the skeletal maturation.
Panel 5: Other statural disorders for which GH has been investigated
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Approximately 8 per cent of children born small for gestational age do not catch-up and grow into short adults. Included in this group are children born with dysmorphic syndromes, such as Russel Silver syndrome.24
The Kabi International Growth Study data have clearly shown an involvement of the GH/IGF-1 axis in this lack of postnatal catch-up in children where GH secretion and/or sensitivity are decreased.25,26,27 GH treatment of these children in two multicentre studies was shown to induce catch-up growth. The response was dose dependent and greatest in younger children. The short-term growth did not occur at the expense of final height which was consistently increased.28 The dosage recommended was 0.1-0.3IU/kg/day (0.03-0.1mg/kg/day).
No data on final height are available and no controlled studies have been conducted long-term to determine final height.
Almost all girls with Turner syndrome29,30,31 have a final height of 142-147cm without treatment and demonstrate a poor growth velocity in childhood and adolescence. The reasons for the short stature are possibly a failure to respond to growth factors at a tissue level or decreased spontaneous GH secretion. A disorder of the GH/IGF-1 axis is a less likely explanation.
There is considerable controversy about GH treatment in Turner syndrome. Growth acceleration occurs with higher than normal rhGH doses (4IU/m2/day), which could favour GH insensitivity as a causative factor. Oestrogen therapy, necessary for complete physical development, causes rapid closure of the epiphysis (growing sector of the bone). It has no role in the sole treatment of short stature, although timing of its commencement can strongly influence final height.
Anabolic steroids, such as oxandrolone, have been used for a long time in the treatment of short stature. They increase growth velocity by a direct action on the growth plates in doses of 0.5mg/kg/day orally.
Oxandrolone also acts synergistically with GH for reasons that are not completely understood. Since final height in Turner syndrome is inversely correlated with age at the onset of GH therapy, oxandrolone can also shorten the duration of GH treatment by augmenting its effects.
At present there are no good randomised controlled studies to indicate the magnitude of the rhGH treatment effect in Turner syndrome.
Chronic renal failure is now a licensed indication for the use of GH.32 A combination of poor nutrition, acidosis, anaemia and GH insensitivity is thought to be responsible for the poor growth velocity in such cases. GH in a dose of 4 IU/m2/day has no adverse effect on renal function and improves growth. The best response has been seen in those children who are not severely growth retarded.
Children with skeletal dysplasias have abnormal body proportions with a shortening of either the spine, limbs or both. A diagnosis is made by skeletal survey. Several studies of GH treatment in skeletal dysplasias, such as achondroplasia and hypochondroplasia, have shown conflicting results. An initial acceleration of growth is followed by a decline and final response is only modest. The doses needed are much higher than for classical GH deficiency. Compared with limb lengthening the GH effects are disappointing and this, coupled with the potential problems of inducing further disproportionate growth, suggests that GH should not be routinely offered to these patients.
GH treatment in idiopathic short stature (where there is normal GH secretion) has been shown to accelerate bone age and puberty. Again, the initial acceleration in growth velocity was followed by a gradual decline and ultimate height increase was only about 3cm. Best responses were seen in younger children and treatment should be ideally started at the earliest opportunity and restricted to pre-puberty patients. As the overall effect is minimal and as the children are not disadvantaged by their short stature, there is no indication for treating these patients with rhGH.33,34
Steroids are used as a treatment for various chronic illnesses and they lead to growth failure. They promote catabolism, inhibit collagen syntheses, impair the action of IGF-1 and suppress GH secretion.
GH treatment increases growth velocity, especially in the first few years of treatment, in those on moderate steroid doses. However, the diabetogenic risk of GH and glucocorticoids together needs further evaluation.
GH responses in other short stature syndromes, such as Down's, and Noonan syndromes, have all shown similar responses to those observed with Turner syndrome.35
GH's role in children with catabolic states, severe burns, patients on total parenteral nutrition and paediatric intensive care units is under further trial.36 GH has been shown to promote healing and hence improve the clinical course.
Other areas of interest that might show a therapeutic response are cystic fibrosis, chronic arthritis and spina bifida.37
Panel 6 outlines the other types of interventional therapy used in GHD
Panel 6: Other interventional therapy in GHD
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It is obvious from the above studies that rhGH will be used for several conditions other than just GHD. There is controversy regarding its justification, especially where the responses are only moderate and where carefully controlled randomised studies have not been conducted.The dilemma whether or not to treat needs careful consideration of cost-benefit ratios, long-term side effects, benefits in relation to final height and other options available.
The question as to whether short children suffer physically or emotionally as a result of their short stature is debatable. Is to be taller, to be better?38
Dr Mehta is specialist registrar in paediatric endocrinology and Dr Hindmarsh is consultant paediatric endocrinologist, Great Ormond Street Hospital for Children NHS trust, London.