Article Text

Growth hormone insensitivity: a widening diagnosis
  1. RAGNAR BJARNASON,
  2. MARTIN O SAVAGE
  1. Paediatric Endocrinology Section, Department of Endocrinology
  2. St Bartholomew’s Hospital, London EC1A 7BE, UK

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    The term growth hormone insensitivity describes a group of disorders, both inherited and acquired, in which there are clinical and endocrine features of insulin-like growth factor I (IGF-I) deficiency and resistance to exogenous human growth hormone, associated with growth hormone secretion that would not be considered abnormally low.1 2 In childhood, the principal result of growth hormone insensitivity is the failure of postnatal growth, leading, if untreated, to adult short stature. This group of disorders classified as growth hormone insensitivity however is becoming larger and more heterogeneous, as diagnostic methods improve and molecular analysis is applied to a wider range of patients with short stature.

    The original description of growth hormone insensitivity3was of a genetic dysmorphic syndrome (Laron syndrome) characterised by extreme short stature, spontaneous hypoglycaemia, abnormal craniofacial development, microphallus in boys, and final adult height of 120–130 cm (less than −5 SDS (standard deviation score)). Several series of patients, mostly originating in consanguineous populations of Middle Eastern origin, have since been described.4-7Biochemical features in this classic form of growth hormone insensitivity consist of raised growth hormone secretion contrasting with low concentrations of serum IGF-I and IGF binding protein 3 (IGFBP-3).1 8 The primary defect in Laron syndrome was demonstrated to be at the level of the growth hormone receptor (GHR), with failure of growth hormone binding to hepatocytes,9and lack of a mitogenic response to growth hormone in T lymphocytes from affected subjects.10 The term GHR deficiency has since also been applied to this disorder.

    For about 20 years since its original description, Laron syndrome remained a very rare untreatable condition. In the late 1980s two pivotal developments occurred, which were to refocus attention on this disorder and subsequently transform the field of growth hormone insensitivity. First, cloning of the GHR in 1987 led to the identification of the first molecular defects of the GHR gene in Laron syndrome.11-13 We now know that most mutations occur in exons coding for the extracellular domain of the GHR, but also that GHR deficiency is genetically heterogeneous with over 30 different mutations described14 including several in the intracellular domain of the receptor.15

    The second development was the availability of recombinant IGF-I for human use. Naturally Laron syndrome, with its severe deficiency of IGF-I, became the prototype disorder in which to conduct early therapeutic trials. IGF-I treatment was soon demonstrated to accelerate linear growth.16 17 The potential for treatment led to a renewed interest in Laron syndrome resulting in the collection of a large, predominantly European series of 82 patients, fulfilling strict biochemical criteria for growth hormone insensitivity.18Because this series was assembled according to biochemical criteria,19 a new clinical and biochemical heterogeneity in patients with growth hormone insensitivity emerged. Height SDS varied from −2.2 to −10.4 and IGFBP-3 SDS from −1.4 to −14.9, these two variables being positively correlated.20 A group of patients with normal growth hormone binding protein (GHBP) values was also identified. Extremes of physical appearance were seen with the classic Laron syndrome phenotype at the severe end and children of completely normal appearance at the mild end of the spectrum. Growth hormone insensitivity was no longer a clearly defined clinical entity.

    The possibility of growth hormone insensitivity occurring in children with short stature who did not have features of Laron syndrome led to the search for biochemical and molecular evidence of growth hormone resistance as a cause of idiopathic short stature (ISS). The demonstration of low GHBP associated with subnormal IGF-I and raised growth hormone secretion resulted in the emergence of so called “partial growth hormone insensitivity”.21 We suggest that a spectrum of growth hormone sensitivity exists that is negatively correlated with quantitative growth hormone secretion—that is, sensitivity to growth hormone is highest in growth hormone deficiency states whereas if growth hormone sensitivity decreases, growth hormone secretion becomes raised as a compensatory mechanism.22Some children might also be short because of failure to increase their growth hormone secretion to match a decrease in sensitivity.

    The biochemical features of partial growth hormone insensitivity are however not yet defined. We have studied two pairs of siblings from a consanguineous family with growth hormone insensitivity and normal appearance who have severely raised growth hormone secretion (Bjarnason, unpublished data, 1999). We have also performed IGF-I generation tests in a series of patients with ISS23; however, it is likely that a modification of the test using a lower dose of human growth hormone and more frequent sampling of IGF-I and IGFBP-3 will increase its specificity for mild degrees of growth hormone insensitivity.

    Goddard and colleagues24 25 have reported heterozygous mutations of the GHR gene in some cases of ISS, although this appears to be a rare cause of short stature. Perhaps the most conclusive proof of genetic defects causing ISS is from the families described by Ayling and colleagues26 and Iida et al, 27 28 where a dominant negative effect of heterozygous GHR mutations on GHR function was demonstrated. The field of partial growth hormone insensitivity associated with ISS remains wide open and relatively unexplored. The lack of growth response to human growth hormone in some growth hormone deficient patients is also a relatively common event and remains largely unexplained.29

    Finally, it is now recognised that acquired growth hormone insensitivity may occur in a number of clinical situations. Predominant among these are states of acute catabolism, such as in intensive care patients.30 Growth hormone insensitivity in acute illness has been much more widely studied in adults; however, the same biochemical features are present in genetic states (high growth hormone and low IGF-I). Growth hormone insensitivity of varying degrees is also seen in other acquired disorders such as juvenile chronic arthritis,31 Crohn’s disease,32 and advanced liver disease.33 When studying these conditions it is worth noting that the changes in growth hormone sensitivity might be tissue specific and not necessarily reflected in markers of growth hormone action such as serum IGF-I.34 For example, in coeliac disease there may be an acquired defect in growth hormone sensitivity.35 36 Successful treatment of the chronic illness may lead to resolution of the growth hormone insensitivity. Studies identifying mechanisms behind growth failure in chronic disease states will increase our understanding of the regulation of normal growth, making diagnostic tests in short stature more precise.

    Consequently, growth hormone insensitivity is becoming recognised in a wide range of paediatric disorders. The effective treatment, aimed to promote linear growth, in these disorders is currently being thwarted by lack of supplies of recombinant IGF-I. Although high dose human growth hormone treatment may promote growth in mild growth hormone insensitivity, treatment with IGF-I is clearly effective on a long term basis in severe GHR deficiency.17 However, the absence of a major indication for IGF-I treatment is restricting its commercial production and hence its use in a wider range of growth hormone insensitive states.

    Acknowledgments

    RB was generously supported by grants from the Swedish Medical Research Council, Wellcome Trust, Royal Swedish Academy of Sciences, The Royal Society, Göteborg University Jubleumsfond, Swedish Medical Society.

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