Growth hormone insensitivity - NCBI

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The term growth hormone insensitivity describes a group of disorders, both inherited .... growth hormone treatment may promote growth in mild growth hormone ...
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4 Lister G, Flack I. Developing NHS Direct. A scoping study commissioned by the Operational Research Branch of the NHS Executive HQ and supported by Coopers & Lybrand, and the South Thames Regional HIS Consortium. London: College of Health, 1998. 5 Department of Health. Single phone line could access all NHS services. October 1998. [Press release 98/435]. 6 Munro J, Nicholl J, O’Cathain A, Knowles E. Evaluation of NHS Direct first wave sites. First interim report to the Department of Health. SheYeld: Medical Care Research Unit, University of SheYeld, 1998. 7 Poole SR, Schmitt BD, Carruth T, Peterson-Smith A, Slusarski M. After hours telephone coverage: the application of an area wide telephone triage and advice system for pediatric practices. Pediatrics 1993;92:670–9. 8 Lattimer V, George S, Thompson F, et al. Safety and eVectiveness of nurse telephone consultation in out of hours primary care: randomised controlled trial. BMJ 1998;317:1054–9. 9 Foster J, Jessop L, Dale J. Concerns and confidence of general practitioners in providing telephone consultations. Br J Gen Pract 1999;49:111–13. 10 Wachter DA, Brillman JC, Lewis J, Sapien RE. Pediatric telephone triage protocols: standardised decisionmaking or a false sense of security? Ann Emerg Med 1999;33:388–94. 11 Hopton J, Hogg R, McKee I. Patients accounts of calling the doctor out of hours: qualitative study in one general practice. BMJ 1996;313:991–4. 12 Leprohon J. Decision making strategies for telephone triage in emergency medical services. Med Decis Making 1995;15:240–53.

13 Accident and emergency services for children: report of a multidisciplinary working party. London: Royal College of Paediatrics and Child Health, 1999. 14 Hart C, Chesson R. Children as consumers. BMJ 1998;316:1600–3. 15 NHS Executive. Protecting and using patient information: consultation document on a national framework. February 1999. http://www.doh.gov.uk/confiden/ patinfo.htm 16 Brahams D, Wyatt J. Decision aids and the law. Lancet 1989;ii:632–4. 17 Hurwitz B. Legal and political considerations of clinical guidelines. BMJ 1999;318:661–4. 18 Kai J. Parents’ diYculties and information needs in coping with acute illness in preschool children: a qualitative study. BMJ 1996;313:987–90. 19 Kai J. What worries parents when their preschool children are acutely ill, and why: a qualitative study. BMJ 1996;313:983–6. 20 Department of Health. New opportunities for NHS Direct. 13 April 1999. [Press release 1999/0227]. 21 Thompson H, Ross S, Wilson P, McConnachie, Watson R. Randomised controlled trial of eVect of Baby Check on the use of health services in first 6 months of life. BMJ 1999;318:1740–4. 22 Jewell D. Helping parents identify severe illness in their children [editorial]. BMJ 1999;318:1711–12. 23 Macfarlane A. Rationing in child health services: a personal view [editorial]. Arch Dis Child 1999;81:1–4.

Growth hormone insensitivity: a widening diagnosis 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 insensitivity3 was 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.4–7 Biochemical 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,9 and lack of a mitogenic response to growth hormone in T lymphocytes from aVected 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 diVerent 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.18 Because 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.22 Some 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,

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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 eVect 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 eVective 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 eVective 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. 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.

RAGNAR BJARNASON MARTIN O SAVAGE Paediatric Endocrinology Section, Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE, UK 1 Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 1994;15:369–90. 2 Savage MO, Rosenfeld RG. Growth hormone insensitivity: a proposed revised classification. Acta Paediatr Suppl 1999;478:147. 3 Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone-a new in born error of metabolism. Isr J Med Sci 1966;2:152–5. 4 Rosenbloom AL, Guevara Aguirre J, Rosenfeld RG, Fielder PJ. The little women of Loja—growth hormone-receptor deficiency in an inbred population of southern Ecuador. N Engl J Med 1990;323:1367–74. 5 Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Diamond Jr FB, Rosenfeld RG. Growth hormone receptor deficiency in Ecuador: clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab 1993;76:417–23.

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6 Yordam N, Kandemir N, Erkul I, Kurdoglu S, Hatun S. Review of Turkish patients with growth hormone insensitivity (Laron type). Eur J Endocrinol 1995;133:539–42. 7 Laron Z. Laron syndrome-Primary growth hormone resistance. In: Jameson JL, ed. Contemporary endocrinology: hormone resistance syndromes. Totowa, NJ: Humana Press Inc, 1999:17–37. 8 Cotterill AM, Holly JM, Taylor AM, et al. The insulin-like growth factor (IGF)-binding proteins and IGF bioactivity in Laron-type dwarfism. J Clin Endocrinol Metab 1992;74:56–63. 9 Eshet R, Laron Z, Pertzelan A, Arnon R, Dintzman M. Defect of human growth hormone receptors in the liver of two patients with Laron-type dwarfism. Isr J Med Sci 1984;20:8–11. 10 GeVner ME, Golde DW, Lippe BM, Kaplan SA, Bersch N, Li CH. Tissues of the Laron dwarf are sensitive to insulin-like growth factor I but not to growth hormone. J Clin Endocrinol Metab 1987;64:1042–6. 11 Godowski PJ, Leung DW, Meacham LR, et al. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc Natl Acad Sci USA 1989;86:8083–7. 12 Leung DW, Spencer SA, Cachianes G, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature 1987;330:537–43. 13 Amselem S, Duquesnoy P, Attree O, et al. Laron dwarfism and mutations of the growth hormone-receptor gene. N Engl J Med 1989;321:989–95. 14 Rosenbloom AL, Guevara-Aguirre J. Lessons from the genetics of Laron syndrome. Trends Endocrinol Metab 1998;9:271–83. 15 Woods KA, Dastot F, Preece MA, et al. Phenotype: genotype relationships in growth hormone insensitivity syndrome. J Clin Endocrinol Metab 1997;82: 3529–35. 16 Laron Z, Klinger B, Erster B, Anin S. EVect of acute administration of insulin-like growth factor I in patients with Laron-type dwarfism. Lancet 1988;ii:1170–2. 17 Ranke M, Savage MO, Chatelain P, Preece MA, Rosenfeld RG, Wilton P. Treatment of growth hormone insensitivity syndrome with insulin-like growth factor I: long-term results of the European multicentre study. Horm Res. [In press.] 18 Savage MO, Blum WF, Ranke MB, et al. Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab 1993;77:1465–71. 19 Blum WF, Cotterill AM, Postel-Vinay MC, Ranke MB, Savage MO, Wilton P. Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls. Pharmacia Study Group on Insulin-like Growth Factor I Treatment in Growth Hormone Insensitivity Syndromes. Acta Paediatr Suppl 1994;399:117–24. 20 Woods KA, Dastot F, Preece MA, et al. Phenotype:genotype relationships in growth hormone insensitivity syndrome. J Clin Endocrinol Metab 1997;82: 3529–35. 21 Carlsson LM. Partial growth hormone insensitivity in childhood. In: Ross RJM, Savage MO, eds. Growth hormone resistance. Baillières Clinical Endocrinology and Metabolism. London: Baillière Tindall, 1996:389–400. 22 Johnston LB, Savage MO. The broad spectrum of genetic growth hormone insensitivity: from Laron syndrome to idiopathic short stature. In: Ranke MB, Wilton P, eds. Growth hormone therapy in KIGS—10 years’ experience. Heidelberg-Leipzig: Johann Ambrosius Barth Verlag, 1999:125–34. 23 Cotterill AM, Camacho-Hubner C, Duquesnoy P, Savage MO. Changes in serum IGF-I and IGFBP-3 concentrations during the IGF-I generation test performed prospectively in children with short stature. Clin Endocrinol 1998;48:719–24. 24 Goddard AD, Dowd P, Chernausek S, et al. Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature. J Pediatr 1997;131:51–5. 25 Goddard AD, Covello R, Luoh SM, et al. Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med 1995;333: 1093–8. 26 Ayling RM, Ross R, Towner P, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet 1997;16: 13–4. 27 Iida K, Takahashi Y, Kaji H, et al. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab 1998;83:531–7. 28 Iida K, Takahashi Y, Kaji H, et al. Functional characterisation of trauncated growth hormone (GH) receptor- (1–277) causing partial GH insensitivity syndrome with high GH-binding protein. J Clin Endocrinol Metab 1999;84: 1011–16. 29 Kristrom B, Karlberg J, Albertsson-Wikland K. Prediction of the growth response of short prepubertal children treated with growth hormone. Swedish Paediatric Study Group for GH treatment. Acta Paediatrica 1995; 84:51–7. 30 Jenkins RC, Ross RJ. Acquired growth hormone resistance in catbolic states. In: Ross RJM, Savage MO, eds. Growth hormone resistance. Baillières Clinical Endocrinology and Metabolism. London: Baillière Tindall, 1996:411–20. 31 Davies UM, Jones J, Reeve J, et al. Juvenile rheumatiod arthritis- EVects of disease activity and recombinant human growth hormone on insulin-like growth factor 1, insulin-like growth factor binding proteins 1 and 3, and osteocalcin. Arthritis Rheum 1997;40:332–40. 32 Beattie RM, Camacho-Hübner C, Wacharasindhu S, Cotteril AM, WalkerSmith JA, Savage MO. Responsiveness of IGF-I and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn’s disease. Clin Endocrinol 1998;49:483–9. 33 Buzi F, Bontempelli AM, Alberti D, et al. Growth, insulin-like growth factor I (IGF-I), and IGF-binding proteins 1 and 3 in children with severe liver disease before and after liver transplantation: a longitudinal and cross-sectional study. Pediatr Res 1998;43:478–83. 34 Bjarnason R, Wickelgren R, Hermansson M, Hammarqvist F, Carlsson B, Carlsson LMS. Growth hormone treatment prevents the decrease in IGF-I gene expression in patients undergoing abdominal surgery. J Clin Endocrinol Metab 1998;83:1566–72. 35 Jansson U, Bjarnason R, Kristiansson B, Albertsson-Wikland K. Changes in IGF-I, IGFBP-3 and leptin in children during standardized five week gluten provocation. Horm Res 1998;50:P30. 36 Bjarnason R, Jansson U, Kristiansson B, Albertsson-Wikland K. Growth hormone secretion in children during standardized five week gluten provocation. Horm Res 1998;50:P77.