Background: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. Design and Methods: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. Results: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; –0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. Conclusions: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.

Keywords:
Acid-labile subunit, Insulin-like growth factor-I, Insulin-like growth factor binding protein, Growth hormone insensitivity, Pubertal delay
1.
Daughaday WH, Rotwein P: Insulin-like growth factor I and II. Peptide, messenger ribonucleic acid and gene structures, serum and tissues concentrations. Endocr Rev 1989;10:68–91.
2.
Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A: Mice carrying null mutations for the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993;75:59–72.
3.
Woods KA, Camacho-Hubner C, Savage MO, Clark AJ: Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996;335:1363–1367.
4.
Bonapace G, Concolino D, Formicola S, Strisciuglio P: A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Gen 2003;40:913–917.
5.
Salmon WD Jr, Daughaday WH: A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 1957;49:825–836.
6.
D’Ercole AJ, Applewhite GT, Underwood LE: Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol 1980;75:315–328.
7.
Isaksson OG, Jansson JO, Gause IA: Growth hormone stimulates longitudinal bone growth directly. Science 1982;216:1237–1239.
8.
Green H, Morikawa M, Nixon T: A dual effector theory of growth-hormone action. Differentiation 1985;29:195–198.
9.
Le Roith D, Bondy C, Yakar S, Liu JL, Butler A: The somatomedin hypothesis: 2001. Endocr Rev 2001;22:53–74.
10.
Sjögren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Tornell J, Isaksson OG, Jansson JO, Ohlsson C: Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal growth in mice. Proc Natl Acad Sci USA 1999;96:7088–7092.
11.
Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D: Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 1999;96:7324–7329.
12.
Ueki I, Ooi GT, Tremblay ML, Hurst KR, Bach LA, Boisclair YR: Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. Proc Natl Acad Sci USA 2000;97:6868–6873.
13.
Domené HM, Bengolea SV, Martínez AS, Ropelato MG, Pennisi P, Scaglia P, Heinrich JJ, Jasper HG: Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004;350:570–577.
14.
Lejarraga H, Orfila G: Estándares de peso y estatura para niñas y niños argentinos desde el nacimiento hasta la madurez. Arch Arg Ped 1987;85:209–222.
15.
Marshall WA, Tanner JM: Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23.
16.
Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist, ed 2. Stanford, Stanford University Press, 1959.
17.
Heuck C, Chen JW, Wolthers OD, Frystyk J: Fasting serum levels of free and bioactive IGF-I during the pubertal development. ESPE/LWPES 7th Joint Meeting on Paediatric Endocrinology, Lyon, France (abstract). Horm Res 2005;64(suppl 1):32.
18.
Frystyk J, Dinesen B, Ørskov H: Non-competitive time resolved immunofluorometric assays for determination of human insulin-like growth factors I and II. Growth Regul 1995;5:169–176.
19.
Frystyk J, Skjaerbaek C, Dinesen B, Ørskov H: Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Lett1994;348:185–191.
20.
Chen J-W, Ledet T, Ørskov H, Jessen N, Lund S, Whittaker J, De Meyts P, Larsen MB, Christiansen JS, Frystyk J: A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. Am J Physiol Endocrinol Metab 2003;284:E1149–E1155.
21.
Krassas GE, Pontikides N, Kaltsas T, Dumas A, Frystyk J, Chen JW, Flyvbjerg A: Free and total insulin-like growth factor (IGF)-I, -II, and IGF-binding protein-1, -2, and -3 serum levels in patients with active thyroid eye disease. J Clin Endocrinol Metab 2003;88:132–135.
22.
Khosravi MJ, Diamandi A, Mistry J, Krishna RG, Khare A: Acid-labile subunit of human insulin-like growth factor-binding protein complex: measurement, molecular, and clinical evaluation. J Clin Endocrinol Metab 1997;82:3944–3951.
23.
LeRoith D, Scavo L, Butler A: What is the role of circulating IGF-I? Trends Endocrinol Metab 2001;12:48–52.
24.
Haluzik M, Yakar S, Gavrilova O, Setser J, Boisclair Y, LeRoith D: Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes 2003;52:2483–2489.
25.
Daughaday WH: Free insulin-like growth factor (IGF) in disorders of IGF binding protein 3 complex formation. J Clin Endocrinol Metab 2004;89:3–5.
26.
Zapf J, Walter H, Froesch ER: Radioimmunological determination of insulin-like growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia. J Clin Invest 1981;68:1321–1330.
27.
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;323:1367–1374.
28.
Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Jasper H, Tepper A, Henrich JJ, Rosenfeld RG: Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003;349:1139–1147.
29.
Woods KA, Clark AJ, Amselem S, Savage MO: Relationship between phenotype and genotype in growth hormone insensitivity syndrome. Acta Paediatr Suppl 1999;88:158–162.
30.
Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D: Circulating levels of IGF-I directly regulate bone growth and density. J Clin Invest 2002;110:771–781.
31.
Ning Y, Schuller AGP, Bradshaw S, Rotwein P, Ludwig T, Frystyk J, Pintar JE: Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. Mol Endocrinol 2006;20:2173–2186.
32.
Hwa V, Haeusler G, Pratt KL, Little BM, Frisch H, Koller D, Rosenfeld RG: Total absence of functional acid labile subunit (ALS), resulting in severe IGF deficiency and moderate growth failure. J Clin Endocrinol Metab 2006;91:1826–1831.
33.
Payet LD, Firth SM, Baxter RC: The role of the acid-labile subunit in regulating insulin-like growth factor transport across human umbilical vein endothelial cell monolayers. J Clin Endocrinol Metab 2004;89:2382–2389.
34.
Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA: Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol 2004;180:247–255.
35.
Nilsson O, Baron J: Impact of growth plate senescence on catch-up growth and epiphyseal fusion. Pediatr Nephrol 2005;20:319–322.
36.
Boisclair YR, Rhoads RP, Ueki I, Wang J, Ooi GT: The acid-labile subunit (ALS) of the 150-kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. J Endocrinol 2001;170:63–70.
37.
Hiney JK, Ojeda SR, Dees WL: Insulin-like growth factor I: a possible metabolic signal involved in the regulation of female puberty. Neuroendocrinol1991;54:420–423.
38.
Hiney JK, Srivastava V, Nyberg CL, Ojeda SR, Dees WL: Insulin-like growth factor I of peripheral origin acts centrally to accelerate the initiation of female puberty. Endocrinology 1996;137:3717–3728.
39.
Kasson BG, Hsueh AJ: Insulin-like growth factor-I augments gonadotropin-stimulated androgen biosynthesis by cultured rat testicular cells. Mol Cell Endocrinol 1987;52:27–34.
40.
Daughaday WH, Domené HM, Martínez A, Jasper HG: Circulating IGF-I deficiency and inactivation of the acid-labile subunit gene. N Engl J Med 2004;350:1906.
41.
Domené HM, Scaglia P, Lteif A, Mahmud F, Kirmani S, Bedecarrás P, Gutiérrez M, Jasper H: Two novel IGFALS gene mutations in a patient presenting with IGF-I deficiency, delay of growth and pubertal development. ESPE/LWPES 7th Joint Meeting on Paediatric Endocrinology, Lyon, France (abstract). Horm Res 2005;64(suppl 1):31.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.