Aims: To determine acid-labile subunit (ALS) levels in short small for gestational age (SGA) children and to assess the relationship between ALS levels and several clinical and laboratory characteristics. Also, to assess whether adding ALS levels to a growth prediction model might improve the long-term growth prediction. Design/Methods: ALS levels were measured in 312 short SGA children at the start of growth hormone (GH) treatment. Results: Median (interquartile range) ALS of all subjects was -0.5 SDS, significantly below the 0 SDS (p < 0.001). In 34 children (11%), ALS levels were ≤-2 SDS. ALS SDS correlated significantly with height SDS (r = 0.24, p < 0.001), weight SDS (r = 0.30, p < 0.001), BMI SDS (r = 0.20, p = 0.001), IGF-I SDS (r = 0.56, p < 0.001) and IGFBP-3 SDS (r = 0.67, p < 0.001). ALS SDS was also positively correlated with fasting insulin (r = 0.41, p < 0.001) and glucose levels (r = 0.33, p < 0.001), and HOMA-IR (r = 0.35, p < 0.001). Baseline ALS levels contributed to the long-term growth prediction of GH treatment (5%, p < 0.001). Conclusion: Short SGA children tend to have lower ALS levels compared to controls, albeit less reduced than IGF-I and IGFBP-3 levels. Our data suggest that ALS may be involved in glucose homeostasis. Determination of ALS levels before the start of GH treatment in short SGA children contributes moderately to a more accurate prediction of the growth response to GH treatment.

Keywords:
Small for gestational age, Acid-labile subunit, Growth
1.
Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den Hartog H, De Muinck Keizer-Schrama SM, Drop SL: Children born small for gestational age: do they catch up? Pediatr Res 1995;38:267-271.
2.
Boguszewski M, Rosberg S, Albertsson-Wikland K: Spontaneous 24-hour growth hormone profiles in prepubertal small for gestational age children. J Clin Endocrinol Metab 1995;80:2599-2606.
3.
Sas T, de Waal W, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A: Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. J Clin Endocrinol Metab 1999;84:3064-3070.
4.
Baxter RC, Martin JL, Beniac VA: High molecular weight insulin-like growth factor binding protein complex. Purification and properties of the acid-labile subunit from human serum. J Biol Chem 1989;264:11843-11848.
5.
Ooi GT, Cohen FJ, Tseng LY, Rechler MM, Boisclair YR: Growth hormone stimulates transcription of the gene encoding the acid-labile subunit (ALS) of the circulating insulin-like growth factor-binding protein complex and ALS promoter activity in rat liver. Mol Endocrinol 1997;11:997-1007.
6.
Domene HM, Hwa V, Argente J, Wit JM, Camacho-Hubner C, Jasper HG, Pozo J, van Duyvenvoorde HA, Yakar S, Fofanova-Gambetti OV, Rosenfeld RG, International ALSCG: Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. Horm Res 2009;72:129-141.
7.
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.
8.
Domene HM, Hwa V, Jasper HG, Rosenfeld RG: Acid-labile subunit deficiency. Best Pract Res Clin Endocrinol Metab 2011;25:101-113.
9.
Arquier N, Geminard C, Bourouis M, Jarretou G, Honegger B, Paix A, Leopold P: Drosophila ALS regulates growth and metabolism through functional interaction with insulin-like peptides. Cell Metab 2008;7:333-338.
10.
de Ridder MA, Stijnen T, Hokken-Koelega AC: Prediction model for adult height of small for gestational age children at the start of growth hormone treatment. J Clin Endocrinol Metab 2008;93:477-483.
11.
Ueki I, Giesy SL, Harvatine KJ, Kim JW, Boisclair YR: The acid-labile subunit is required for full effects of exogenous growth hormone on growth and carbohydrate metabolism. Endocrinology 2009;150:3145-3152.
12.
Arends NJ, Boonstra VH, Mulder PG, Odink RJ, Stokvis-Brantsma WH, Rongen-Westerlaken C, Mulder JC, Delemarre-Van de Waal H, Reeser HM, Jansen M, Waelkens JJ, Hokken-Koelega AC: GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol (Oxf) 2003;59:779-787.
13.
Van Dijk M, Mulder P, Houdijk M, Mulder J, Noordam K, Odink RJ, Rongen-Westerlaken C, Voorhoeve P, Waelkens J, Stokvis-Brantsma J, Hokken-Koelega A: High serum levels of growth hormone and insulin-like growth factor-I during high-dose growth hormone treatment in short children born small for gestational age. J Clin Endocrinol Metab 2006;91:1390-1396.
14.
Lem AJ, Jobse I, van der Kaay DC, de Ridder MA, Raat H, Hokken-Koelega AC: Health-related quality of life in short children born small for gestational age: effects of growth hormone treatment and postponement of puberty. Horm Res Paediatr 2012;77:170-179.
15.
Usher R, McLean F: Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in seven dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74:901-910.
16.
Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ, Brugman E, Roede MJ, Verloove-Vanhorick SP, Wit JM: Continuing positive secular growth change in the Netherlands 1955-1997. Pediatr Res 2000;47:316-323.
17.
Tanner JM, Whitehouse RH: Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976;51:170-179.
18.
Yu H, Mistry J, Nicar MJ, Khosravi MJ, Diamandis A, van Doorn J, Juul A: Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation. J Clin Lab Anal 1999;13:166-172.
19.
Wit JM, van Duyvenvoorde HA, Scheltinga SA, de Bruin S, Hafkenscheid L, Kant SG, Ruivenkamp CA, Gijsbers AC, van Doorn J, Feigerlova E, Noordam C, Walenkamp MJ, Claahsen-van de Grinten H, Stouthart P, Bonapart IE, Pereira AM, Gosen J, Delemarre-van de Waal HA, Hwa V, Breuning MH, Domene HM, Oostdijk W, Losekoot M: Genetic analysis of short children with apparent growth hormone insensitivity. Horm Res Paediatr 2012;77:320-333.
20.
Cole TJ: The lms method for constructing normalized growth standards. Eur J Clin Nutr 1990;44:45-60.
21.
Hokken-Koelega AC, Hackeng WH, Stijnen T, Wit JM, de Muinck Keizer-Schrama SM, Drop SL: Twenty-four-hour plasma growth hormone profiles, urinary growth hormone excretion, and plasma insulin-like growth factor-I and -II levels in prepubertal children with chronic renal insufficiency and severe growth retardation. J Clin Endocrinol Metab 1990;71:688-695.
22.
Rikken B, van Doorn J, Ringeling A, Van den Brande JL, Massa G, Wit JM: Plasma levels of insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation of childhood growth hormone deficiency. Horm Res 1998;50:166-176.
23.
Levy JC, Matthews DR, Hermans MP: Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998;21:2191-2192.
24.
Arends NJ, Boonstra VH, Duivenvoorden HJ, Hofman PL, Cutfield WS, Hokken-Koelega AC: Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age. Clin Endocrinol (Oxf) 2005;62:44-50.
25.
Juul A, Moller S, Mosfeldt-Laursen E, Rasmussen MH, Scheike T, Pedersen SA, Kastrup KW, Yu H, Mistry J, Rasmussen S, Muller J, Henriksen J, Skakkebaek NE: The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency. J Clin Endocrinol Metab 1998;83:4408-4415.
26.
Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebaek NE: Serum insulin-like growth factor-I in 1,030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 1994;78:744-752.
27.
Baxter RC: Circulating levels and molecular distribution of the acid-labile (α) subunit of the high molecular weight insulin-like growth factor-binding protein complex. J Clin Endocrinol Metab 1990;70:1347-1353.
28.
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.
29.
Van Duyvenvoorde HA, Kempers MJ, Twickler TB, van Doorn J, Gerver WJ, Noordam C, Losekoot M, Karperien M, Wit JM, Hermus AR: Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. Eur J Endocrinol 2008;159:113-120.
30.
Fofanova-Gambetti OV, Hwa V, Wit JM, Domene HM, Argente J, Bang P, Hogler W, Kirsch S, Pihoker C, Chiu HK, Cohen L, Jacobsen C, Jasper HG, Haeusler G, Campos-Barros A, Gallego-Gomez E, Gracia-Bouthelier R, van Duyvenvoorde HA, Pozo J, Rosenfeld RG: Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium. J Clin Endocrinol Metab 2010;95:4184-4191.
31.
Albertsson-Wikland K, Rosberg S, Karlberg J, Groth T: Analysis of 24-hour growth hormone profiles in healthy boys and girls of normal stature: relation to puberty. J Clin Endocrinol Metab 1994;78:1195-1201.
32.
Fofanova-Gambetti OV, Hwa V, Kirsch S, Pihoker C, Chiu HK, Hogler W, Cohen LE, Jacobsen C, Derr MA, Rosenfeld RG: Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins. Horm Res 2009;71:100-110.
33.
Bang P, Fureman A, Nilsson A, Boström J, Kriström B, Ekström K, Hwa V, Rosenfeld RG, Carlsson-Skwirut C: A novel missense mutation of the ALSIGF gene causing a L172F substitution in LRR6 is associated with short stature in two Swedish children homozygous or compound heterozygous for the mutation. Horm Res 2009;72(suppl 3):86.
34.
Iniguez G, Argandona F, Medina P, Gonzalez C, San Martin S, Kakarieka E, Johnson MC, Cassorla F: Acid-labile subunit gene expression and protein content in human placentas: differences according to birth weight. J Clin Endocrinol Metab 2011;96:187-191.
35.
Fukuda I, Hotta M, Hizuka N, Takano K, Ishikawa Y, Asakawa-Yasumoto K, Tagami E, Demura H: Decreased serum levels of acid-labile subunit in patients with anorexia nervosa. J Clin Endocrinol Metab 1999;84:2034-2036.
36.
Dai J, Baxter RC: Regulation in vivo of the acid-labile subunit of the rat serum insulin-like growth factor-binding protein complex. Endocrinology 1994;135:2335-2341.
37.
Clayton P, Bonnemaire M, Dutailly P, Maisonobe P, Naudin L, Pham E, Zhang Z, Grupe A, Thiagalingam A, Denefle P, the ESG: Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study. J Clin Endocrinol Metab 2013;98:E1122-E1130.
38.
De Waal WJ, Hokken-Koelega AC, Stijnen T, de Muinck Keizer-Schrama SM, Drop SL: Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone. Clin Endocrinol (Oxf) 1994;41:621-630.
39.
Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A: Adult height after long-term, continuous growth hormone treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response growth hormone trial. J Clin Endocrinol Metab 2003;88:3584-3590.
© 2014 S. Karger AG, Basel
2014
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.