Background: The insulin-like growth factor (IGF) receptor (IGF1R) is essential for normal development and growth. IGF1R mutations cause IGF-1 resistance resulting in intrauterine and postnatal growth failure. The phenotypic spectrum related to IGF1R mutations remains to be fully understood. Methods: Auxological and endocrinological data of a patient identified previously were assessed. The patient's fibroblasts were studied to characterize the IGF1R deletion, mRNA fate, protein expression and signalling capabilities. Results: The boy, who carries a heterozygous IGF1R exon 6 deletion caused by Alu element-mediated recombination and a heterozygous SHOX variant (p.Met240Ile), was born appropriate for gestational age but developed proportionate short stature postnatally. IGF-1 levels were low-normal. None of the stigmata associated with SHOX deficiency or sporadically observed in IGF1R mutation carriers were present. Nonsense-mediated mRNA decay led to a substantial decline of IGF1R dosage and IGF-1-dependent receptor autophosphorylation but not impaired downstream signalling. Conclusion: We present the first detailed report of an intragenic IGF1R deletion identified in a patient who, apart from short stature, deviates from all established markers that qualify a growth-retarded child for IGF1R analysis. Although such children will usually escape routine clinical mutation screenings, they can contribute to the understanding of factors and mechanisms that cooperate with the IGF1R.

Keywords:
Short stature, Insulin-like growth factor receptor type 1, Mutation, Insulin-like growth factor resistance, Nonsense-mediated mRNA decay, Short stature homeobox gene
1.
Durand C, Rappold GA: Height matters - from monogenic disorders to normal variation. Nat Rev Endocrinol 2013;9:171-177.
2.
Wit JM, Kiess W, Mullis P: Genetic evaluation of short stature. Best Pract Res Clin Endocrinol Metab 2011;25:1-17.
3.
Gibson G: Rare and common variants: twenty arguments. Nat Rev Genet 2011;13:135-145.
4.
Kemper KE, Visscher PM, Goddard ME: Genetic architecture of body size in mammals. Genome Biol 2012;13:244.
5.
Pfäffle R, Kiess W, Klammt J: Downstream insulin-like growth factor. Endocr Dev 2012;23:42-51.
6.
Labarta JI, Barrio E, Audi L, Fernandez-Cancio M, Andaluz P, de Arriba A, Puga B, Calvo MT, Mayayo E, Carrascosa A, Ferrandez-Longas A: Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I receptor (IGF1R) gene. Clin Endocrinol (Oxf) 2013;78:255-262.
7.
Gannage-Yared MH, Klammt J, Chouery E, Corbani S, Megarbane H, Abou GJ, Choucair N, Pfaffle R, Megarbane A: Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. Eur J Endocrinol 2013;168:K1-K7.
8.
Rudaks LI, Nicholl JK, Bratkovic D, Barnett CP: Short stature due to 15q26 microdeletion involving IGF1R: report of an additional case and review of the literature. Am J Med Genet 2011;155:3139-3143.
9.
Fang P, Cho YH, Derr MA, Rosenfeld RG, Hwa V, Cowell CT: Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). J Clin Endocrinol Metab 2012;97:E243-E247.
10.
Kansra AR, Dolan LM, Martin LJ, Deka R, Chernausek SD: IGF receptor gene variants in normal adolescents: effect on stature. Eur J Endocrinol 2012;167:777-781.
11.
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr: Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995;16:143-163.
12.
Laviola L, Natalicchio A, Giorgino F: The IGF-I signaling pathway. Curr Pharm Des 2007;13:663-669.
13.
Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, Nordsiek G, Heinrich U, Breuning MH, Ranke MB, Rosenthal A, Ogata T, Rappold GA: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997;16:54-63.
14.
Huber C, Rosilio M, Munnich A, Cormier-Daire V: French SHOX GeNeSIS Module. High incidence of SHOX anomalies in individuals with short stature. J Med Genet 2006;43:735-739.
15.
Marchini A, Rappold G, Schneider KU: SHOX at a glance: from gene to protein. Arch Physiol Biochem 2007;113:116-123.
16.
Rao E, Blaschke RJ, Marchini A, Niesler B, Burnett M, Rappold GA: The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Hum Mol Genet 2001;10:3083-3091.
17.
Marchini A, Daeffler L, Marttila T, Schneider KU, Blaschke RJ, Schnölzer M, Rommelaere J, Rappold G: Phosphorylation on Ser106 modulates the cellular functions of the SHOX homeodomain protein. J Mol Biol 2006;355:590-603.
18.
Marchini A, Hacker B, Marttila T, Hesse V, Emons J, Weiss B, Karperien M, Rappold G: BNP is a transcriptional target of the short stature homeobox gene SHOX. Hum Mol Genet 2007;16:3081-3087.
19.
Decker E, Durand C, Bender S, Rodelsperger C, Glaser A, Hecht J, Schneider KU, Rappold G: FGFR3 is a target of the homeobox transcription factor SHOX in limb development. Hum Mol Genet 2011;20:1524-1535.
20.
Caliebe J, Broekman S, Boogaard M, Bosch CA, Ruivenkamp CA, Oostdijk W, Kant SG, Binder G, Ranke MB, Wit JM, Losekoot M: IGF1, IGF1R and SHOX mutation analysis in short children born small for gestational age and short children with normal birth size (idiopathic short stature). Horm Res Paediatr 2012;77:250-260.
21.
Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB: Serum levels of insulin-like growth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 1993;76:1610-1616.
22.
Wallborn T, Wuller S, Klammt J, Kruis T, Kratzsch J, Schmidt G, Schlicke M, Muller E, van de Leur HS, Kiess W, Pfaffle R: A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 2010;95:2316-2324.
23.
Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD: IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211-2222.
24.
Vashisth H, Abrams CF: All-atom structural models for complexes of insulin-like growth factors IGF1 and IGF2 with their cognate receptor. J Mol Biol 2010;400:645-658.
25.
Deininger PL, Batzer MA: Alu repeats and human disease. Mol Genet Metab 1999;67:183-193.
26.
Sen SK, Han K, Wang J, Lee J, Wang H, Callinan PA, Dyer M, Cordaux R, Liang P, Batzer MA: Human genomic deletions mediated by recombination between Alu elements. Am J Hum Genet 2006;79:41-53.
27.
Maquat LE: Nonsense-mediated mRNA decay in mammals. J Cell Sci 2005;118:1773-1776.
28.
Fang P, Schwartz ID, Johnson BD, Derr MA, Roberts CT Jr, Hwa V, Rosenfeld RG: Familial short stature caused by haploinsufficiency of the insulin-like growth factor I receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab 2009;94:1740-1747.
29.
Raile K, Klammt J, Schneider A, Keller A, Laue S, Smith R, Pfaffle R, Kratzsch J, Keller E, Kiess W: Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor I receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R. J Clin Endocrinol Metab 2006;91:2264-2271.
30.
Choi JH, Kang M, Kim GH, Hong M, Jin HY, Lee BH, Park JY, Lee SM, Seo EJ, Yoo HW: Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2-qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure. J Clin Endocrinol Metab 2011;96:E130-E134.
31.
Klammt J, Kiess W, Pfaffle R: IGF1R mutations as cause of SGA. Best Pract Res Clin Endocrinol Metab 2011;25:191-206.
32.
Siebler T, Lopaczynski W, Terry CL, Casella SJ, Munson P, De LDD, Phang L, Blakemore KJ, McEvoy RC, Kelley RI, et al: Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15. J Clin Endocrinol Metab 1995;80:3447-3457.
33.
Walenkamp MJ, de Muinck Keiser-Schrama SM, de Mos M, Kalf ME, van Duyvenvoorde HA, Boot AM, Kant SG, White SJ, Losekoot M, Den Dunnen JT, Karperien M, Wit JM: Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2-qter deletion detected by multiplex ligation probe amplification. J Clin Endocrinol Metab 2008;93:2421-2425.
34.
Ester WA, van Duyvenvoorde HA, de Wit CC, Broekman AJ, Ruivenkamp CA, Govaerts LC, Wit JM, Hokken-Koelega AC, Losekoot M: Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype. J Clin Endocrinol Metab 2009;94:4717-4727.
35.
Okubo Y, Siddle K, Firth H, O'Rahilly S, Wilson LC, Willatt L, Fukushima T, Takahashi S, Petry CJ, Saukkonen T, Stanhope R, Dunger DB: Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab 2003;88:5981-5988.
36.
Kruis T, Klammt J, Galli-Tsinopoulou A, Wallborn T, Schlicke M, Muller E, Kratzsch J, Korner A, Odeh R, Kiess W, Pfaffle R: Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 2010;95:1137-1142.
37.
Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, Ohtsuka Y, Hisatome I, Ninomoya H, Nanba E, Fukushima T, Takahashi S: Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab 2005;90:4679-4687.
38.
Rappold G, Blum WF, Shavrikova EP, Crowe BJ, Roeth R, Quigley CA, Ross JL, Niesler B: Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007;44:306-313.
39.
Ranke MB: Towards a consensus on the definition of idiopathic short stature. Horm Res 1996;45(suppl 2):64-66.
40.
Wit JM, Oostdijk W, Losekoot M: Spectrum of insulin-like growth factor deficiency. Endocr Dev 2012;23:30-41.
41.
Wit JM, van Duyvenvoorde HA, Scheltinga SA, de Bruin S, Hafkenscheid L, Kant SG, Ruivenkamp CAL, Gijsbers ACJ, 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, Domené HM, Oostdijk W, Losekoot M: Genetic analysis of short children with apparent growth hormone insensitivity. Horm Res Paediatr 2012;77:320-333.
42.
Muller E, Dunstheimer D, Klammt J, Friebe D, Kiess W, Kratzsch J, Kruis T, Laue S, Pfaffle R, Wallborn T, Heidemann PH: Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation. PLoS One 2012;7:e38220.
43.
Musebeck J, Mohnike K, Beye P, Tonnies H, Neitzel H, Schnabel D, Gruters A, Wieacker PF, Stumm M: Short stature homeobox-containing gene deletion screening by fluorescence in situ hybridisation in patients with short stature. Eur J Pediatr 2001;160:561-565.
44.
Schiller S, Spranger S, Schechinger B, Fukami M, Merker S, Drop SL, Troger J, Knoblauch H, Kunze J, Seidel J, Rappold GA: Phenotypic variation and genetic heterogeneity in Leri-Weill syndrome. Eur J Hum Genet 2000;8:54-62.
45.
Marchini A, Marttila T, Winter A, Caldeira S, Malanchi I, Blaschke RJ, Hacker B, Rao E, Karperien M, Wit JM, Richter W, Tommasino M, Rappold GA: The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes. J Biol Chem 2004;279:37103-37114.
46.
Wang Y, Cheng Z, Elalieh HZ, Nakamura E, Nguyen MT, Mackem S, Clemens TL, Bikle DD, Chang W: IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway. J Bone Miner Res 2011;26:1437-1446.
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