![]() | |||||||||
![]() | |||||||||
Rev Esp Endocrinol Pediatr 2017;8 Suppl(1):8-13 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2017.Apr.388 | |||||||||
![]() | |||||||||
ALS deficiency in idiopathic short stature | |||||||||
![]() | |||||||||
El déficit de ALS en la talla baja idiopática | |||||||||
![]() | |||||||||
Sent for review: 3 Apr. 2017 | Accepted: 3 Apr. 2017 | Published: 5 May. 2017 | |||||||||
![]() | |||||||||
Horacio M. Domené | |||||||||
![]() | |||||||||
Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI– División de Endocrinología. Hospital de Niños Ricardo Gutiérrez. Buenos Aires (Argentina) | |||||||||
![]() | |||||||||
Correspondence:Horacio M. Domené, Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI– División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina E-mail: hdomene@cedie.org.ar | |||||||||
![]() | |||||||||
![]() | |||||||||
| |||||||||
![]() | |||||||||
Idiopathic short stature is essentially a diagnosis of exclusion made after physical examination and biochemical assessment ruled out other causes of short stature. Different molecular defects have been characterized in ISS. Complete ALS deficiency (ACLSD), characterized by severe deficiencies of IGF-I, IGFBP-3, and ALS, is caused by mutations in the IGFALS gene. Milder cases of ACLSD, heterozygous carriers of IGFALS gene variants, may be present in a subgroup of ISS children. By studding 218 normal and 117 ISS children, we determined that non-synonymous IGFALS variants were more frequent in ISS (15.5% vs. 4.8%; P=0.0039). From 16 ISS children with non-synonymous variants, one presented ACLSD (compound heterozygous for p.Glu35Glyfs*17/p.Ser490Trp) and other five presented partial ACLSD (heterozygous carriers for p.Glu35Glyfs*17, p.Arg277His, p.Pro287Leu, and 2 p.Arg548Trp). One variant affected ALS synthesis (p.Glu35Glyfs*17) and other two, with normal synthesis and secretion, albeit to lower ALS concentrations (p.Ala330Asp, p.Arg548Trp). Complete ACLSD represented 1%, and partial ACLSD 5% of ISS children, presenting IGALS pathogenic or still no classified variants. Identification of partial ACLSD may have practical implications, considering that these children, different to what was reported in complete ACLSD, retain their ability to respond to rhGH treatment. To prove the efficacy of this treatment requires large follow-up until adult height. | |||||||||
![]() | |||||||||
References | |||||||||
1. Ranke MB: Towards a consensus on the definition of idiopathic short stature. Horm Res 1996;45 (Suppl 2):64-66. 2. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM on behalf of the 2007 ISS Consensus Workshop participants: Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008;93:4210-4217.[Pubmed] 3. Argente J. Challenges in the Management of short stature. Horm Res Paediatr 2016;85:2-10.[Pubmed] 4. Goddard AD, Covello R, Luoh SM, Clackson T, Attie KM, Gesundheit N, Rundle AC, Wells JA, Carlsson LM: Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group. N Engl J Med 1995;333:1093-1098.[Pubmed] 5. Sanchez JE, Perera E, Baumbach L, Cleveland WW: Growth hormone receptor mutations in children with idiopathic short stature. J Clin Endocrinol Metab 1998;83:4079-4083.[Pubmed] 6. Salerno M, Balestrieri B, Matrecano E, Officioso A, Rosenfeld RG, Di Maio S, Fimiani G, Ursini MV, Pignata C: Abnormal GH receptor signaling in children with idiopathic short stature. J Clin Endocrinol Metab 2001;86:3882-3888.[Pubmed] 7. Sjoberg M, Salazar T, Espinosa C, Dagnino A, Avila A, Eggers M, Cassorla F, Carvallo P, Mericq MV: Study of GH sensitivity in Chilean patients with idiopathic short stature. J Clin Endocrinol Metab 2001;86:4375-4381.[Pubmed] 8. Bonioli E, Tarò M, Rosa CL, Citana A, Bertorelli R, Morcaldi G, Gastaldi R, Coviello DA: Heterozygous mutations of growth hormone receptor gene in children with idiopathic short stature. Growth Horm IGF Res 2005;15:405-410.[Pubmed] 9. Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K: Brief report: short stature caused by a mutant growth hormone. N Engl J Med 1996;334:432-436. Erratum in: N Engl J Med 334:1207. 10. Takahashi Y, Shirono H, Arisaka O, Takahashi K, Yagi T, Koga J, Kaji H, Okimura Y, Abe H, Tanaka T, Chihara K: Biologically inactive growth hormone caused by an amino acid substitution. J Clin Invest 1997;100:1159-1165.[Pubmed] 11. 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.[Pubmed] 12. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D, de Kerdanet M, Kadiri A, Epelbaum J, Le Bouc Y, Amselem S: Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 2006;116:760-768.[Pubmed] 13. Pantel J, Legendre M, Nivot S, Morisset S, Vie-Luton MP, le Bouc Y, Epelbaum J, Amselem S: Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. J Clin Endocrinol Metab 2009;94:4334-4341.[Pubmed] 14. Inoue H, Kangawa N, Kinouchi A, Sakamoto Y, Kimura C, Horikawa R, Shigematsu Y, Itakura M, Ogata T, Fujieda K; on behalf of the Japan Growth Genome Consortium: Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature. J Clin Endocrinol Metab 2011;96:E373-8.[Pubmed] 15. Olney RC, Bükülmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, Warman ML. Heterozygous mutations in Natriuretic Peptide Receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab 2006;91:1229-1232.[Pubmed] 16. Hisado-Oliva A, Garre-Vázquez AI, Santaolalla-Caballero F, Belinchón A, Barreda-Bonis AC, Vasques GA, Ramirez J, Luzuriaga C, Carlone G, González-Casado I, Benito-Sanz S, Jorge AA, Campos-Barros A, Heath KE. Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis. J Clin Endocrinol Metab. 2015;100:E1133-E1142.[Pubmed] 17. Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, Lui JC, Hirschhorn JN, Baron J, Dauber A. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J Clin Endocrinol Metab 2014;99:E1510-E1518.[Pubmed] 18. Quintos JB, Guo MH, Dauber A. Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. J Pediatr Endocrinol Metab 2015;28:927-932.[Pubmed] 19. Edouard T, Grünenwald S, Gennero I, Salles JP, Tauber M: Prevalence of IGF1 deficiency in prepubertal children with isolated short stature. Eur J Endocrinol 2009;161:34:43-50.[Pubmed] 20. Clayton PE, Ayoola O, Whatmore AJ: Patient selection for IGF-I therapy. Horm Res 2006;65 (Suppl 1):28-34. 21. Attie KM, Carlsson LM, Rundle AC, Sherman BM: Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. The National Cooperative Growth Study. J Pediatr 1995;127:244-250.[Pubmed] 22. Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3-34.[Pubmed] 23. Baxter RC: Circulating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulin-like growth factor-binding protein complex. J Clin Endocrinol Metab 1990;70:1347-1353.[Pubmed] 24. Guler HP, Zapf J, Schmid C, Froesch ER: Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol (Copenh) 1989;121:753-758.[Pubmed] 25. Baxter RC, Martin JL: Structure of the Mr 140,000 growth hormone-dependent insulin-like growth factor binding protein complex: determination by reconstitution and affinity-labeling. Proc Natl Acad Sci U S A 1989;86:6898-6902.[Pubmed] 26. 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.[Pubmed] 27. Baxter RC: Circulating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulin-like growth factor-binding protein complex. J Clin Endocrinol Metab 1990;70:1347-1353.[Pubmed] 28. Lewitt MS, Scott FP, Clarke NM & Baxter RC: Developmental regulation of circulating insulin-like growth factor-binding proteins in normal pregnancies and in pre-eclampsia. Progress in Growth Factor Research 1995;6:475–480. 29. Barrios V, Pozo J, Muñoz MT, Buño M, Argente J: Normative data for total and free acid-labile subunit of the human insulin-like growth factor-binding protein complex in pre- and full-term newborns and healthy boys and girls throughout postnatal development. Horm Res 2000;53:148-153.[Pubmed] 30. 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.[Pubmed] 31. Laron Z, Pertzelan A, Mannheimer S: Genetic pituitary dwarfism with high serum concentration of growth hormone: a new inborn error of metabolism? Isr J MedSci 1966;2:152-155. 32. 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.[Pubmed] 33. Domené HM, Hwa V, Argente J, Wit JM, Camacho-Hübner C, Jasper HG, Pozo J, van Duyvenvoorde HA, Yakar S, Fofanova-Gambetti OV, Rosenfeld RG, International ALS Collaborative Group: Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences Horm Res 2009;72:129-41. Erratum in: Horm Res 2010;73:80. 34. Fofanova-Gambetti OF, Hwa V, Wit JM, Domené HM, Argente J, Bang P, Högler W, Kirsch S, Pihoker C, Chiu HK, Cohen L, Jacobsen C, Jasper HG, Haeusler G, Campos-Barros A, Gallego-Gómez 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 ALS Consortium. J Clin Endocrinol Metab 2010;95:4184-4191.[Pubmed] 35. Högler W, Martin DD, Crabtree N, Nightingale P, Tomlinson J, Metherell L, Rosenfeld R, Hwa V, Rose S, Walker J, Shaw N, Barrett T, Frystyk J. IGFALS gene dosage effects on serum IGF-I and glucose metabolism, body composition, bone growth in length and width, and the pharmacokinetics of recombinant human IGF-I administration. J Clin Endocrinol Metab 2014;99:E703-E712.[Pubmed] 36. Domené HM, Scaglia PA, Martínez AS, Keselman AC, Karabatas LM, Pipman VR, Bengolea SV, Guida MC, Ropelato MG, Ballerini MG, Lescano EM, Blanco MA, Heinrich JJ, Rey RA, Jasper HG: Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system. Horm Res Paediatr 2013;80:413-423.[Pubmed] 37. Venturini G, Rose AM, Shah AZ, Bhattachrya SS, Rivolta C. CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS Genet 2012;8:1003040. 38. Martucci LC, Gutiérrez ML, Karabatas LM, Scaglia PA, Rey RA, Domené HM, Jasper HG, Domené S. Assessment of pathogenicity of natural IGFALS gene variants by in silico bioinformatics tools and in vitro functional studies. Mol Cell Endocrinol 2016;429:19-28.[Pubmed] 39. Legendre M, Dastotb F, Collotb N, Duquesnoy P, Cohen E , Sobriera M-L, Adiceam P, Andersond D, Barone S, Cabrol S, Callewaert B, Cartigny M, Craen M, Crock P, Ladjouze A, Lazea C, Polak M, Savendahl L, Touzani A, Amselem S. Contribution of GHR and IGFALS mutations to growth hormone resistance. Identification of new variants and impact on the inheritance pattern. Horm Res Paediatr 2016;86 (Suppl 1):114-115. 40. Shapiro L, Savage M, Davies K, Metherell L, Storr H. Whole exome sequencing can Identify defects not detected by candidate gene sequencing in patients with short stature and features of growth hormone insensitivity (GHI). Horm Res Paediatr 2016;86 (Suppl 1):47. 41. Hess O, Khayat M, Hwa V, Heath KE, Teitler A, Hritan Y, Allon-Shalev S, Tenenbaum-Rakover Y: A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1). Clin Endocrinol (Oxf) 2013;79:838-844.[Pubmed] 42. Gallego-Gómez E, Sanchez del Pozo J, Cruz-Rojo J, Gómez A, García Bouthelier R, Heath KE, Campos-Barros A. Patients with heterozygous mutations associated with postnatal growth déficit and low IGF-I may benefit from treatment with rhGH. Horm Res 2011;76 (Suppl 2):90-91. 43. Grandone A, Miraglia del Giudice E, Cirillo G, Abbondanza C, Cioffi M, Romano T, Micillo F, Marzuillo P, Perrone L. Clinical features of a new acid-labile subunit (IGFALS) heterozygous mutation: anthropometric and biochemical characterization and response to growth hormone administration. Horm Res Paediatr. 2014;81:67-72.[Pubmed] | |||||||||
![]() |