Background/Aims: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. Patients and Design: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height –2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). Results: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from –1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from –2.41 ± 0.71 to –1.81 ± 0.87; p < 0.001), and IGF-1 values (from –0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = –0.618, p = 0.032), bone age (r = –0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. Conclusion: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.

Binder G: Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr 2011;75:81–89.
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.
Marchini A, Marttila T, Winter A, Caldeira S, Malanchi I, Blaschke RJ, Häcker 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.
Schiller S, Spranger S, Schechinger B, Fukami M, Merker S, Drop SL, Tröger J, Knoblauch H, Kunze J, Seidel J, Rappold GA: Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome. Eur J Hum Genet 2000;8:54–62.
Chen J, Wildhardt G, Zhong Z, Röth R, Weiss B, Steinberger D, Decker J, Blum WF, Rappold G: Enhancer deletions of the SHOX gene as a frequent cause of short stature: the essential role of a 250 kb downstream regulatory domain. J Med Genet 2009;46:834–839.
Benito-Sanz S, Aza-Carmona M, Rodríguez-Estevez A, Rica-Etxebarria I, Gracia R, Campos-Barros A, Heath KE: Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature. Eur J Hum Genet 2012;20:125–127.
Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, Scambler PJ, Winter RM: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 1998;19:70–73.
Cormier-Daire V, Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M, Le Merrer M, Munnich A: SHOX gene mutations and deletions in dyschondrosteosis or Leri-Weill syndrome. Acta Paediatr 1999;88:55–59.
Ellison JW, Wardak Z, Young MF, Gehron Robey P, Laig-Webster M, Chiong W: PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 1997;6:1341–1347.
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.
Kosho T, Muroya K, Nagai T, Fujimoto M, Yokoya S, Sakamoto H, Hirano T, Terasaki H, Ohashi H, Nishimura G, Sato S, Matsuo N, Ogata T: Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J Clin Endocrinol Metab 1999;84:4613–4621.
Stephure DK, Canadian Growth Hormone Advisory Committee: Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab 2005;90:3360–3366.
Binder G, Schwarze CP, Ranke MB: Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone. J Clin Endocrinol Metab 2000;85:245–249.
Blum WF, Crowe BJ, Quigley CA, Jung H, Cao D, Ross JL, Braun L, Rappold G: SHOX Study Group. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab 2007;92:219–228.
Blum WF, Cao D, Hesse V, Fricke-Otto S, Ross JL, Jones C, Quigley CA, Binder G: Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009;71:167–172.
Lohman TG, Roche AF, Martorell R: Anthropometric Standardization Reference manual. Human Champaign, Human Kinetics Books, 1988.
Cacciari E, Milani S, Balsamo A, Spada E, Bona G, Cavallo L, Cerutti F, Gargantini L, Greggio N, Tonini G, Cicognani A: Italian cross-sectional growth charts for height, weight and BMI (2 to 20 years). J Endocrinol Invest 2006;29:581–593.
Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303.
Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist, ed 2. Stanford, Stanford University Press, 1959.
Iughetti L, Capone L, Elsedfy H, Bertorelli R, Predieri B, Bruzzi P, Forabosco A, El Kholy M: Unexpected phenotype in a boy with trisomy of the SHOX gene. J Pediatr Endocrinol Metab 2010;23:159–169.
Tanner JM, Goldstein H, Whitehouse RH: Standards for children’s height at ages 2–9 years allowing for heights of parents. Arch Dis Child 1970;45:755–762.
Scalco RC, Melo SS, Pugliese-Pires PN, Funari MF, Nishi MY, Arnhold IJ, Mendonca BB, Jorge AA: Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency. J Clin Endocrinol Metab 2010;95:328–332.
Thuestad IJ, Ivarsson SA, Nilsson KO, Wattsgård C: Growth hormone treatment in Léri-Weill syndrome. J Pediatr Endocrinol Metab 1996;9:201–204.
Urakami T, Hasegawa M, Morimoto S, Saitoh H, Mugishima H: Effect of growth hormone therapy in two sisters with SHOX haploinsufficiency. Pediatr Int 2009;51:574–599.
Iughetti L, Madeo S, Predieri B: Growth hormone therapy in patients with short stature homebox-gene (SHOX) deficiency. J Endocrinol Invest 2010;33:34–38.
Shanske A, Ellison J, Vuguin P, Dowling P, Wasserman E, Heinrich J, Saenger P: Deletion of the pseudoautosomal region in a male with a unique Y;13 translocation and short stature. Am J Med Genet 1999;82:34–39.
Munns CF, Berry M, Vickers D, Rappold GA, Hyland VJ, Glass IA, Batch JA: Effect of 24 months of recombinant growth hormone on height and body proportions in SHOX haploinsufficiency. J Pediatr Endocrinol Metab 2003;16:997–1004.
Salmon-Musial AS, Rosilio M, David M, Huber C, Pichot E, Cormier-Daire V, Nicolino M: Clinical and radiological characteristics of 22 children with SHOX anomalies and familial short stature suggestive of Léri-Weill dyschondrosteosis. Horm Res Paediatr 2011;76:178–185.
Jorge AA, Funari MF, Nishi MY, Mendonca BB: Short stature caused by isolated SHOX gene haploinsufficiency: update on the diagnosis and treatment. Pediatr Endocrinol Rev 2010;8:79–85.
Davenport ML, Crowe BJ, Travers SH, Rubin K, Ross JL, Fechner PY, Gunther DF, Liu C, Geffner ME, Thrailkill K, Huseman C, Zagar AJ, Quigley CA: Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab 2007;92:3406–3416.
Ogata T, Matsuo N, Nishimura G: SHOX haploinsufficiency and overdosage: impact of gonadal function status. J Med Genet 2001;38:1–6.
GH Research Society: Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J Clin Endocrinol Metab 2001;86:1868–1870.
Quigley CA, Gill AM, Crowe BJ, Robling K, Chipman JJ, Rose SR, Ross JL, Cassorla FG, Wolka AM, Wit JM, Rekers-Mombarg LT, Cutler GB Jr: Safety of growth hormone treatment in pediatric patients with idiopathic short stature. J Clin Endocrinol Metab 2005;90:5188–5196.
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