Human growth, from fetal life to adolescence, is dynamic and a good marker of health. Growth is a complex process influenced by genetic, hormonal, nutritional and environmental factors, both pre- and postnatally. To date, no international agreement regarding normal height has been established. Auxological parameters are fundamental to investigate potential short stature (SS), either with a known diagnosis, e.g. disproportionate or proportionate, prenatal and/or postnatal onset, or an unknown diagnosis, i.e. idiopathic SS. The incidence/prevalence of SS is difficult to establish. The measurement of choice in children aged <2 years is length, while in those >2 years of age it is height. A number of monogenic diseases that lead to proportionate SS due to either isolated growth hormone deficiency, multiple pituitary hormone deficiency, growth hormone insensitivity, primary acid-labile subunit deficiency, primary IGF-1 deficiency, IGF-1 resistance, primary IGF-2 deficiency or primary protease deficiency have been discovered in the last 30 years. In addition, the Nosology and Classification of Genetic Skeletal Disorders revised in 2015 includes 436 conditions, with a number of genes of 364. A practical algorithm for the evaluation of SS as well as therapeutic options are discussed.

1.
Rosenfeld RG: Insulin-like growth factors and the basis of growth. N Engl J Med 2003;349:2184-2186.
2.
Rogol AD, Hayden GF: Etiologies and early diagnosis of short stature and growth failure in children and adolescents. J Pediatr 2014;164(5 suppl):S1-S14.e6.
3.
Allen DB, Cuttler L: Short stature in childhood - challenges and choices. N Engl J Med 2013;368:1220-1228.
4.
Bonafe L, Cormier-Daire V, Hall C, et al: Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 2015, Epub ahead of print.
5.
Donaldson J, Aftab S, Bradish C: Achondroplasia and limb lengthening: results in a UK cohort and review of the literature. J Orthop 2015;12:31-34.
6.
Martos-Moreno GÁ, Argente J: The ‘glacier crevice' sign, from image to diagnosis. J Pediatr 2014;164:1237-1237.e1.
7.
Rappold G, Blum WF, Shavrikova EP, et al: Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007;44:306-313.
8.
Ross Jl, Scott C Jr, Marttila P, et al: Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 2001;86:5674-5680.
9.
Benito-Sanz S, Thomas S, Huber C, et al: PAR1 deletions excluding the SHOX gene are found in Léri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS). Am J Hum Genet 2005;77:533-544.
10.
Bertorelli R, Capone L, Ambrosetti F, et al: The homozygous deletion of the 3′ enhancer of the SHOX gene causes Langer mesomelic dysplasia. Clin Genet 2007;72:490-491.
11.
Bartels CF, Bukulmez H, Padayatti P, et al: Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004;75:27-34.
12.
Hisado-Oliva A, Garre-Vázquez AI, Santaolalla-Caballero F, et al: Heterozygous NPR2 mutations cause disproportionate short stature, similar to Léri-Weill dyschondrosteosis. J Clin Endocrinol Metab 2015;100:E1133-E1142.
13.
Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A: Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007;92:804-810.
14.
Mullis PE, Argente J, Amselem S, et al: Genetics and molecular biology in short stature. Acta Paediatr Suppl 1995;411:75-80.
15.
Pérez Jurado LA, Argente J, Barrios V, et al: Molecular diagnosis and endocrine evaluation of a patient with a homozygous 7.0 kb deletion of the growth hormone (GH) gene cluster: response to biosynthetic GH therapy. J Pediatr Endocrinol Metab 1997;10:185-190.
16.
Hamid R, Phillips JA, Holladay C, et al: A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II. J Clin Endocrinol Metab 2009;94:4728-4734.
17.
Dauber A, Rosenfeld RG, Hirschhorn JN: Genetic evaluation of short stature. J Clin Endocrinol Metab 2014;99:3080-3092.
18.
Pfäffle RW, DiMattia GE, Parks JS, et al: Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992;257:1118-1121.
19.
Wu W, Cogan JD, Pfäffle RW, et al: Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998;18:147-149.
20.
Netchine I, Sobrier ML, Krude H, et al: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 2000;25:182-186.
21.
Machinis K, Pantel J, Netchine I, et al: Syndromic short stature in patients with germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001;69:961-968.
22.
Dattani MT, Martinez-Barbera JP, Thomas PQ, et al: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998;19:125-133.
23.
Jayakody SA, Andoniadou CL, Gaston-Massuet C, et al: SOX2 regulates the hypothalamic-pituitary axis at multiple levels. J Clin Invest 2012;122:3635-3646.
24.
Woods KS, Cundall M, Turton J, et al: Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 2005;76:833-849.
25.
Diaczok D, Romero C, Zunich J, et al: A novel dominant negative mutation of OXT2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab 2008;93:4351-4359.
26.
França MM, Jorge AA, Carvalho LR, et al: Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab 2010;95:E384-E391.
27.
Argente J, Flores R, Gutiérrez-Arumí, et al: Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency. EMBO Mol Med 2014;3:299-306.
28.
Laron Z, Pertzelan A, Mannheimer S: Genetic pituitary dwarfism with high serum concentration of growth hormone - a new inborn error of metabolism? Isr J Med Sci 1966;2:152-155.
29.
Amselem S, Duquesnoy P, Attree O, et al: Laron dwarfism and mutations of the growth hormone-receptor gene. N Engl J Med 1989;321:989-995.
30.
Rosenbloom AL, Rosenfeld RG, Guevara-Aguirre J: Growth hormone insensitivity. Pediatr Clin North Am 1997;44:423-442.
31.
Goddard AD, Covello R, Luoh SM, et al: 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.
32.
Kofoed EM, Hwa V, Little B, et al: Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003;349:1139-1147.
33.
Domené HM, Bengolea SV, Martínez AS, et al: 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.
34.
Heath KE, Argente J, Barrios V, et al: Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. J Clin Endocrinol Metab 2008;93:1616-1624.
35.
Domené HM, Hwa V, Argente J, et al: Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. Horm Res 2009;72:129-141.
36.
Woods KA, Camacho-Hübner C, Savage MO, et al: 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.
37.
Abuzzahab MJ, Schneider A, Goddard A, et al: IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211-2222.
38.
Kawashima Y, Takashi SI, Kanzaki S: Familial short stature with IGF-I receptor gene anomaly. Endocr J 2012;59:179-185.
39.
Begemann M, Zin B, Santen G, et al: Paternally inherited IGF2 mutation and growth retardation. N Engl J Med 2015;373:349-356.
40.
Muñoz-Calvo MT, Barrios V, Pozo J, et al: A new syndrome of short stature, mild microcephaly, skeletal abnormalities and high circulating IGF1, IGFBP3 and ALS associated with a homozygous mutation in the gene for pregnancy-associated plasma protein A2 (PAPP-A2, pappalysin2). 97th Annual Meeting of the Endocrine Society. San Diego, March 6, 2015.
41.
Cohen P, Rogol AD, Deal CL, et al: 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.
42.
Wit JM, Clayton PE, Rogol AD, et al: Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008;18:89-110.
43.
Wit JM, Reiter EO, Ross JL, et al: Idiopathic short stature: management and growth hormone treatment. Growth Horm IGF Res 2008;18:111-135.
44.
Murray PG, Dattani MT, Clayton PE: Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence. Arch Dis Child 2015, Epub ahead of print.
45.
Bang P, Ahmed SF, Argente J, et al: Identification and management of poor response to growth-promoting therapy in children with short stature. Clin Endocrinol (Oxf) 2012;77:169-181.
46.
Guo MH, Shen Y, Walvoord EC, et al: Whole exome sequencing to identify genetic causes of short stature. Horm Res Paediatr 2014;82:44-52.
47.
Soriano-Guillén L, Argente J: Idiopathic short stature and treatment with biosynthetic growth hormone: clinical and ethical reflections on an arbitrary diagnosis (in Spanish). An Pediatr (Barc) 2012;76:53-57.
48.
Backeljauw PF, Kuntze J, Frane J, et al: Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I. Horm Res Paediatr 2013;80:47-56.
49.
Bang P, Polak M, Woelfle J, Houchard A; EU IGFD Registry Study Group: Effectiveness and safety of rhIGF-1 therapy in children: The European Increlex® Growth Forum Database Experience. Horm Res Paediatr 2015;83:345-357.
50.
Backeljauw PF, Miller BS, Dutailly P, et al: Recombinant human growth hormone plus recombinant human insulin-like growth factor-1 coadministration therapy in short children with low insulin-like growth factor-1 and growth hormone sufficiency: results from a randomized, multicenter, open-label, parallel-group, active treatment-controlled trial. Horm Res Paediatr 2015;83:268-279.
51.
Rosenfeld RG: How aggressively should we treat short stature? Horm Res Paediatr 2015;83:280-281.
52.
Wit JM, Oostdijk W: Novel approaches to short stature therapy. Best Pract Res Clin Endocrinol Metab 2015;29:353-366.
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