Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader-Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH-insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent's height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent's heights ≤-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent's height and BA are clinical predictors of monogenic FSS.

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague Czech Republic

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Plachy L, Strakova V, Elblova L, Obermannova B, Kolouskova S, Snajderova M, Zemkova D, Dusatkova P, Sumnik Z, Lebl J, et al.High prevalence of growth plate gene variants in children with familial short stature treated with growth hormone. Journal of Clinical Endocrinology and Metabolism 20191044273–4281. (10.1210/jc.2018-02288) PubMed DOI

Dauber A Rosenfeld RG & Hirschhorn JN. Genetic evaluation of short stature. Journal of Clinical Endocrinology and Metabolism 2014993080–3092. (10.1210/jc.2014-1506) PubMed DOI PMC

Vasques GA Andrade NLM & Jorge AAL. Genetic causes of isolated short stature. Archives of Endocrinology and Metabolism 20196370–78. (10.20945/2359-3997000000105) PubMed DOI PMC

Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, et al.Defining the role of common variation in the genomic and biological architecture of adult human height. Nature Genetics 2014461173–1186. (10.1038/ng.3097) PubMed DOI PMC

Baron J Sävendahl L Luca de F Dauber A Phillip M Wit JM & Nilsson O. Short and tall stature: a new paradigm emerges. Nature Reviews Endocrinology 2015736–746. (10.1038/nrendo.2015.165) PubMed DOI PMC

Murray PG Clayton PE & Chernausek SD. A genetic approach to evaluation of short stature of undetermined cause. Lancet. Diabetes and Endocrinology 20186564–574. (10.1016/S2213-8587(1830034-2) PubMed DOI

Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Hormone Research in Paediatrics 20117581–89. (10.1159/000324105) PubMed DOI

Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, Kucerova P, Toni L, Kolouskova S, Snajderova M, et al.NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. Journal of Clinical Endocrinology and Metabolism 2020105105.e746–e752. (10.1210/clinem/dgaa037) PubMed DOI

Vasques GA Amano N Docko AJ Funari MFA Quedas EPS Nishi MY Arnhold IJP Hasegawa T & Jorge AAL. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. Journal of Clinical Endocrinology and Metabolism 201398E1636–E1644. (10.1210/jc.2013-2142) PubMed DOI

Amano N Mukai T Ito Y Narumi S Tanaka T Yokoya S Ogata T & Hasegawa T. Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. Journal of Clinical Endocrinology and Metabolism 201499E713–E718. (10.1210/jc.2013-3525) PubMed DOI

Wang SR, Jacobsen CM, Carmichael H, Edmund AB, Robinson JW, Olney RC, Miller TC, Moon JE, Mericq V, Potter LR, et al.Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Human Mutation 201536474–481. (10.1002/humu.22773) PubMed DOI PMC

Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Elblova L, Kolouskova S, Snajderova M, Obermannova B, Zemkova D, Sumnik Z, et al.Familial Short Stature - a novel phenotype of growth plate collagenopathies. Journal of Clinical Endocrinology and Metabolism 20211061742–1749. (10.1210/clinem/dgab084) PubMed DOI

Roberts AE Allanson JE Tartaglia M & Gelb BD. Noonan syndrome. Lancet 2013381333–342. (10.1016/S0140-6736(1261023-X) PubMed DOI PMC

Mullis PE. Genetics of growth hormone deficiency. Endocrinology and Metabolism Clinics of North America 20073617–36. (10.1016/j.ecl.2006.11.010) PubMed DOI

Dattani MT. Growth hormone deficiency and combined pituitary hormone deficiency: does the genotype matter? Clinical Endocrinology 200563121–130. (10.1111/j.1365-2265.2005.02289.x) PubMed DOI

Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz ID, Rockstroh D, Colombo R, Sanchez MA, Vokurkova D, Kowalczyk J, et al.Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nature Communications 201892105. (10.1038/s41467-018-04521-0) PubMed DOI PMC

Voigt M Fusch C Olbertz D Hartmann K Rochow N Renken C & Schneider K. Analyse des Neugeborenenkollektivs der Bundesrepublik Deutschland. Geburtshilfe und Frauenheilkunde 200666956–970. (10.1055/s-2006-924458) DOI

Kobzová J Vignerová J Bláha P Krejćovsky L & Riedlová J. The 6th nationwide anthropological survey of children and adolescents in the Czech Republic in 2001. Central European Journal of Public Health 200412126–130. PubMed

Fredriks AM Buuren van S Heel van WJM Dijkman-Neerincx RHM Verloove-Vanhorick SP & Wit JM. Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders. Archives of Disease in Childhood 200590807–812. (10.1136/adc.2004.050799) PubMed DOI PMC

Kommunehospital A. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH research society. GH research society. Journal of Clinical Endocrinology and Metabolism 2000853990–3993. (10.1210/jcem.85.11.6984) PubMed DOI

Clayton PE Cianfarani S Czernichow P Johannsson G Rapaport R & Rogol AD. 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. Journal of Clinical Endocrinology and Metabolism 200792804–810. (10.1210/jc.2006-2017) PubMed DOI

Cox LA. Tanner-Whitehouse method of assessing skeletal maturity: problems and common errors. Hormone Research 199645(Supplement 2) 53–55. (10.1159/000184848) PubMed DOI

Pruhova S Dusatkova P Sumnik Z Kolouskova S Pedersen O Hansen T Cinek O & Lebl J. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatric Diabetes 201011529–535. (10.1111/j.1399-5448.2010.00646.x) PubMed DOI

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 201517405–424. (10.1038/gim.2015.30) PubMed DOI PMC

Kopanos C Tsiolkas V Kouris A Chapple CE Albarca Aguilera M Meyer R & Massouras A. VarSome: the human genomic variant search engine. Bioinformatics 2019351978–1980. (10.1093/bioinformatics/bty897) PubMed DOI PMC

Jarvik GP & Browning BL. Consideration of cosegregation in the pathogenicity classification of genomic variants. American Journal of Human Genetics 2016981077–1081. (10.1016/j.ajhg.2016.04.003) PubMed DOI PMC

Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, Klinger P, Kraus C, Trautmann U, Zenker M, et al.Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genetics in Medicine 201820630–638. (10.1038/gim.2017.159) PubMed DOI PMC

Homma TK, Freire BL, Honjo Kawahira RS, Dauber A, Funari MFA, Lerario AM, Nishi MY, Albuquerque EV, Vasques GA, Collett-Solberg PF, et al.Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing. Journal of Pediatrics 2019215192–198. (10.1016/j.jpeds.2019.08.024) PubMed DOI

Huang Z, Sun Y, Fan Y, Wang L, Liu H, Gong Z, Wang J, Yan H, Wang Y, Hu G, et al.Genetic evaluation of 114 Chinese short stature children in the next generation era: a Single Center study. Cellular Physiology and Biochemistry 201849295–305. (10.1159/000492879) PubMed DOI

Kim YM Lee YJ Park JH Lee HD Cheon CK Kim SY Hwang JY Jang JH & Yoo HW. High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing. Clinical Genetics 201792594–605. (10.1111/cge.13038) PubMed DOI

Freire BL Homma TK Funari MFA Lerario AM Vasques GA Malaquias AC Arnhold IJP & Jorge AAL. Multigene sequencing analysis of children born small for gestational age with isolated short stature. Journal of Clinical Endocrinology and Metabolism 20191042023–2030. (10.1210/jc.2018-01971) PubMed DOI

Zhang H Yang R Wang Y Ye J Han L Qiu W & Gu X. A pilot study of gene testing of genetic bone dysplasia using targeted next-generation sequencing. Journal of Human Genetics 201560769–776. (10.1038/jhg.2015.112) PubMed DOI

Wakeling EL, Brioude F, Lokulo-Sodipe O, O’Connell SM, Salem J, Bliek J, Canton APM, Chrzanowska KH, Davies JH, Dias RP, et al.Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nature Reviews. Endocrinology 201713105–124. (10.1038/nrendo.2016.138) PubMed DOI

Van Der BI. Noonan syndrome. Orphanet Journal of Rare Diseases 200721. PubMed PMC

Gibson BG & Briggs MD. The aggrecanopathies; An evolving phenotypic spectrum of human genetic skeletal diseases. Orphanet Journal of Rare Diseases 20161186. (10.1186/s13023-016-0459-2) PubMed DOI PMC

Loche S Carta L Ibba A & Guzzetti C. Growth hormone treatment in non-growth hormone-deficient children. Annals of Pediatric Endocrinology and Metabolism 2014191–7. (10.6065/apem.2014.19.1.1) PubMed DOI PMC

Romano AA Dana K Bakker B Davis DA Hunold JJ Jacobs J & Lippe B. Growth response, near-adult height, and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone. Journal of Clinical Endocrinology and Metabolism 2009942338–2344. (10.1210/jc.2008-2094) PubMed DOI

Blum WF Ross JL Zimmermann AG Quigley CA Child CJ Kalifa G Deal C Drop SLS Rappold G & Cutler GB. GH treatment to final height produces similar height gains in patients with SHOX deficiency and turner syndrome: results of a multicenter trial. Journal of Clinical Endocrinology and Metabolism 201398E1383–E1392. (10.1210/jc.2013-1222) PubMed DOI

Massart F Miccoli M Baggiani A & Bertelloni S. Height outcome of short children with hypochondroplasia after recombinant human growth hormone treatment: a meta-analysis. Pharmacogenomics 2015161965–1973. (10.2217/pgs.15.129) PubMed DOI

Dauber A. Response to letter to the editor: ‘genetic testing for the child with short stature: has the time come to change our diagnostic paradigm?’ Journal of Clinical Endocrinology and Metabolism 2020105e1927. (10.1210/clinem/dgz178) PubMed DOI

Toni L, Plachy L, Dusatkova P, Amaratunga SA, Elblova L, Sumnik Z, Kolouskova S, Snajderova M, Obermannova B, Pruhova S, et al.The genetic landscape of children born small for gestational age with persistent short stature (SGA-SS). Hormone Research in Paediatrics 2023. (10.1159/000530521) PubMed DOI

Gregory LC, Cionna C, Cerbone M, GOSgene & Dattani MT. Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders. Genetics in Medicine 202325100881. (10.1016/j.gim.2023.100881) PubMed DOI

Monogenic causes of familial short stature

Etiology of combined pituitary hormone deficiency: GNAO1 as a novel candidate gene