J Pediatr Genet 2019; 08(03): 123-132
DOI: 10.1055/s-0039-1691788
Original Article
Georg Thieme Verlag KG Stuttgart · New York

SHOX Deficiency in Argentinean Cohort: Long-Term Auxological Follow-Up and a Family's New Mutation

1   Department of Growth and Development, Hospital Garrahan, Buenos Aires, Argentina
,
Miriam Aza-Carmona
2   Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, UAM, IdiPAZ, Madrid, Spain
3   Skeletal dysplasia multidisciplinary Unit (UMDE), Hospital Universitario La Paz, UAM, Madrid, Spain
4   CIBERER, ISCIII, Madrid, Spain
,
David Medino-Martín
2   Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, UAM, IdiPAZ, Madrid, Spain
,
Abel Gomez
5   Department of Genetics, Hospital Garrahan, Buenos Aires, Argentina
,
Karen E. Heath
2   Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, UAM, IdiPAZ, Madrid, Spain
3   Skeletal dysplasia multidisciplinary Unit (UMDE), Hospital Universitario La Paz, UAM, Madrid, Spain
4   CIBERER, ISCIII, Madrid, Spain
,
Virginia Fano
1   Department of Growth and Development, Hospital Garrahan, Buenos Aires, Argentina
,
María Gabriela Obregon
5   Department of Genetics, Hospital Garrahan, Buenos Aires, Argentina
› Author Affiliations
Funding This work was supported in part by the following grants:MINECO (SAF2015–66831-R and SAF2017–84646-R).
Further Information

Publication History

23 November 2018

16 April 2019

Publication Date:
28 May 2019 (online)

Abstract

A cohort study on the growth of 19 Argentinean children, aged 0 to 18 years, and 11 of their first-degree relatives with alterations in the SHOX gene or its regulatory regions is reported. Children are born shorter and experience a growth delay during childhood with a stunted pubertal growth spurt. Body disproportion, with a sitting height/height ratio above +2 standard deviation score (SDS), was already present as early as 2 years old. Hand length was normal. Shortening of the radius, with a length below –1.9 SDS, was the earliest and most frequent radiological sign detected as early as 45 days old. We found a previously unreported mutation in a family with a highly variable phenotype, the boy had a severe phenotype with a milder presentation in other affected members of the family. We conclude that body disproportion and a shorter radius length on X-ray are useful tools for selecting children to undergo SHOX molecular studies.

 
  • References

  • 1 Belin V, Cusin V, Viot G. , et al. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet 1998; 19 (01) 67-69
  • 2 Shears DJ, Vassal HJ, Goodman FR. , et al. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 1998; 19 (01) 70-73
  • 3 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 (05) 306-313
  • 4 Marchini A, Ogata T, Rappold GA. A track record on SHOX: from basic research to complex models and therapy. Endocr Rev 2016; 37 (04) 417-448
  • 5 Malaquias AC, Scalco RC, Fontenele EGP. , et al. The sitting height/height ratio for age in healthy and short individuals and its potential role in selecting short children for SHOX analysis. Horm Res Paediatr 2013; 80 (06) 449-456
  • 6 Rosilio M, Huber-Lequesne C, Sapin H, Carel JC, Blum WF, Cormier-Daire V. Genotypes and phenotypes of children with SHOX deficiency in France. J Clin Endocrinol Metab 2012; 97 (07) E1257-E1265
  • 7 Binder G, Ranke MB, Martin DD. Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in school-age children with unexplained short stature. J Clin Endocrinol Metab 2003; 88 (10) 4891-4896
  • 8 Ross JL, Scott Jr C, Marttila P. , et al. Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 2001; 86 (12) 5674-5680
  • 9 Kosho T, Muroya K, Nagai T. , et al. 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 (12) 4613-4621
  • 10 Garcia Rudaz C, Martínez AS, Heinrich JJ. , et al. Growth of Argentinian girls with Turner syndrome. Ann Hum Biol 1995; 22 (06) 533-544
  • 11 Binder G, Renz A, Martinez A. , et al. SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity. J Clin Endocrinol Metab 2004; 89 (09) 4403-4408
  • 12 Lejarraga H, del Pino M, Fano V, Caíno S, Cole TJ. Growth references for weight and height for Argentinian girls and boys from birth to maturity: incorporation of data from the World Health Organisation from birth to 2 years and calculation of new percentiles and LMS values [in Spanish]. Arch Argent Pediatr 2009; 107 (02) 126-133
  • 13 Mazicioglu MM, Hatipoglu N, Ozturk A, Gun I, Ustunbas HB, Kurtoglu S. Age references for the arm span and stature of Turkish children and adolescents. Ann Hum Biol 2009; 36 (03) 308-319
  • 14 Del Pino M, Orden AB, Arenas MA, Fano V. Argentine references for the assessment of body proportions from birth to 17 years of age. Arch Argent Pediatr 2017; 115 (03) 234-240
  • 15 Lejarraga H, Heinrich J. Rodríguez. Normas y técnicas de mediaciones antropométricas. Rev Hosp Nino (Lima) 1975; 17: 171
  • 16 Saunders CL, Lejarraga H, del Pino M. Assessment of head size adjusted for height: an anthropometric tool for clinical use based on Argentinian data. Ann Hum Biol 2006; 33 (04) 415-423
  • 17 Feingold M, Bossert WH. Normal values for selected physical parameters: an aid to syndrome delineation. Birth Defects Orig Artic Ser 1974; 10 (13) 1-16
  • 18 Tanner JM. , ed. Growth at Adolescence. 2nd ed. Oxford/London/Edinburgh/Melbourne: Blackwell Scientific Publications; 1973
  • 19 Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970; 45 (239) 13-23
  • 20 Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44 (235) 291-303
  • 21 Gindhart PS. Growth standards for the tibia and radius in children aged one month through eighteen years. Am J Phys Anthropol 1973; 39 (01) 41-48
  • 22 Cole TJ. Fitting smoothed centile curves to reference data. J R Stat Soc Ser A Stat Soc 1988; 151: 385
  • 23 Cole TJ, Green PJ. Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 1992; 11 (10) 1305-1319
  • 24 Pan H, Cole TJ. LMS growth, a Microsoft Excel add-in to access growth references based on the LMS method; 2012; Version 2.77. Available at: http://www.healthforallchildren.co.uk/ . Accessed November 8, 2018
  • 25 Montalbano A, Juergensen L, Roeth R. , et al. Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency. EMBO Mol Med 2016; 8 (12) 1455-1469
  • 26 Fukami M, Nishi Y, Hasegawa Y. , et al. Statural growth in 31 Japanese patients with SHOX haploinsufficiency: support for a disadvantageous effect of gonadal estrogens. Endocr J 2004; 51 (02) 197-200
  • 27 Bundak R, Bas F, Furman A. , et al. Sitting height and sitting height/height ratio references for Turkish children. Eur J Pediatr 2014; 173 (07) 861-869
  • 28 Fredriks AM, van Buuren S, van Heel WJ, Dijkman-Neerincx RH, 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. Arch Dis Child 2005; 90 (08) 807-812
  • 29 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 (08) E1133-E1142
  • 30 Hisado-Oliva A, Ruzafa-Martin A, Sentchordi L. , et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. Genet Med 2018; 20 (01) 91-97
  • 31 Gkourogianni A, Andrew M, Tyzinski L. , et al. Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. J Clin Endocrinol Metab 2017; 102 (02) 460-469
  • 32 Sentchordi-Montané L, Aza-Carmona M, Benito-Sanz S. , et al. Heterozygous aggrecan variants are associated with short stature and brachydactyly: description of 16 probands and a review of the literature. Clin Endocrinol (Oxf) 2018; 88 (06) 820-829
  • 33 Vasques GA, Funari MFA, Ferreira FM. , et al. IHH gene mutations causing short stature with nonspecific skeletal abnormalities and response to growth hormone therapy. J Clin Endocrinol Metab 2018; 103 (02) 604-614
  • 34 Schiller S, Spranger S, Schechinger B. , et al. Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome. Eur J Hum Genet 2000; 8 (01) 54-62
  • 35 Grigelioniene G, Schoumans J, Neumeyer L. , et al. Analysis of short stature homeobox-containing gene (SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity. Hum Genet 2001; 109 (05) 551-558
  • 36 Benito-Sanz S, Royo JL, Barroso E. , et al. Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer. J Med Genet 2012; 49 (07) 442-450
  • 37 Bunyan DJ, Baker KR, Harvey JF, Thomas NS. Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5 kb deletion 160 kb downstream with a variable phenotypic effect. Am J Med Genet A 2013; 161A (06) 1329-1338