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Ann Pediatr Endocrinol Metab > Volume 20(3); 2015 > Article
Choi, Seo, Yoo, Kim, and Kwak: A Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of SHOX gene


Leri-Weill dyschondrosteosis is characterized by SHOX deficiency, Madelung deformity, and mesomelic short stature. In addition, SHOX deficiency is associated with idiopathic short stature, Turner syndrome, and Langer mesomelic dysplasia. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by SHOX gene mutation analysis in Korea. The patient, who was a 7-year-old female, showed short stature. Her height and weight were 108.9 cm (<3rd percentile) and 19.7 kg (5th-10th percentile), respectively. Her arm span, height of trunk, leg length, and sitting length were 100.5 cm, 58 cm, 50.9 cm, and 62.5 cm, respectively. Her body proportion was 1.13:1. Extremities to trunk ratio was 2.61. Her hand radiograph showed Madelung deformity. And the growth hormone stimulation test showed a normal response. Furthermore, because of Madelung deformity with idiopathic short stature, she was suspected of SHOX deficiency. We performed SHOX gene mutation analysis and found a c.491G>A (p.W164X) mutation of the SHOX gene. Accordingly, this patient was diagnosed with Leri-Weill dyschondrosteosis. Recently, many mutations have been reported in the SHOX gene. However, to date, mutation analysis of the SHOX gene for Leri-Weill dyschondrosteosis has not been reported in Korea as yet. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of the SHOX gene.


Short stature is a common cause for referral to pediatric endocrinologists and other physicians related to children's health1). The cause of short stature is thought to be multifactorial, with a strong genetic component. One of the common causes of short stature is a defect of the short stature homeobox containing (SHOX) gene, which is located in the pseudoautosomal region 1, on the distal end of the short arm of the Xp22.33 and Yp11.32 chromosomes2,3). The SHOX gene encodes a transcription factor expressed in the developing limb and pharyngeal arch in the human embryo4) and plays an essential role in chondrocyte function in the growth plate as a regulator of cellular proliferation and differentiation5,6). SHOX deficiency is associated with Leri-Weill dyschondrosteosis (LWD)2,7), idiopathic short stature2,3,6), Turner syndrome4,8), and Langer mesomelic dysplasia9,10). More than 380 different SHOX gene mutations have been identified, distributed throughout the coding regions of the gene3,11). To date, however, no case of SHOX gene mutation has been reported in Korea through genetic analysis. Therefore, we report the first case of a LWD patient confirmed by mutation analysis of the SHOX gene.

Case report

A 7-year-old female was visited for short stature on October 24th, 2014. She was born at term weighing 3,250 g by uncomplicated spontaneous vaginal delivery. Motor and language development showed normal development. In physical examination, her height was 106.1 cm (<3rd percentile) and weight was 17.5 kg (5th-10th percentile). Furthermore, body mass index (BMI) was 15.55 kg/m2 (25th-50th percentile). She showed mesomelic disproportion of limbs. Her father's and mother's height was 165 cm and 154 cm respectively. Her father showed similar features but did not take a special examination for diagnosis. Laboratory findings were as follows: hemoglobin, 12.6 g/dL; white blood cell count, 9,350/µL; platelet, 301,000/µL; aspartate transaminase, 33 IU/L; alanine transaminase, 17 IU/L; T3, 175.9 ng/dL; free T4, 1.54 ng/dL; thyroid-stimulating hormone, 1.23 µIU/mL; insulin-like growth factor (IGF)-1, 95.36 ng/mL; and IGF-BP3, 1,902.41 ng/mL. Therefore, laboratory findings showed normal results. Her hand radiograph showed Madelung deformity. Bone age determined by the Greulich-Pyle method was 5 years 9 months at the chronological age of 7 years 2 months (Fig. 1). Except for mesomelic short stature and Madelung deformity, she did not show other physical abnormalities.
Chromosome analysis revealed the normal female karyotype 46,XX. To determine the cause of short stature, the patient was admitted on April 28th, 2015. Her height and weight were 108.9 cm (<3rd percentile) and 19.7 kg (5th-10th percentile), respectively. Over the six-month monitoring period, her growth velocity was 5.6 cm/yr. BMI was 16.6 kg/m2 (50th-75th percentile). Arm span, height of trunk, leg length, sitting height, and upper segment/lower segment ratio were 100.5 cm, 58 cm, 50.9 cm, 62.5 cm, and 1.13 (normal, 1.2), respectively.
Extremities to trunk ratio was 2.42 (normal, 2.49). For evaluation of growth hormone secretion function, a growth hormone stimulation test was done and showed a normal response.
Therefore, growth hormone secretion was normal. Because the patient showed mesomelic short stature, normal female karyotype, Madelung deformity, and low extremities to trunk ratio, she was suspected of having SHOX deficiency. Accordingly, we performed mutation analysis of the SHOX gene and found a c.491G>A (p.W164X) mutation (Fig. 2). Finally, the patient was diagnosed with LWD due to a SHOX gene mutation.


SHOX deficiency leads to short stature with variable phenotype that is frequently nonspecific in preschool children because the main characteristics of mesomelic disproportion of the limbs and Madelung deformity of the forearm develop over time and appear during the second decade of life, if at all5,11,12,13). In addition, females are more severely affected than males, and this is explained by the presence of higher estrogen levels in females. The skeletal defects tend to worsen with puberty3,14). SHOX deficiency is associated with LWD2,15,16), idiopathic short stature2,3,6,11), Turner syndrome4,8), and Langer mesomelic dysplasia9,10). Heterozygous mutations of SHOX cause LWD characterized by wrist deformity and mesomelic short stature, as well as idiopathic short stature without apparent skeletal malformations2,10,15).
Prevalence of SHOX deficiency accounts for approximately 80% and 2%-16% of genetic causes of LWD and idiopathic short stature, respectively3,5,6,7,11). Also, Turner syndrome is associated with the loss of one SHOX gene because of the numerical or structural aberration of the X chromosome associated with this syndrome3,8). The loss of both SHOX alleles causes the complete lack of SHOX and an extreme phenotype of osteodysplasia called Langer mesomelic dysplasia9,15,17). Prevalence of this syndrome is relatively rare in comparison to what could be expected from the typical effects of SHOX haploinsufficiency in short children3).
The characteristic skeletal deformity of SHOX deficiency is the Madelung deformity. This deformity is a cluster of anatomical changes in the forearm including bowing and shortening of the radius, prominence of the ulnar head, and palmar and ulnar deviation ("pyramidal configuration") of the carpal bones7).
Also, SHOX deficiency is accompanied by short stature, mesomelic shortening of the limbs, decreased extremities to trunk ratio, increased sitting height, and radiological signs such as lucency in the ulnar border of the distal radius3,7,11,12). In addition, SHOX deficiency shows features of Turner syndrome. These include shortening of the fourth and fifth metacarpals, high arched palate, increased carrying angle of the elbow, scoliosis, and micrognathia7,11). Muscular hypertrophy of the calves is found in one third of SHOX deficiency cases7,11).
Many mutations of SHOX deficiency have been reported, and most mutations are of the missense variety. Although more than 380 different SHOX gene mutations have been identified3,11), mutations of the SHOX gene have not been reported in Korea, to date, through genetic analysis. To this point, only a single case of LWD by clinical description has been reported in Korea3,11). We report the first case of a LWD patient confirmed by mutation analysis of the SHOX gene. In idiopathic short stature, the same mutation like this patient was reported by Rappold et al.11)
In SHOX deficiency, recombinant human growth hormone (rhGH) therapy has been approved by the U.S. Food and Drug Administration and supported by data from several randomized controlled trials. Treatment with rhGH is effective in growth promotion in children with SHOX deficiency, and the growth-promoting effect of rhGH therapy depends on age at treatment initiation3,18,19). However, rhGH therapy for SHOX deficiency is excluded from rhGH treatment indications criteria of the Korean National Health Insurance. Thus, SHOX deficiency patients do not receive medical insurance benefits in Korea.
Until now, cases of the SHOX gene mutation have not been reported in Korea through genetic analysis. Therefore, our case report should serve as a valuable finding of SHOX deficiency via genetic analysis. Additionally, our report should encourage researchers to analyze other genetic mutations related to SHOX deficiency, and can provide hope to advocate for rhGH treatment of SHOX deficiency patients.


This work has supported by clinical research grant from Pusan National University Hospital 2014.


Conflict of interest: No potential conflict of interest relevant to this article was reported.


1. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, 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. PMID: 18782877.
crossref pmid pdf
2. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997;16:54–63. PMID: 9140395.
crossref pmid pdf
3. Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr 2011;75:81–89. PMID: 21325865.
crossref pmid
4. Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, Zeller R, et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet 2000;9:695–702. PMID: 10749976.
crossref pmid pdf
5. 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:E1257–E1265. PMID: 22518848.
crossref pmid
6. Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bettendorf M, et al. Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab 2002;87:1402–1406. PMID: 11889216.
crossref pmid
7. Seki A, Jinno T, Suzuki E, Takayama S, Ogata T, Fukami M. Skeletal deformity associated with SHOX deficiency. Clin Pediatr Endocrinol 2014;23:65–72. PMID: 25110390.
crossref pmid pmc
8. Blaschke RJ, Rappold GA. SHOX: growth, Léri-Weill and Turner syndromes. Trends Endocrinol Metab 2000;11:227–230. PMID: 10878753.
crossref pmid
9. Leka SK, Kitsiou-Tzeli S, Kalpini-Mavrou A, Kanavakis E. Short stature and dysmorphology associated with defects in the SHOX gene. Hormones (Athens) 2006;5:107–118. PMID: 16807223.
crossref pmid
10. Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, et al. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet 1998;19:67–69. PMID: 9590292.
crossref pmid pdf
11. Rappold G, Blum WF, Shavrikova EP, Crowe BJ, Roeth R, Quigley CA, et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007;44:306–313. PMID: 17182655.
crossref pmid
12. 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;88:4891–4896. PMID: 14557470.
crossref pmid
13. Jorge AA, Souza SC, Nishi MY, Billerbeck AE, Liborio DC, Kim CA, et al. SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Clin Endocrinol (Oxf) 2007;66:130–135. PMID: 17201812.
crossref pmid
14. Fukami M, Nishi Y, Hasegawa Y, Miyoshi Y, Okabe T, Haga N, et al. Statural growth in 31 Japanese patients with SHOX haploinsufficiency: support for a disadvantageous effect of gonadal estrogens. Endocr J 2004;51:197–200. PMID: 15118270.
crossref pmid
15. Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, et al. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 1998;19:70–73. PMID: 9590293.
crossref pmid pdf
16. Binder G, Renz A, Martinez A, Keselman A, Hesse V, Riedl SW, 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;89:4403–4408. PMID: 15356038.
crossref pmid
17. Zinn AR, Wei F, Zhang L, Elder FF, Scott CI Jr, Marttila P, et al. Complete SHOX deficiency causes Langer mesomelic dysplasia. Am J Med Genet 2002;110:158–163. PMID: 12116254.
crossref pmid
18. Blum WF, Crowe BJ, Quigley CA, Jung H, Cao D, Ross JL, et al. 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. PMID: 17047016.
crossref pmid pdf
19. Scalco RC, Melo SS, Pugliese-Pires PN, Funari MF, Nishi MY, Arnhold IJ, et al. 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. PMID: 19926713.
crossref pmid
Fig. 1

Left hand radiograph. Bone age determined by the Greulich-Pyle method was 5 years 9 months (chonological age was 7 years 2 months). Madelung deformity is shown: triangularization of the distal radial epiphysis, and lucent ulnar side of distal radius (arrow).

Fig. 2

Partial genomic DNA sequencing of the SHOX gene of the patient: heterogygous mutation of c.491G>A (p.W164X) in the SHOX gene.



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