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Ann Pediatr Endocrinol Metab > Volume 29(3); 2024 > Article
Kang, Kim, Yoo, and Cheon: Identification of a novel mutation of the SHOX gene in a patient with Leri-Weill dyschondrosteosis accompanied by growth hormone deficiency


· Leri-Weil dyschondrosteosis (LWD) is a rare pseudoautosomal form of skeletal dysplasia. We report the case of a 9-year-old girl who was diagnosed with growth hormone deficiency (GHD), and later diagnosed with LWD. This case shows the efficacy of recombinant human growth hormone therapy for patients with LWD and GHD.
To the editor,
Leri-Weill dyschondrosteosis (LWD) (OMIM #127300) is a rare pseudoautosomal form of skeletal dysplasia characterized by short stature, mesomelic limb shortening, and Madelung deformity of the wrist [1]. LWD is predominantly caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX) (OMIM #312865), which is located on the sex chromosomes (Xp22.33, Yp11.32) [2]. The prevalence of LWD is unknown, but it has been estimated to affect approximately 1 in 1,000–2,000 individuals in the general population [3]. In Korea, a few cases have been reported; however, related research and studies are lacking. Here, we report a case of a patient with LWD diagnosed with growth hormone (GH) deficiency (GHD), introduce a novel variant of the SHOX gene, and demonstrate the efficacy of recombinant human GH (rhGH) therapy.
A 9-year-2-month-old girl with no medical history was referred to our pediatric endocrine clinic because of short stature. She had been delivered vaginally at 41 weeks of gestation and weighing 2.96 kg (standard deviation score [SDS], -1.55). Although she had been slightly shorter than her peers since childhood, no significant developmental abnormalities were observed. Her height and weight at the first visit were 122.8 cm (SDS, -2.07) and 26.5 kg (SDS, -0.9), respectively. Her father’s height was 163 cm (SDS, -2.15) and her mother's height was 154 cm (SDS, -1.48). These standard deviations are based on the heights of adults in Korea. Laboratory findings were within their normal ranges. Her bone age was confirmed by radiography of the left wrist and hand to be 8 years old using the Greulich-Pyle method, which is 1 year 2 months younger than her chronological age. A chromosome test initially performed to differentiate Turner syndrome indicated 46,XX, a normal female karyotype. A test was performed to detect GHD, and the peak GH level during the arginine stimulation test was 0.378, while the peak GH level during the clonidine stimulation test was 7.74. As both of these values were <10, GHD was diagnosed. The patient received rhGH therapy beginning from the age of 9 years 5 months; in the sixth month of treatment, she reported pain in the right wrist. Wrist radiographs were obtained again by a pediatric orthopedic surgeon, and a Madelung deformity was confirmed (Fig. 1). Irregular growth regions of both radii were observed in both wrists, and the end of the ulnar bone did not appear to fit properly with the end of the radius, particularly in the right arm. A genetic work-up was planned to evaluate suspected skeletal dysplasia. Whole-genome sequencing (WGS) revealed a possible 763-kb deletion including the SHOX gene, and a breakpoint region was confirmed by Sanger sequencing. Thus, LWD was confirmed. Genetic counseling and familial mutation testing confirmed that her father and younger brother had a 763-kb deletion including the SHOX gene, while her mother had a wild-type version of the SHOX gene (Fig. 2). She continued to receive rhGH therapy for her short stature, and a good response was observed during 27 months of treatment. Her height was 125.2 cm (SDS, -1.93) in April 2021, and it steadily increased to 140.3 cm (SDS, -1.18) over the course of treatment.
The SHOX gene is one of the most frequently mutated genes associated with short stature. During this study, we identified a novel variant of the SHOX gene; specifically, a large deletion (763 kb) encompassing the SHOX gene (chrX:341409-1103971del). This case confirmed this genetic mutation using WGS. Because the SHOX gene was largely deleted in our patient, if genetic testing had been performed using other methods, such as Sanger sequencing or WES, then the abnormality would not have been found.
Because most patients with SHOX deficiency exhibit short stature, GH treatment can be used to increase their height. Therefore, administration of rhGH therapy (dose, 50 μg/kg of body weight/day) is recommended during the prepubertal period of patients with SHOX gene defects accompanied by short stature. According to previous research [4-6], the use of high-dose rhGH for diseases associated with the SHOX gene defect increases the height growth effect of patients similar to in Turner syndrome.
The U.S. Food and Drug Administration has approved rhGH therapy for LWD [7]; however, it has not yet been approved by the Korean National Health Insurance. Our case, as well as other reports [4-6], demonstrate the positive effects of rhGH therapy in patients with SHOX deficiency, and, as early intervention is necessary, it is hoped that LWD will be considered as an indication for rhGH therapy in Korea.


Conflicts of interest

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


This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical statement

The study protocol was approved by the Institutional Review Board (IRB) of Pusan National University Yangsan Hospital (IRB No. 55-2023-020). All procedures were performed in accordance with the Declaration of Helsinki.

Fig. 1.
Wrist radiographs of both hands. Madelung deformity is shown: There are bowing and shortening of radius (black arrow), pyramidalization of carpus (white dotted inverted triangle), lucent ulnar side of distal radius (white hollow arrow) and triangularization of the distal radial epiphysis (black dotted triangle).
Fig. 2.
Sanger sequencing confirmation of the heterozygous mutation of SHOX gene.


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