Identification of a novel mutation of the SHOX gene in a patient with Leri-Weill dyschondrosteosis accompanied by growth hormone deficiency

Highlights• Leri-Weil dyschondrosteosis (LWD) is a rare pseudoautosomal form of skeletal dysplasia.We report the 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-