Ogata et al. (2002) reported the clinical and molecular findings in a Japanese family consisting of a male infant with SHOX nullizygosity and his 4 family members with SHOX haploinsufficiency. The male infant had Langer mesomelic dysplasia (249700), the prepubertal sister had idiopathic short stature phenotype with no discernible skeletal features, the father had mild Leri-Weill dyschondrosteosis (127300), and the mother and the maternal grandmother had moderate Leri-Weill dyschondrosteosis. The 5 subjects lacked clinically recognizable short metacarpals, cubitus valgus, high-arched palate, short neck, and micrognathia, as well as recurrent otitis media and hearing loss. Fluorescence in situ hybridization and sequence analyses showed that the proband had a pseudoautosomal microdeletion involving SHOX (312865.0003) and a 502C-T transition in the homeobox domain at exon 4 that resulted in an arg-to-trp missense mutation at codon 168 (R168W). The father was heterozygous for the SHOX deletion, and the sister, the mother, and the grandmother were heterozygous for the C502T mutation. The authors concluded that these results, in conjunction with the previous findings, suggest that mesomelic skeletal features such as Langer mesomelic dysplasia and Leri-Weill dyschondrosteosis, which are absent or rare in Turner syndrome, are primarily caused by SHOX dosage effect and the bone maturing effect of gonadal estrogens, whereas other skeletal features such as short metacarpals, cubitus valgus, and various craniofacial and cervical skeletal stigmata, which are common in Turner syndrome, are largely contributed by a compressive effect of distended lymphatics and lymphedema on the developing skeletal tissues.
