Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: Implications for the development of Turner syndrome

We report on clinical features in 14 Japanese patients (4 males and 10 fema les) with partial monosomy of the short arm pseudoautosomal region involvin g SHOX (n = 11) or total monosomy of the pseudoautosomal region with no inv olvement of disease genes on the sex-differential regions (n = 3). Skeletal assessment showed that three patients had no discernible skeletal abnormal ities, one patient exhibited short 4th metacarpals and borderline cubitus v algus, and the remaining 10 patients had Madelung deformity and/or mesomeli a characteristic of Leri-Weill dyschondrosteosis (LWD), together with short 4th metacarpals and/or cubitus valgus. Skeletal lesions were more severe i n females and became obvious with age. Growth evaluation revealed that pati ents without LWD grew along by the -2 SD growth curve before puberty and sh owed a normal or exaggerated pubertal growth spurt, whereas those with LWD grew along by the standard growth curves before puberty but exhibited an at tenuated pubertal growth spurt and resultant short stature. Maturational as sessment indicated a tendency of relatively early maturation in patient; wi th LWD. There was no correlation between the clinical phenotype and the del etion size. These findings suggest that haploinsufficiency of SHOX causes not only shor t stature but also Turner skeletal anomalies (such as short 4th metacarpals , cubitus valgus, and LWD) and that growth pattern is primarily dependent o n the presence or absence of LWD. Because skeletal lesions have occurred in a female-dominant and age-influenced fashion, it is inferred that estrogen s exert a maturational effect on skeletal tissues that are susceptible to p remature fusion of growth plates because of haploinsufficiency of SHOX, fac ilitating the development of skeletal lesions.