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Phenotypes Associated with SHOX Deficiency

Departments of Pediatrics (J.L.R., C.S., K.K., A.N.) and Orthopedic Surgery (J.A., L.O.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Alfred I. DuPont Hospital for Children (J.L.R., C.S.), Wilmington, Delaware 19803; Molecular Endocrinology, Research and Development (P.M.), Esoterix Endocrinology, Calabasas Hills, California 91301; Laboratory Corporation of America (P.P.), Research Triangle Park, North Carolina 27709; Biomedical Computing (H.K.), Philadelphia, Pennsylvania 19115; Texas Scottish Rite Hospital for Children (P.C., M.E.), Dallas, Texas 75219; Department of Pathology (F.E.), The University of Texas Southwestern Medical School, Dallas, Texas 75219; and Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine (F.W., H.C., A.R.Z.), The University of Texas Southwestern Medical School, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Judith L. Ross, M.D., Thomas Jefferson University, Department of Pediatrics, 1025 Walnut Street, Philadelphia, Pennsylvania 19107. E-mail: Judith.Ross@mail.tju.edu (or Andrew.Zinn{at}UTSouthwestern.edu)

Abstract

Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3–56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype.

SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean ± SD = -2.2 ± 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations.

In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.

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