Clinical characteristics: The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to nonspecific short stature at the mild end of the spectrum. In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shortened in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of short stature caused by SHOX deficiency in the absence of mesomelia and Madelung deformity (called SHOX-deficient short stature in this GeneReview) is highly variable, even within the same family.

Diagnosis/testing: The diagnosis of SHOX deficiency is established in a proband with either a pathogenic SHOX variant or a deletion, duplication, or insertion that can encompass the SHOX coding region and/or the enhancer region regulating SHOX expression.

Management: Treatment of manifestations: For prepubertal children with SHOX-deficient short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. For individuals with LWD and painful bilateral Madelung deformity (which is uncommon): wrist splints and supports during periods of increased discomfort and the use of ergonomic devices such as ergonomic computer keyboards. Different operative procedures have been attempted to decrease pain and restore wrist function.

Surveillance: For children with a SHOX deficiency disorder: biannual measurement of growth.

Agents/circumstances to avoid: If Madelung deformity is associated with discomfort, physical activities such as lifting, gripping, writing, typing, and sports that strain the wrist should be limited and ergonomic aids sought.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment are warranted for sibs at risk for SHOX-deficient short stature in order to identify as early as possible those who would benefit from recombinant human growth hormone (rhGH) treatment.

Genetic counseling: SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (Yp) follow the rules of autosomal inheritance; thus, a SHOX pathogenic variant responsible for SHOX deficiency can be located on either the X or the Y chromosome of an affected male, or on either of the X chromosomes of an affected female.

Each child of an individual with a SHOX deficiency disorder has a 50% chance of inheriting the SHOX pathogenic variant. If both parents have SHOX deficiency, the offspring have a 50% chance of having a SHOX deficiency disorder, a 25% chance of having Langer type of mesomelic dwarfism, and a 25% chance of having neither condition. If the SHOX pathogenic variant has been identified in one or both parents, prenatal testing for pregnancies at increased risk is possible; however, the phenotype of the SHOX deficiency disorder cannot be accurately predicted on the basis of prenatal molecular genetic testing results.