Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Léri-Weill Dyschondrosteosis (LWD), Langer Mesomelic Dysplasia (LMD) [Q77.8, Q87.1]

OMIM numbers: 127300 (LWD), 249700 (LMD), 312865 (SHOX)

Dipl.-Biol. Christine Schack, Dipl.-Biol. Christina Sofeso

Scientific Background

The Léri-Weill dyschondrosteosis (LWD) is a pseudo-autosomal dominant syndrome marked by disproportionate short stature mainly characterized by mesomelic shortening of the extremities. A typical feature is Madelung deformity of the wrists, which develops in the course of life, usually during puberty. In most cases, the disease is caused by a haploinsufficiency of the SHOX gene, which is located in the pseudo-autosomal region (PAR1) on the short arm of both sex chromosomes. The SHOX protein is a transcriptional activator in osteogenic cells and is therefore influencing the cell cycle and growth regulation. 

Among Caucasians, mutations in the SHOX gene have an incidence of approximately 1 in 1,000. Heterozygous mutations in the SHOX gene are detected in up to 70% of all LWD cases. Approximately 90% of these mutations are deletions of large regions or the entire gene and its regulatory elements. The remaining cases are caused by point mutations, small deletions and insertions in the SHOX gene. A complete loss of SHOX activity due to homozygous or compound heterozygous mutations in the SHOX gene results in a Langer mesomelic dysplasia (LMD). LMD has a considerably more severe course than LWD.

Mutations in the SHOX gene have, apart from LWD and LMD, also been associated with the skeletal changes of the Turner syndrome as well as with 2–5% of all cases of idiopathic short stature. This can complicate a distinction between LWD and other types of short stature significantly. Moreover, the clinical phenotype of SHOX mutations varies strongly and may range from severe disproportionate short stature to mild short stature with or without anomalies detectable during radiologic examination, even within one family.