Léri-Weill dyschondrosteosis (LWD) is a pseudoautosomal-dominantly inherited disproportionate short stature syndrome characterized mainly by mesomelic shortening of the limbs. A typical feature is Madelung deformity of the wrists, which tends to develop during life, most commonly during puberty. In most cases, the cause of LWD is 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 (short stature homeobox) gene encodes a transcription factor that plays a role in chondrocyte function in the growth plate region and is necessary for normal limb development.
Pathogenic alterations of the SHOX gene occur in the Caucasian population at an incidence of approximately 1:1,000. Causative variants in the SHOX gene can be detected in up to 70% of LWD cases. More than 80% of these are deletions encompassing all or large portions of the gene and its regulatory elements. Sequence variants in the SHOX gene are causative in the remainder of these cases. Complete loss of SHOX activity due to homozygous or combined heterozygous alterations of the SHOX gene results in Langer mesomelic dysplasia (LMD). LMD is a much more severe form than LWD.
In addition to LWD and LMD, SHOX deficiency is also associated with the skeletal changes of Ullrich-Turner syndrome and with up to 2-5% of cases of idiopathic short stature. This can significantly complicate the differentiation of LWD from other syndromes associated with short stature. The clinical phenotype in individuals with SHOX alterations varies widely. In some cases, it can manifest as anything from very severe disproportionate short stature to mild short stature, with or without clinically and radiologically detectable abnormalities. This variability can occur even within the same family among carriers of the same alteration. Molecular genetic diagnostics can aid in the timely diagnosis of SHOX deficiency and the potential treatment of this growth disorder with growth hormone.
References
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