SHOX – Leri-Weill Dyschondrosteosis

SHOX encodes a paired-like homeodomain transcription factor located in the pseudoautosomal region 1 of the X and Y chromosomes. Heterozygous loss-of-function variants cause Leri-Weill dyschondrosteosis (LWD), an autosomal dominant skeletal dysplasia characterized by mesomelic short stature and Madelung deformity of the wrist ([PMID:9590293]).

Linkage analyses in multiple large pedigrees yielded lod scores up to 8.68 and identified submicroscopic deletions and point mutations in SHOX in over 100 affected individuals from more than 18 families, with full co-segregation of genotype and phenotype in both sexes ([PMID:9590293]; [PMID:10713888]). This consistent inheritance pattern supports a pseudoautosomal dominant mode of transmission.

The SHOX variant spectrum includes complete gene deletions, splice-site variants, frameshift and nonsense changes, and homeodomain missense substitutions. A representative pathogenic allele is c.597C>G (p.Tyr199Ter), which truncates the protein within the homeodomain and abolishes DNA binding ([PMID:9590293]). Population studies have also revealed recurrent large (>800 kb) deletions with founder effects in specific cohorts.

Functional studies demonstrate that homeodomain missense variants, such as c.517C>T (p.Arg173Cys), disrupt the nuclear localization signal and prevent nuclear import of SHOX protein ([PMID:15173321]). Chromatin immunoprecipitation and reporter assays confirm that SHOX directly activates targets including NPPB and cooperates with SOX5/SOX6 to drive aggrecan enhancer activity, consistent with haploinsufficiency as the pathogenic mechanism ([PMID:17881654]; [PMID:21262861]).

No studies to date refute the SHOX–LWD association. Variable expressivity and incomplete penetrance reflect dosage sensitivity and the contribution of distant regulatory elements, but no alternative disease loci have been implicated in classic LWD presentations.

In conclusion, heterozygous SHOX haploinsufficiency is a definitive cause of Leri-Weill dyschondrosteosis. Genetic testing by deletion analysis and sequencing of SHOX and its enhancers is essential for diagnosis, enabling early intervention with growth hormone therapy and informed genetic counseling.

Key Take-home: SHOX haploinsufficiency underlies Leri-Weill dyschondrosteosis, guiding accurate molecular diagnosis, tailored therapeutic strategies, and precise familial risk assessment.

References

• Nature genetics • 1998 • Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. PMID:9590293
• European journal of human genetics • 2000 • Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome PMID:10713888
• Journal of cell science • 2004 • Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome PMID:15173321
• Human molecular genetics • 2007 • BNP is a transcriptional target of the short stature homeobox gene SHOX PMID:17881654
• Human molecular genetics • 2011 • SHOX interacts with the chondrogenic transcription factors SOX5 and SOX6 to activate the aggrecan enhancer PMID:21262861

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