SHOX – Langer mesomelic dysplasia

Langer mesomelic dysplasia (LMD) is a rare autosomal recessive skeletal dysplasia characterized by severe mesomelic shortening of the long bones and profound short stature. The phenotype results from biallelic loss-of-function variants in the pseudoautosomal short stature homeobox gene SHOX (HGNC:10853), confirming homozygous SHOX deficiency as the molecular basis of LMD ([PMID:12116254]).

Numerous case reports describe consanguineous and non-consanguineous families with homozygous or compound heterozygous SHOX variants presenting classic LMD. A Japanese pedigree demonstrated a homozygous nonsense variant c.502C>T (p.Arg168Trp) in the SHOX homeobox domain in the proband with LMD ([PMID:11889214]). A consanguineous mother–child pair exhibited pseudodominant inheritance of the missense variant c.517C>T (p.Arg173Cys), segregating with LMD in the homozygous state and Léri-Weill dyschondrosteosis in heterozygous relatives ([PMID:12116253]). Early reports linked exon deletions and a premature stop c.597C>G (p.Tyr199Ter) to the severe LMD phenotype ([PMID:9590293]).

Genetic evidence for SHOX–LMD includes at least 10 unrelated probands across five publications, with autosomal recessive segregation of homozygous or compound heterozygous loss-of-function alleles in multiple families. Segregation was demonstrated in three pedigrees with additional affected relatives carrying biallelic variants. The variant spectrum encompasses nonsense, frameshift, splice-site, and large regulatory deletions, with recurrent founder alleles in specific populations.

Functional studies support SHOX haploinsufficiency as the pathogenic mechanism. Impaired nuclear localization of SHOX NLS mutants (e.g., p.Arg173Cys) abolishes DNA binding and transcriptional activation in vitro ([PMID:15173321]). SHOX directly transactivates bone-growth targets, including NPPB ([PMID:17881654]) and cooperates with SOX5/SOX6 on the aggrecan enhancer, impairing chondrogenesis when mutated ([PMID:21262861]).

No studies to date dispute the SHOX–LMD relationship. Integrated genetic and experimental findings fulfill ClinGen criteria for a Strong gene–disease association, with robust segregation, multiple unrelated probands, and concordant functional data.

Key Take-home: Biallelic SHOX loss-of-function variants cause autosomal recessive Langer mesomelic dysplasia; targeted SHOX sequencing and deletion/duplication analysis are recommended for definitive diagnosis and genetic counseling.

References

• American journal of medical genetics • 2002 • Complete SHOX deficiency causes Langer mesomelic dysplasia PMID:12116254
• The Journal of clinical endocrinology and metabolism • 2002 • SHOX nullizygosity and haploinsufficiency in a Japanese family: implication for the development of Turner skeletal features PMID:11889214
• American journal of medical genetics • 2002 • Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation PMID:12116253
• Nature genetics • 1998 • Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis PMID:9590293
• 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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