The SHOX (short-stature homeobox-containing) gene encodes isoforms of a homeodomain transcription factor important in human limb development. SHOX haploinsufficiency has been implicated in three human growth disorders: Turner syndrome, idiopathic short stature, and Leri-Weill dyschondrosteosis. Langer mesomelic dysplasia is thought to be the homozygous form of dyschondrosteosis. However, complete SHOX deficiency has not been demonstrated for any postnatal patient with the classic Langer phenotype. We studied four adults and one child with Langer mesomelic dysplasia. SHOX abnormalities were detected in all five probands. One was a homozygote or hemizygote and two were compound heterozygotes. The homozygous or hemizygous mutation was in exon 6a, implying that the SHOXa isoform is essential for normal skeletal development. These findings confirm clinical inferences that Langer mesomelic dysplasia is the homozygous form of Leri-Weill dyschondrosteosis and add to our understanding of genotype/phenotype relationships in SHOX deficiency disorders.
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Mild phenotypes in patients with different deletions in the 3' enhancer region of SHOX.
Eur J Hum Genet
June 2024
Shriners Hospital for Children, Montreal, QC, Canada.
Haploinsufficiency of the short stature homeobox-containing (SHOX) gene leads to a phenotypic spectrum ranging from Leri-Weill dyschondrosteosis (LWD) to SHOX-deficient short stature. SHOX nullizygosity leads to Langer mesomelic dysplasia. Pathogenic variants can include whole or partial gene deletions or duplications, point mutations within the coding sequence, and deletions of upstream and downstream regulatory elements.
View Article and Find Full Text PDFCombined achondroplasia and short stature homeobox-containing (SHOX) gene deletion in a Danish infant.
Eur J Med Genet
February 2024
Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark; Department of Clinical Genetics, Aarhus University Hospital, Denmark; Centre for Rare Diseases, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
Short stature or shortening of the limbs can be the result of a variety of genetic variants. Achondroplasia is the most common cause of disproportionate short stature and is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3). Short stature homeobox (SHOX) deficiency is caused by loss or defects of the SHOX gene or its enhancer region.
View Article and Find Full Text PDFRARE DOSAGE ABNORMALITIES - COPY NUMBER VARIATIONS FLANKING THE SHOX GENE.
Acta Endocrinol (Buchar)
August 2023
Research Department, "C.I. Parhon" National Institute of Endocrinology Bucharest, Romania.
Background: Molecular defects in the gene including deletions, duplications or pathogenic point mutations are responsible for well-known pathologies involving short stature as a clinical manifestation: Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome or idiopathic short stature. Duplications flanking the gene (upstream or downstream of the intact gene involving conserved non-coding cis-regulatory DNA elements - CNEs) have been described but their clinical involvement is still difficult to understand.
Results: We describe two cases with short stature and normal GH-IGF1 status.
Leri-Weill Dyschondrosteosis Caused by a Leaky Homozygous Splice-Site Variant.
Genes (Basel)
April 2023
Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri-Weill dyschondrosteosis (LWD) as well as nonspecific short stature. haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD).
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