ESPE Abstracts (2015) 84 P-3-1025


New Point Mutation in Short Stature Homeobox Gene Leads to Phenotype of Lery-Weill Dyschondrosteosis

Eva Koffemana, Gera Hoorweg-Nijmanb, Hanneke van Santena & Nienke Volker-Touwc


aDepartment of Pediatrics, Wilhelmina Children’s Hospital, Utrecht, The Netherlands; bDepartment of Pediatrics, St. Antonius Hospital, Nieuwegein, The Netherlands; cDepartment of Clinical Genetics, Wilhelmina Children’s Hospital, Utrecht, The Netherlands

Background: Short stature homeobox (SHOX)-related haploinsufficiency is associated with a wide clinical variability, all characterized by growth failure with or without mesomelia and/or Madelung deformity. In patients, the effect of GH therapy on final height is comparable to the effect that can be obtained in Turner syndrome. The majority of the patients with SHOX-related haploinsufficiency disorder have deletions of varying sizes in SHOX. Point mutations in SHOX account for 30% of the SHOX-related haploinsufficiency disorders1.

Case presentation: An 11 year old girl of Moroccan descent, presented with non-familiar short stature. Her target height was 0 S.D. on the Dutch growth chart. Her height was −2.5 S.D. below target height (−2 S.D. for girls of Moroccan descent), sitting height/height ratio was +2 S.D. Clinical and radiological examination showed Madelung deformity of the wrists. Karyotyping showed 46, XX and Multiplex Ligation-dependent Probe Amplification (MLPA)-analysis of the SHOX gene identified no deletions. Because Lery-Weill dyschondrosteosis was clinically suspected, sequence analysis of the SHOX gene was requested. This identified heterozygosity for a de novo c.836T>G p.(Leu279Arg) unclassified, but likely pathogenic variant in the SHOX gene. GH therapy was initiated at the age of 13 years.

Conclusion: We identified a new, likely pathogenic point mutation in the SHOX gene in a girl with a clinical phenotype of Lery-Weill dyschondrosteosis. Although point mutations make up one third of the SHOX-related haploinsufficiency disorders, standard analysis for point mutations after negative screening for deletions was not common practice in the Netherlands at the time we requested diagnostics. SHOX-related haploinsufficiency is an indication for GH therapy. Therefore, we recommend that sequence analysis or mutation scanning of the SHOX gene should always be performed in children with a clinical phenotype of SHOX-related haploinsufficiency, when deletion/duplication analysis of the SHOX gene does not confirm the diagnosis.

1. SHOX-Related Haploinsufficiency Disorders, Last Update February 1, 2008

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