Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation

Am J Med Genet A. 2016 Nov;170(11):3028-3032. doi: 10.1002/ajmg.a.37847. Epub 2016 Jul 13.

Abstract

Haploinsufficiency of SATB2 causes cleft palate, intellectual disability with deficient speech, facial and dental abnormalities, and other variable features known collectively as SATB2-associated syndrome. This phenotype was accompanied by osteoporosis, fractures, and tibial bowing in two previously reported adult patients; each possessed SATB2 mutations either predicted or demonstrated to escape nonsense-mediated decay, suggesting that the additional bone defects result from a dominant negative effect and/or age-dependent penetrance. These hypotheses remain to be confirmed, as do the specific downstream defects causing bone abnormalities. We report a SATB2 mutation (c.2018dupA; p.(H673fs)) in a 15-year-old patient whose SATB2-associated syndrome phenotype is accompanied by osteoporosis, fractures, progressive tibial bowing, and scoliosis. As this homeodomain-disrupting and predicted truncating mutation resides within the final exon of SATB2, escape from nonsense-mediated decay is likely. Thus, we provide further evidence of bone phenotypes beyond those typically associated with SATB2-associated syndrome in individuals with potential dominant-negative SATB2 alleles, as well as evidence for age-dependence of bone features. Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine ratio, and osteocalcin in the patient indicate increased bone turnover. We propose surveillance and treatment with osteoclast inhibitors to prevent fractures and to slow progressive bone deformities. © 2016 Wiley Periodicals, Inc.

Keywords: Glass syndrome; SATB2; bone remodeling; osteoclastic activity; tibial bowing.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis*
  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Biomarkers
  • Bone Remodeling / genetics
  • Brain / pathology
  • Exons*
  • Fractures, Bone / genetics
  • Frameshift Mutation*
  • Haploinsufficiency
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Matrix Attachment Region Binding Proteins / genetics*
  • Osteoporosis / genetics
  • Phenotype*
  • Radiography
  • Scoliosis / genetics
  • Transcription Factors / genetics*

Substances

  • Biomarkers
  • Matrix Attachment Region Binding Proteins
  • SATB2 protein, human
  • Transcription Factors