• Open Access

A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with marfan and loeys–dietz syndrome


  • Conflict of interest: none.
  • This paper is dedicated to the memory of Victor A. McKusick and to the vitality of Beatrice.

Correspondence to:

Hugh Y. Rienhoff, Jr., M.D., Children's Hospital Oakland Research Institute, 2729 Debbie Court, San Carlos, CA 94070.

E-mail: hrienhoff@datahooks.com


The transforming growth factor β (TGF-β) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys–Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-β signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth. © 2013 Wiley Periodicals, Inc.