Date Published: August 03, 2013
Publisher: Wiley Periodicals, Inc.
Author(s): Hugh Young Rienhoff, Chang-Yeol Yeo, Rachel Morissette, Irina Khrebtukova, Jonathan Melnick, Shujun Luo, Nan Leng, Yeon-Jin Kim, Gary Schroth, John Westwick, Hannes Vogel, Nazli McDonnell, Judith G Hall, Malcolm Whitman.
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.
The transforming growth factor β (TGFB) 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 syndrome (LDS, OMIM #609192). We describe a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development without evidence of vascular disease; some 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 TGFB 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.
The proband is a 9-year-old European-American female born to nonconsanguineous, healthy parents with two older healthy children and no previous miscarriages. Mother was 34 years old and father was 42 at delivery. No cytogenetic abnormality was observed on chromosome samples obtained at 19 weeks gestation by amniocentesis. The pregnancy was unremarkable and the mother reported that the fetus moved in utero similarly to older siblings. The child was born at full term by repeat caesarian; Apgars were 9 and 9 at 1 and 5 min, respectively. The birth weight was 2.9 kg (5th centile), length was 51 cm (50th centile), and OFC was 35.75 (>50th centile). The physical exam showed contractures in the right hand, most severe in the 3rd and 4th fingers (see Fig. S1 in Supplementary online material) and all toes. The digits on the left hand and foot showed minimal contractures. Range of motion of knees, hips, elbows, jaws, and back were considered normal. Hands and feet appeared long and narrow although no measurements were taken. There was a midline facial nevus flammeus and mild hypotonia.
Genomic DNA was extracted from peripheral mononuclear blood cells from the proband, two unaffected sibs, and parents. The details of the exome and Sanger sequencing and the Xenopus and cultured cell methods are described in Supplementary online material. The focus of the sequence data filtering was for novel non-synonymous variants that were unique. These included heterozygous novel missense and nonsense substitutions and frame-shifting insertions and deletions (in/dels) not detected in other family members. In addition, we looked for homozygous non-synonymous variants (missense or nonsense substitutions or frame-shifting in/dels) where she was the only family member homozygous for the damaging allele, and where both parents were heterozygous. Finally, we looked compound heterozygosity of deleterious alleles in genes associated with heritable disorders of connective tissue.
The proband shared the clinical feature of low muscle mass with hypotonia with three related conditions: Marfan, Loeys–Dietz, and Beals–Hecht syndrome (BHS, OMIM # 121050). She was hyperteloric and had a bifid uvula, the two non-vascular findings that define LDS; the skeletal findings typical of MFS included arachnodactyly, pectus excavatum, pes planus, and hyperextensible large joints. The proposita did not meet the diagnostic criteria established for MFS, BHS or LDS. Among the inconsistencies with these diagnoses were significant growth retardation, the absence of cardiovascular findings, and the distinct muscle histopathology. These three syndromes are allied in their pathophysiology. TGF-β signaling is dysregulated in the first two conditions and analogous pathophysiology is suspected in BHS, given the similar functions of FBN1 and FBN2. The clinical overlap with these autosomal dominant syndromes and the unaffected status of the parents suggested a de novo mutation acting as a dominant trait in a gene affecting TGF-β signaling. Analysis of the six genes (TGFB2, TGFBR1, TGFBR2, SMAD3, FBN1, FBN2) associated with MFS, LDS, or BHS identified no mutation. We sought to identify de novo mutations through exome sequencing; consistent with expectations [Neale et al., 2012], we found two nucleotide changes unequivocally unique to the proband, in CDH2 and TGFB3.
The principal clinical concerns for this patient have been growth retardation, weakness related to decreased muscle mass and uncertainty about her risk for vascular disease. Distal arthrogryposis indicative of reduced fetal movement suggested an inborn error of development affecting muscle mass and other developing mesenchymal tissues, including the soft palate.