title: Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation.
abstract: BACKGROUND
  The Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder characterized by thoracic aortic aneurysm and dissection and widespread systemic connective tissue involvement. LDS type 1 to 4 are caused by mutations in genes of the TGF-β signaling pathway: TGFBR1 and TGFBR2 encoding the TGF-β receptor (LDS1 and LDS2), SMAD3 encoding the TGF-β receptor cytoplasmic effector (LDS3), and TGFB2 encoding the TGF-β2 ligand (LDS4). LDS4 represents the mildest end of the LDS spectrum, since aneurysms are usually observed in fourth decade and the progression of the disease is slower than in the other forms.
  
  
  METHODS
  We report the clinical and molecular findings of an LDS4 Italian family. Genetic testing included TGFBR1, TGFBR2, SMAD3, and TGFB2 analysis by Sanger sequencing. In order to verify the effect of the identified splice mutation, RT-PCR analysis was performed.The proband, a 57-year-old woman, showed high palate, hypoplasic uvula, easy bruising, joint hypermobility, chronic pain, scoliosis, multiple relapsing hernias, dural ectasia, and mitral valve prolapse. Magnetic resonance angiography revealed tortuosity and ectasia of carotid, vertebral, cerebral, and segmental pulmonary arteries. Arterial aneurysm and dissection never occurred. Her 39- and 34-year-old daughters presented with a variable degree of musculoskeletal involvement. Molecular analysis disclosed the novel c.839-1G>A splice site mutation in the TGFB2 gene. This mutation activates a cryptic splice acceptor site in exon 6 leading to frameshift, premature termination codon and haploinsufficiency (p.Gly280Aspfs*41).
  
  
  CONCLUSIONS
  Our data confirm that loss-of-function mutations in TGFB2 gene do not always lead to aggressive vascular phenotypes and that articular and skeletal signs are prevalent, therefore suggesting that LDS4 must be considered in patients with sparse signs of LDS and related disorders also in the absence of vascular events.
authors.forename: Marco
authors.initials: M
authors.lastname: Ritelli
authors.forename: Nicola
authors.initials: N
authors.lastname: Chiarelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Dordoni
authors.forename: Stefano
authors.initials: S
authors.lastname: Quinzani
authors.forename: Marina
authors.initials: M
authors.lastname: Venturini
authors.forename: Roberto
authors.initials: R
authors.lastname: Maroldi
authors.forename: Piergiacomo
authors.initials: P
authors.lastname: Calzavara-Pinton
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, Medical Faculty, University of Brescia, Viale Europa 11, Brescia 25123, Italy. marina.colombi@unibs.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
mesh_terms: D000328:Adult; D018389:Codon, Nonsense; D005260:Female; D016368:Frameshift Mutation; D057895:Haploinsufficiency; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D012326:RNA Splicing; D053781:Transforming Growth Factor beta2 / Q000235:genetics*; D014652:Vascular Diseases / Q000235:genetics* / Q000473:pathology*
chemical_list: D018389:Codon, Nonsense; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2