title: Loeys-Dietz syndrome type I and type II: clinical findings and novel mutations in two Italian patients.
abstract: BACKGROUND
  Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder showing the involvement of cutaneous, cardiovascular, craniofacial, and skeletal systems. In particular, LDS patients show arterial tortuosity with widespread vascular aneurysm and dissection, and have a high risk of aortic dissection or rupture at an early age and at aortic diameters that ordinarily are not predictive of these events. Recently, LDS has been subdivided in LDS type I (LDSI) and type II (LDSII) on the basis of the presence or the absence of cranio-facial involvement, respectively. Furthermore, LDSII patients display at least two of the major signs of vascular Ehlers-Danlos syndrome. LDS is caused by mutations in the transforming growth factor (TGF) beta-receptor I (TGFBR1) and II (TGFBR2) genes. The aim of this study was the clinical and molecular characterization of two LDS patients.
  
  
  METHODS
  The exons and intronic flanking regions of TGFBR1 and TGFBR2 genes were amplified and sequence analysis was performed.
  
  
  RESULTS
  Patient 1 was a boy showing dysmorphic signs, blue sclerae, high-arched palate, bifid uvula; skeletal system involvement, joint hypermobility, velvety and translucent skin, aortic root dilatation, tortuosity and elongation of the carotid arteries. These signs are consistent with an LDSI phenotype. The sequencing analysis disclosed the novel TGFBR1 p.Asp351Gly de novo mutation falling in the kinase domain of the receptor. Patient 2 was an adult woman showing ascending aorta aneurysm, with vascular complications following surgery intervention. Velvety and translucent skin, venous varicosities and wrist dislocation were present. These signs are consistent with an LDSII phenotype. In this patient and in her daughter, TGFBR2 genotyping disclosed in the kinase domain of the protein the novel p.Ile510Ser missense mutation.
  
  
  CONCLUSIONS
  We report two novel mutations in the TGFBR1 and TGFBR2 genes in two patients affected with LDS and showing marked phenotypic variability. Due to the difficulties in the clinical approach to a TGFBR-related disease, among patients with vascular involvement, with or without aortic root dilatation and LDS cardinal features, genotyping is mandatory to clarify the diagnosis, and to assess the management, prognosis, and counselling issues.
authors.affiliation: Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy. brunodrera@hotmail.com
authors.forename: Bruno
authors.initials: B
authors.lastname: Drera
authors.forename: Marco
authors.initials: M
authors.lastname: Ritelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.forename: Anita
authors.initials: A
authors.lastname: Wischmeijer
authors.forename: Maria
authors.initials: M
authors.lastname: Gnoli
authors.forename: Rossella
authors.initials: R
authors.lastname: Fattori
authors.forename: Pier Giacomo
authors.initials: PG
authors.lastname: Calzavara-Pinton
authors.forename: Sergio
authors.initials: S
authors.lastname: Barlati
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
mesh_terms: D002648:Child; D005260:Female; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human