title: Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature.
abstract: Beals-Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23-34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2-positive patients. In our FBN2-positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z-score: 4.09) and his father (z-score: 2.94), warranting echocardiographic follow-up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2-negative patients in this cohort were clinically indistinguishable from all published FBN2-positive patients harboring a FBN2 mutation, suggesting locus heterogeneity.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Belgium.
authors.forename: Bert L
authors.initials: BL
authors.lastname: Callewaert
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Anna
authors.initials: A
authors.lastname: Ficcadenti
authors.forename: Sascha
authors.initials: S
authors.lastname: Vermeer
authors.forename: Magnus
authors.initials: M
authors.lastname: Landgren
authors.forename: Hester Y
authors.initials: HY
authors.lastname: Kroes
authors.forename: Yuval
authors.initials: Y
authors.lastname: Yaron
authors.forename: Michael
authors.initials: M
authors.lastname: Pope
authors.forename: Nicola
authors.initials: N
authors.lastname: Foulds
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.forename: Francisco
authors.initials: F
authors.lastname: Galán
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van der Aa
authors.forename: Iratxe
authors.initials: I
authors.lastname: Salcedo
authors.forename: Marielle E
authors.initials: ME
authors.lastname: Swinkels
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.forename: Orazio
authors.initials: O
authors.lastname: Gabrielli
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Anne M
authors.initials: AM
authors.lastname: De Paepe
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D054119:Arachnodactyly / Q000473:pathology*; D002648:Child; D003286:Contracture / Q000151:congenital / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D000071840:Fibrillin-2; D000071837:Fibrillins; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D013577:Syndrome
chemical_list: C000605723:FBN2 protein, human; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins