title: Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A.
abstract: Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.
authors.affiliation: Cedars Sinai Medical Center, Medical Genetics Institute, Los Angeles, CA, USA. reinstein.eyal@gmail.com
authors.forename: Eyal
authors.initials: E
authors.lastname: Reinstein
authors.forename: Sophia
authors.initials: S
authors.lastname: Frentz
authors.forename: Tim
authors.initials: T
authors.lastname: Morgan
authors.forename: Sixto
authors.initials: S
authors.lastname: García-Miñaúr
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.forename: George
authors.initials: G
authors.lastname: McGillivray
authors.forename: Mitchel
authors.initials: M
authors.lastname: Pariani
authors.forename: Anthony
authors.initials: A
authors.lastname: van der Steen
authors.forename: Michael
authors.initials: M
authors.lastname: Pope
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.forename: Richard
authors.initials: R
authors.lastname: Scott
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Thompson
authors.forename: Terry
authors.initials: T
authors.lastname: Robertson
authors.forename: Brian
authors.initials: B
authors.lastname: Coppin
authors.forename: Robert
authors.initials: R
authors.lastname: Siegel
authors.forename: Montserrat
authors.initials: M
authors.lastname: Bret Zurita
authors.forename: Jose I
authors.initials: JI
authors.lastname: Rodríguez
authors.forename: Carmen
authors.initials: C
authors.lastname: Morales
authors.forename: Yuri
authors.initials: Y
authors.lastname: Rodrigues
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arcas
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.forename: Margaret
authors.initials: M
authors.lastname: Horton
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D001158:Arteries / Q000473:pathology*; D001483:Base Sequence; D015153:Blotting, Western; D015331:Cohort Studies; D003238:Connective Tissue / Q000473:pathology*; D003285:Contractile Proteins / Q000235:genetics*; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D064448:Filamins; D006801:Humans; D007150:Immunohistochemistry; D007593:Joint Instability / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009520:New Zealand; D054091:Periventricular Nodular Heterotopia / Q000235:genetics* / Q000473:pathology*; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology*
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins