Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

Eyal Reinstein, Sophia Frentz, Tim Morgan, Sixto Garcia-Minaur, Richard Leventer, George McGillivray, Mitchel Pariani, Anthony van der Steen, Michael Pope, Muriel Holder-Espinasse, Richard Scott, Elizabeth Thompson, Terry Robertson, Brian Coppin, Robert Siegel, Montserrat Bret Zurita, Jose Rodriguez, Carmen Morales, Yuri Rodrigues, Joaquin ArcasAnand Saggar, Margaret Horton, Elaine Zackai, John Graham, David Rimoin, Stephen Robertson

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    78 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)494-502
    Number of pages9
    JournalEuropean Journal of Human Genetics
    Issue number5
    Publication statusPublished - May 2013


    • Ehlers-Danlos syndrome
    • Filamin A
    • Periventricular heterotopia
    • Screening


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