RESEARCH LETTER Arterial Tortuosity in Patients With Filamin A- Associated Vascular Aneurysms Eyal Reinstein, 1 * Shaine A. Morris, 2 David L. Rimoin, 3# Stephen P. Robertson, 4 and Ronald V. Lacro 5 1 Medical Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel 2 Division of Pediatric Cardiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, Texas 3 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 4 Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand 5 Department of Cardiology, Children’s Hospital Boston, Boston, Massachusetts Manuscript Received: 6 January 2014; Manuscript Accepted: 3 July 2014 TO THE EDITOR: Previous reports linked mutations in FLNA to a connective tissue disorder, termed as Ehlers-Danlos syndrome-periventricular het- erotopia subtype (EDS-PH), characterized by joint, skin, and vascular abnormalities, primarily dilatation of the thoracic aorta [Sheen et al., 2005; Go ´ mez-Garre et al., 2006]. We recently reported on the molecular and clinical manifestations in a cohort of 11 patients with X-linked-PH and suggested that EDS-PH is not a separate syndrome from XL-PH, but rather part of the clinical spectrum associated with XL-PH [Reinstein et al., 2013]. Arterial tortuosity of the head and neck vessels, as measured by the Vertebral Artery Tortuosity Index (VTI), was recently demonstrated to be elevated in patients with Loeys-Dietz (LDS) and Marfan syndromes (MS), and correlated with adverse cardiovascular outcomes in those patients [Morris et al., 2011]. We aimed to evaluate the vascular tortuosity in a mother-daughter pair with vascular aneurysms due to a mutation in the FLNA gene. This family is part of the recently published cohort of patients with FLNA mutations [Reinstein et al., 2013]. The proband is a 38-year-old female diagnosed with a 48 mm thoracic aortic aneurysm that was expanded to 57 mm under treatment with a beta-receptor antago- nist, necessitating a valve-sparing aortic root repair. A medical genetics consult was requested for evaluation of a possible Marfan syndrome. The patient reported a history of clumsiness, recurrent falls, and joint laxity during childhood, but no dislocations or fractures. She bruises normally and has normal scar formation. Physical examination revealed normal habitus with non-dysmor- phic facial features. Oral exam revealed single uvula and normal palate. There was no pectus deformity and a well-healed sternal scar was noted. Joint hypermobility was noted with Beighton score of 6/ 9 while thumb and wrist signs were negative. The skin examination revealed no striae atrophica, normal scars, and soft non-hyper- extensible skin. An ophthalmological exam confirmed myopia and excluded lens and retinal abnormalities. FBN1 gene sequencing yielded normal results. The identification of brain gray-matter heterotopias on MRI suggested a diagnosis of XL-PH and sequenc- ing of the FLNA gene revealed an 8-bp deletion in exon 6, c.883_890 that constitutes a null FLNA allele. The patient’s 19-year-old daughter is loose jointed, bruises easily, and has soft skin albeit with normal elasticity. She was found to carry the same FLNA mutation and imaging studies revealed a normal aorta but an aneurysm of the proximal right subclavian artery up to 2.4 cm (Fig. 1), and bilateral widespread neuronal heterotopia, similar to her mother. The subclavian aneurysm has slightly enlarged over last three years to 2.7cm, and surgery is pending. Calculation of arterial tortuosity following magnetic resonance angiography analysis was performed as previously described [Morris et al., 2011]. Briefly, the VTI is a result of the ratio between the actual length to the straight length of the vertebral artery. Actual length was measured by tracing the course of the vessel through 3D space from origin to end. Straight distance was calculated by measuring the linear distance from the origin to the end of the vessel. Distance factor was calculated by the formula: [actual distance/straight line dis- tanceÀ1] x100. The VTI was compared to the previously reported cohort of patients with heritable disorders of connective tissue. The VTIs of the mother and daughter were 6 and 5, respectively (Fig. 2A and B compare to 2C – increased VTI in a patient with Loeys-Dietz How to Cite this Article: Reinstein E, Morris SA, Rimoin DL, Robertson SP, Lacro RV. 2014. Arterial tortuosity in patients with Filamin A- associated vascular aneurysms. Am J Med Genet Part A. 9999:1–3. Conflict of interest: none. # Deceased. Ã Correspondence to: Eyal Reinstein, M.D., PhD, Medical Genetics Institute, Rabin Medical Center, Petach-Tikva, Israel. E-mail: Reinstein.eyal@gmail.com or eyalre1@clalit.org.il Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36717 Ó 2014 Wiley Periodicals, Inc. 1