Abstract
Non-syndromic familial thoracic aortic aneurysms and dissections (TAAD) are inherited in an autosomal dominant manner. We report a missense mutation in the smooth muscle α-actin (ACTA2; MIM*102620) gene in a 3 generational family from Northern Ireland in which iris flocculi were an ocular marker of the disease.
Non-syndromic familial thoracic aortic aneurysms and dissections (TAAD) are inherited in an autosomal dominant manner. We report a missense mutation in the smooth muscle α-actin (ACTA2; MIM*102620) gene in a three generational family from Northern Ireland () in which iris flocculi were an ocular marker of the disease.
The male proband died aged 37 years following a thoracic aortic dissection. The father and uncle of this patient had both died at the age of 55 years from a suspected acute aortic dissection. Six “at risk” family members underwent full ocular examination, imaging for asymptomatic aortic aneurysms and genetic evaluation. Four individuals had evidence of iris flocculi of varying degrees (). High resolution anterior segment optical coherence tomography demonstrated the cystic nature of the iris lesions (). Two individuals were found to have thoracic aortic aneurysms which required surgical repair. Following DNA extraction, mutational analysis of ACTA2 was performed by bidirectional sequencing. A heterozygous 492C > T substitution in ACTA2 resulting in a non-conservative amino acid substitution of arginine to cysteine at codon 149 (p.Arg149Cys) was detected in the five affected family members and absent from controls. Iris flocculi and aortic aneurysms segregated with the p.Arg149Cys mutation in this family corroborating that iris flocculi are an ocular marker of TAAD.
Familial TAAD is characterised by cardiovascular manifestations that include dilatation, aneurysms and dissections of the thoracic aorta involving the ascending or descending segments, in the absence of a systemic features of Marfan, Loeys-Dietz and Ehlers-Danlos syndrome. Other reported features of familial TAAD include: cerebral aneurysm, bicuspid aortic valve, patent ductus arteriosus, inguinal hernias, livedo reticularis and iris flocculi.Citation1,Citation2 Iris flocculi are primary iris cysts located at the pupillary border, arising from a double layer of posterior iris pigmented epithelial cells and have previously been reported in TAAD.Citation3,Citation4
Familial TAAD is a genetically heterogeneous disease with low penetrance and variable expression. Mutation in the ACTA2. MYH11. MYLK. TGFBR1. TGFBR2 and FBN1 genes can result in inherited thoracic aneurysm with dissection.Citation5 Mutation in the ACTA2 gene which encodes for the vascular smooth muscle cell specific isoform of α-actin are the most common cause of TAAD and are reported to occur in 14% of cases.Citation1 The p.Arg149Cys ACTA2 mutation detected in our family has been reported previously in 44 patients in the literature.Citation1,Citation6–8 Fifteen of these patients were documented to have iris flocculi of varying degrees and seven of these patients (46.7%) required surgery for aortic dissection, whereas seven of the 30 patients (23.3%) without iris flocculi required surgery. The presence of iris flocculi may be associated with an increased risk of dissection in patients with this mutation. There is only one case reported with familial TAAD due to an ACTA2 mutation (IVS4 + 1 G > A) that had iris flocculi and did not have the p.Arg149Cys mutation.Citation8 Further studies are required to establish if iris flocculi associated with TAAD are specific only to the p.Arg149Cys mutation in ACTA2 and if they are associated with an increased risk of aortic dissection. Recently a multisystemic smooth muscle dysfunction syndrome resulting from a mutation in ACTA2 (p.R179H) characterised by congenital fixed dilated pupils with loss of accommodation, persistent ductus arteriosus, pulmonary hypertension, aortic and cerebrovascular disease and hypotonic bladder and bowel was reported.Citation9
In conclusion, iris flocculi and congenital mydrasis should alert ophthalmologists to the possibility of ACTA2 mutations and should prompt further investigation for life-threatening cardiovascular associations.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Guo DC, Pannu H, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007;39:1488–1493
- Milewicz DM, Guo DC, Tran-Fadulu V, et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet 2008;9:283–302
- Bixler D, Antley RM. Familial aortic dissection with iris anomalies – a new connective tissue disease syndrome? Birth Defects Orig Artic Ser 1976;12:229–234
- Lewis RA, Merin LM. Iris flocculi and familial aortic dissection. Arch Ophthalmol 1995;113:1330–1331
- Jondeau G, Boileau G. Genetics of thoracic aortic aneurysms. Curr Atheroscler Rep 2012;14:219–226
- Hashida N, Ohguro N, Morimoto Y, et al. Ultrastructural appearance of iris flocculi associated with a thoracic aortic aneurysm and dissections. Br J Ophthalmol 2009;93:1409–1410
- Morisaki H, Akutsu K, Ogino H, et al. Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD). Hum Mutat 2009;30:1406–1411
- Disabella E, Grasso M, Gambarin FI, et al. Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2). Heart 2011;97:321–326
- Moller HU, Fledelius HC, Milewicz DM, et al. Eye features in three Danish patients with multisystemic smooth muscle dysfunction syndrome. Br J Ophthalmol 2012;96:1227–1231