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ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome
Author(s) -
Meuwissen Marije E.C.,
Lequin Maarten H.,
Bindelsde Heus Karen,
Bruggenwirth Hennie T.,
Knapen Maarten F.C.M.,
Dalinghaus Michiel,
de Coo René,
van Bever Yolande,
Winkelman Beerend H.J.,
Mancini Grazia M.S.
Publication year - 2013
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35858
Subject(s) - ductus arteriosus , medicine , corpus callosum , white matter , marfan syndrome , ehlers–danlos syndrome , cardiology , pathology , radiology , magnetic resonance imaging
Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys–Dietz syndrome, caused by mutations in the fibrillin‐1, the TGFβ‐receptor 1‐ and ‐2 genes, the SMAD3 and TGFβ2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C > T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature. © 2013 Wiley Periodicals, Inc.