Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome

Abstract

De novo heterozygous mutations changing R179 to histidine, leucine, or cysteine in the ACTA2 gene are associated with Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). Characteristic hallmarks of this condition, caused only by these specific ACTA2 mutations, are congenital mydriasis (mid-dilated, non-reactive pupils), a large persistent ductus arteriosus (PDA), aortic aneurysms evolving during childhood, and cerebrovascular anomalies. We describe two patients, a 3-day-old newborn and a 26-year-old woman, with this unique mutation in association with a huge PDA and an aorto-pulmonary window. In addition, one showed a coarctation of the aortic arch and the other a complete interruption of the aortic arch type A; thereby expanding the spectrum of cardiac congenital heart defect of this syndrome. Each patient displayed a huge PDA and an extra-cardiovascular phenotype consistent with MSMDS. These observations exemplify that a functional alpha 2 smooth muscle actin is necessary for proper cardiovascular organ development, and demonstrate that a very exceptional congenital heart defect (aortopulmonary window) can be caused by a mutation in a gene encoding a contractile protein of vascular smooth muscle cells. © 2017 Wiley Periodicals, Inc.

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations

“…With a single exception, all cases are due to de novo mutations. Seven SMDS cases were initially reported 1 , followed by reports of cases with similar presentation and additional complications often resulting in poor health outcomes and early deaths 2 – 13 .…”

Neonatal diagnosis of ACTA2‐related disease: A case report and review of literature

“…In association with MYH11 gene, that encodes for the beta‐myosin heavy chain, ACTA2 gene accounts for the genetic base of vascular smooth muscle cells contraction. Several mutations in ACTA2 gene have been described but particularly a specific heterozygous missense variant changing arginine 179 to histidine, leucine or cysteine is associated to multisystemic smooth muscle dysfunction syndrome (MSMDS) (Kaw et al, 2022; Logeswaran et al, 2017).…”

“…A typical cerebrovascular pattern characterized by dilatation of proximal internal carotid artery and at the same time occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries were described in MSMDS patients (Georgescu et al, 2015, Richer et al, 2012. Ardhanari et al, 2020;Brodsky et al, 2014;Chen et al, 2019;D'Arco et al, 2018;Georgescu et al, 2015;Logeswaran et al, 2017;Milewicz et al, 2010;Moller et al, 2012;Moosa et al, 2013;Munot et al, 2012;Prabhu et al, 2017;Richer et al, 2012;Roulez et al, 2014;Rutledge et al, 2016;Sabo et al, 2020;She et al, 2021;Taubenslag et al, 2019;Yang et al, 2021;Yetman et al, 2015;Yeung et al, 2017).…”

“…In patients with R179H variant have also been described pulmonary anomalies such as emphysematous lung alterations and pulmonary hypertension with an histopathological findings of medial thickening, and sub-intimal proliferation of SMCs in the pulmonary vessels (Logeswaran et al, 2017, Milewicz et al, 2010.…”

“…In association to the cardiac features at 38 weeks of pregnancy, an ultrasound scan detected in our patient an enlarged bladder. According to literature review, the most common genitourinary anomalies in patients with R179H ACTA2 mutation were hypocontractile bladder and hydronephrosis, rarely prune-belly syndrome (Table 1) (Amans et al, 2013, Ardhanari et al, 2020, Brodsky et al, 2014, Chen et al, 2019, D'Arco et al, 2018, Georgescu et al, 2015, Logeswaran et al, 2017, Milewicz et al, 2010, Moller et al, 2012, Moosa et al, 2013, Munot et al, 2012, Prabhu et al, 2017, Richer et al, 2012, Roulez et al, 2014, Rutledge et al, 2016, Sabo et al, 2020, She et al, 2021, Taubenslag et al, 2019, Yang et al, 2021, Yetman et al, 2015, Yeung et al, 2017.…”