Milewicz et al. (2010) described 7 unrelated patients ranging in age from 11 to 27 years who had clinical findings suggestive of vascular disease, consistent with previous ACTA2 mutations. However, there was higher penetrance and earlier onset of ... Milewicz et al. (2010) described 7 unrelated patients ranging in age from 11 to 27 years who had clinical findings suggestive of vascular disease, consistent with previous ACTA2 mutations. However, there was higher penetrance and earlier onset of vascular disease and additional multisystem smooth muscle dysfunction was manifest. Three of these patients had been previously described by Kahn et al. (2004), Lemire et al. (2004), and Ades et al. (1999), respectively. All patients shared the features of congenital mydriasis or fixed dilated pupils, as well as patent ductus arteriosus requiring repair in infancy. The patient previously reported by Lemire et al. (2004) had aortic coarctation that was repaired at age 4 months. All patients subsequently developed fusiform ascending aortic aneurysms extending to the arch during childhood, and 5 of 7 required surgical repair at age 10 to 25 years. The patient previously reported by Ades et al. (1999) had a dissection at 14 years of age. In addition to the aortic disease, all patients had cerebral vascular abnormalities including fusiform dilatation of the intimal carotid artery from the cavernous to the clinoidal segments, and the terminal region of the internal carotid arteries showed mild to moderate tapering indicative of stenosis of the artery and consistent with changes observed in Moyamoya disease (see 252350). Two of the patients, one reported by Milewicz et al. (2010) and one reported by Kahn et al. (2004), underwent neurosurgical bypass for revascularization for Moyamoya disease. All 5 patients for whom imaging was reported had bilateral periventricular white matter hyperintensities, and 1 had changes consistent with a middle and anterior cerebral artery stroke. One patient had colpocephaly with a thin corpus callosum and somewhat small cerebral vermis and was diagnosed with developmental delay. In addition to the vascular abnormality, additional evidence of smooth muscle dysfunction included congenital mydriasis, hypotonic bladder, malrotation, and hyperperistalsis of the GI tract. Two patients had malrotation. One patient had gallstones that spontaneously resolved and subsequently presented with hydrops of the gallbladder without evidence of residual gallstones. Biopsies of the esophagus, stomach, and small intestine revealed normal ganglionic cells and no specific neural or smooth muscle pathology. Four of the 5 patients for whom data were available had tachypnea at birth. One patient had hyperinflation of the upper lung segment, a hypoplastic lower lung segment, and a dilated pulmonary trunk at 14 years of age. The patient previously reported by Lemire et al. (2004) had evidence of cystic lung disease as an infant with biopsies showing alveolar dysgenesis consistent with developmental defect. One patient was diagnosed with primary pulmonary hypertension and underwent bilateral lung transplantation at age 18 months. The lung pathology showed pulmonary arterial hypertensive changes with smooth muscle cell hyperplasia and neointimal fibrocellular proliferative lesions. In addition, 2 out of 3 males had unilateral undescended testes. Two of the patients had asthma, and several patients had microaneurysms. One patient had microaneurysms of the retina, and one had a right ophthalmic artery occlusion.
In 7 unrelated patients of northern European descent with multisystemic smooth muscle dysfunction syndrome, Milewicz et al. (2010) identified heterozygosity for a de novo R179H mutation in the ACTA2 gene (102620.0004).