R179H mutation in ACTA2 expanding the phenotype to include prune‐belly sequence and skin manifestations

Abstract

Mutations in ACTA2 (smooth muscle cell-specific isoform of aactin) lead to a predisposition to thoracic aortic aneurysms and other vascular diseases. More recently, the ACTA2 R179H mutation has been described in individuals with global smooth muscle dysfunction. We report a patient heterozygous for the mutation in ACTA2 R179H who presented with megacystis at 13 weeks gestational age and, at birth, with prune-belly sequence. He also had deep skin dimples and creases on his palms and soles, a finding not previously described but possibly related to ACTA2. To our knowledge, this is the first report of the R179H mutation in ACTA2 in a child with prune-belly sequence. We think the R179H mutation in ACTA2 should be included in the differential diagnosis of individuals presenting with the sequence without an identified mechanical obstruction. Furthermore, as ACTA2 R179H has been reported in patients with severe vasculomyopathy and premature death, we recommend that molecular testing for this mutation be considered in fetuses presenting with fetal megacystis with a normal karyotype, particularly if the bladder diameter is 15 mm or more, to allow expectant parents to make an informed decision.

Variants of the ACTG2 gene correlate with degree of severity and presence of megacystis in chronic intestinal pseudo-obstruction

“…17 On the other hand, the p.(R179H) variant in ACTA2 causes severe multisystem smooth muscle cell dysfunction with early-onset vascular disease similar to moyamoya disease, 18 and has also been reported in a patient with prune belly sequence and first trimester-onset fetal megacystis. 19 Interestingly, variants of Arg179 in ACTA2 cause more severe phenotypes than variants of Arg258, 17 thus confirming similar effects of substitutions at paralogous nucleotide positions of ACTA2 and ACTG2 genes and, therefore, the genotype-phenotype correlation we propose for variants at residues Arg257 and Arg178 of the ACTG2 gene. The cases of variants of codons Arg38 and Arg148 need to be also considered.…”

Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution

“…Pathogenic variants in ACTA2 are predominantly associated with vascular symptoms including familial thoracic aneurysms, 5 but may in rare cases involve visceral organs including the urinary and gastrointestinal tracts. 6,7 On the other hand, ACTG2 was recently found mutated in a family with FVM and adult gastrointestinal problems, 14 as well as in the MMIH syndrome with severe neonatal symptoms from the intestines and the urinary tract. 15,16 The family investigated in this study shows a phenotypic overlap with both FVM and the MMIH syndrome but our observations on the variable onset as well as the involvement of the bile tract and uterus add to previous reports.…”

“…4,5 Later, variants in ACTA2 were shown to be associated with multisystemic smooth muscle dysfunction syndrome (MIM: 613834) and a broad phenotypic spectrum. 6,7 A group among the visceral myopathies comprises the enteric visceral myopathies characterized predominantly by impaired gastrointestinal propulsion resulting in pain, distention, malabsorption and even death. 8,9 Reports on familial cases have indicated an autosomal dominant inheritance.…”

Progressive Aortic Dilation Associated With ACTA2 Mutations Presenting in Infancy

“…Although previous reports on other ACTA2 mutations have noted no aortic dilation in affected children, 11 few data exist on the prevalence and rate of progression of aortic aneurysmal disease in association with this specific Arg179His mutation. Two reports of aortic dilation and/or aortic dissection in childhood exist, 2,5 but the presence and severity of aortic aneurysmal disease in childhood overall remain unknown. Our data suggest that aortic dilation begins shortly after birth and progresses relatively rapidly during childhood.…”