Congenital mydriasis and prune belly syndrome in a child with an ACTA2 mutation

Brodsky, Michael C.; Turan, Kadriye Erkan; Khanna, Cheryl L.; Patton, Alice; Kirmani, Salman

doi:10.1016/j.jaapos.2014.02.010

Cited by 17 publications

(19 citation statements)

References 10 publications

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“…The unusual combination of fixed pupils, lack of accommodation, and PDA had been noticed even before linking ACTA2 mutations with this complex disorder [Graef and Jungherr, ]. We like to stress that the rare symptom of fixed and dilated pupils requires thorough examination by an ophthalmologist, to distinguish other possible pathologies of the anterior chamber and the lens [Moller et al, ; Brodsky et al, ; Roulez et al, ]. Our examinations confirm that the unresponsive pupil is present as early as 4 days after birth.…”

Section: Discussionsupporting

confidence: 63%

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

Logeswaran

Friedburg

Hofmann

et al. 2017

American J of Med Genetics Pt A

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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.

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Section: Discussionsupporting

confidence: 63%

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

Logeswaran

Friedburg

Hofmann

et al. 2017

American J of Med Genetics Pt A

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“…Lastly, there have been 12 published multiplex pedigrees without causal genes identified in most [19][20][21][23][24][25][26][27][28][29][30][31]. More recently, five autosomal genes, including CHRM3, HNF1β, ACTA2, ACTG2 and STIM1, have been reported with potentially causal DNA variants, including structural, copy number, and single nucleotide variants, however these genes each only account for one or two PBS cases or one PBS multiplex consanguineous kindred [32][33][34][35][36][37][38]. Moreover, none of the currently suggested candidate genes fit an X-linked recessive mode of inheritance and functional data is lacking for many of these candidate genetic variants.…”

Section: Introductionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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Background: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. Methods: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. Results: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin ) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1). Conclusions: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

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“…The classic prune triad (deficient midline abdominal musculature, urinary tract distension, and cryptorchidism) typically occurs in isolation, and we define this group as ‘isolated PBS’ (Fig. ) . However, many patients with PBS have extra‐GU malformations outside the typical PBS phenotype, which we have sub‐classified into two categories: ‘syndromic PBS’ and ‘PBS‐plus’.…”

Section: Introductionmentioning

confidence: 99%

“… (gene proposed: CHRM 3 ); (e) Brodsky et al. (gene proposed ACTA 2 ); (f) Awad and Lall ; (g) Wangler et al. (gene proposed: ACTG 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic severity scoring system and categorisation for prune belly syndrome: application to a pilot cohort of 50 living patients

et al. 2018

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Congenital mydriasis and prune belly syndrome in a child with an ACTA2 mutation

Cited by 17 publications

References 10 publications

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

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

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Phenotypic severity scoring system and categorisation for prune belly syndrome: application to a pilot cohort of 50 living patients

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