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Case Report on Megacystis and association with underlying ACTA2 Variant and Diagnosis of Multisystemic Smooth Muscle Dysfunction Syndrome


Key takeaways

  • Colorado Fetal Care Center report on megacystis due to ACTA2 variant causing multisystemic smooth muscle dysfunction syndrome.

  • Authors recommend genetic testing after identifying fetal megacystis to confirm any genetic diagnoses.

  • This finding significantly altered the postnatal care of the individual in the report.

Background: fetal megacystis and multisystemic smooth muscle dysfunction syndrome diagnosis

Fetal megacystis is characterized by an enlarged fetal bladder and has a highly variable postnatal prognosis, depending on the underlying cause and any additional findings.

Conditions that can cause megacystis

  • Posterior urethral valves
  • Prune belly syndrome
  • Urethral atresia or stenosis
  • Cloacal abnormalities
  • Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS)
  • Multisystemic smooth muscle dysfunction syndrome (MSMDS)
    • Caused by specific missense variant in ACTA2 gene at R179 residue, often replaced with Histidine
    • Primary characterizations:
      • Large patent ductus arteriosus
      • Early onset aortic aneurysm
      • Cerebrovascular disease with Moya-Moya type
      • Abnormal white matter intensity
      • Congenital mydriasis
      • Bladder hypotonia
      • Intestinal malrotation
      • Hypoperistalsis of the gastrointestinal tract

Role of ACTA2 gene ACTA2 encodes smooth muscle alpha-actin type 2, playing large role in contracting smooth muscle cells.

  • Pathogenic variants lead to:
  • Vascular phenotype
  • Predisposition to aortic, coronary artery aneurysm and dissection
  • Missense changes altering R179 lead to systemic smooth muscle dysfunction
  • Involves aortic, cerebral arteries
  • Smooth muscle of the bowel, bladder, iris

Case report: multisystemic smooth muscle dysfunction syndrome diagnosis from megacystis with underlying ACTA2 variant

This case report by a multidisciplinary team of experts at Children’s Hospital Colorado, including  Kestutis Micke, Nicholas Stence, MD, Mariana Meyers, MD, Kathryn Chatfield, MD, and Vijaya Vemulakonda, MD, describes a pregnant patient with megacystis later identified with ACTA2 missense variant consistent with multisystemic smooth muscle dysfunction syndrome.

Referral and diagnosis

  • 20- and 24-week imaging did not reveal obvious abnormalities
  • Cell-free DNA screening low risk

Fetal MRI, ultrasound and echocardiogram revealed:

  • Fetal megacystis without dilation of upper urinary tract
    • Prenatal genetic testing recommended due to abnormal presentation
    • Declined amniocentesis
  • No urinary bladder wall thickening
  • Below mean lung volumes, within 2 standard deviations
  • Normal fetal growth, amniotic fluids
  • Normal heart anatomy, size, function, rate, rhythm

Delivery and postnatal care

At 37 weeks, 6 days gestation, mother was admitted to the Colorado Fetal Care Center with spontaneous labor.

  • Female infant delivered via C-section after failing to progress
    • APGAR scores 8 and 9 at 1 and 5 minutes, respectively
    • Meconium-stained amniotic fluid
    • Required respiratory support in NICU
    • Treated with antibiotics for presumed pneumonia
    • Bactrim prophylaxis for urinary tract infection prophylaxis related to hypotonic bladder
  • Echocardiogram results
    • Pulmonary hypertension
    • Large PDA with predominant right-to-left shunting
    • Left ventricular dysfunction
    • Ectatic dilation of left, right coronary arteries
  • Surgery at 1 month of age

Additional testing and evaluations

Exome sequencing

  • De novo variant in ACTA2 resulting in Arg179Cys found
  • Confirmed suspected multisystemic smooth muscle dysfunction

Additional evaluations

  • Ophthalmologic exam revealed congenital mydriasis
  • Brain MRI/MRA confirmed multiple characteristic findings of multisystemic smooth muscle dysfunction
    • Not clearly visible, even in retrospect, on fetal MRI

Significance of case report

This was the first reported case of mild ventricular hypertrophy and moderately diminished systolic function of both ventricles in individuals with multisystemic smooth muscle dysfunction. Study authors suggest, in some patients, predisposition to left ventricular dysfunction may be an additional feature of this genetic disorder.

Discussion and conclusion: consider multisystemic smooth muscle dysfunction in cases of fetal megacystis

Key points

  • Consider multisystemic smooth muscle dysfunction in cases of fetal megacystis, especially with atypical bladder outlet obstruction
    • Differentials include
      • Prune belly syndrome
      • MMIHS
    • Megacystis may be only fetal sign of multisystemic smooth muscle dysfunction prior to delivery
    • Case highlights variability of multisystemic smooth muscle dysfunction genitourinary phenotype
    • Whole exome sequencing for atypical megacystis broadly inclusive of various genetic causes
    • Confirmed diagnosis will alter patient counseling, care

This case report was the third individual to be reported with multisystemic smooth muscle dysfunction and the appearance of bladder outlet obstruction. In this patient, the diagnosis of multisystemic smooth muscle dysfunction substantially changed postnatal management.