Actg2-Related Disorders
Summary
Clinical characteristics.
ACTG2-related disorders are a subset of visceral myopathy with variable involvement of the bladder and intestine. Bladder involvement can range from neonatal megacystis and megaureter (with its most extreme form of prune belly syndrome) at the more severe end, to recurrent urinary tract infections and bladder dysfunction at the milder end. Chronic bladder dysfunction carries a high risk for urinary tract infections, dilation of the upper urinary tract, and impaired renal function. Intestinal involvement can range from malrotation, neonatal manifestations of microcolon, megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS), and chronic intestinal pseudoobstruction (CIPO) in neonates, children, and adults. Affected infants (with or without evidence of intestinal malrotation) often present with feeding intolerance and findings of non-mechanical bowel obstruction that persist after successful surgical correction of malrotation. Individuals who develop manifestations of CIPO in later childhood or adulthood often experience episodic waxing and waning of bowel motility. They may undergo frequent abdominal surgeries (perhaps related to malrotation or adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel, often becoming dependent on total parenteral nutrition (TPN).
Diagnosis/testing.
The diagnosis of an ACTG2-related disorder is established in a proband by the presence of a heterozygous pathogenic variant in ACTG2.
Management.
Treatment of manifestations: Management requires a multidisciplinary approach that includes primary care providers, gastroenterologists, general surgeons, urologists, nephrologists, dieticians, and social workers. Chronic bladder dysfunction typically requires management by a urologist and can involve routine urinary catheterization or diversion to reduce the risk of dilation of the upper urinary tract and associated risk for urinary tract infection and renal functional impairment. CIPO typically requires management by a gastroenterologist and nutritionist familiar with intestinal motility disorders.
Prevention of secondary complications: Clean and safe practices in the use of indwelling intravenous catheters for administration of TPN and bladder catheterization can help prevent infections. Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period.
Surveillance: Should be individualized, taking into account:
- The association between urinary tract infections and chronic bladder dysfunction and the increased risk for dilation of the upper urinary tract, and renal functional impairment
- Need for routine evaluation of liver function in those dependent on long-term TPN.
Agents/circumstances to avoid: For those with CIPO, high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort.
Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in relatives at risk as early diagnosis may help prevent unnecessary surgery for symptoms of intestinal obstruction and may allow early evaluation of bladder function, the urinary tract (for evidence of dilation), and renal function.
Pregnancy management: When a fetus at risk for an ACTG2-related disorder has evidence of bladder distention on prenatal ultrasound examination, consultation with a maternal fetal medicine specialist is recommended.
Genetic counseling.
ACTG2-related disorders are inherited in an autosomal dominant manner. While the exact proportion of inherited vs de novo pathogenic variants is unknown, current data suggest that de novo pathogenic variants are common. Each child of an individual with an ACTG2-related disorder has a 50% chance of inheriting the pathogenic variant. Although penetrance of ACTG2-related disorders appears to be complete, the severity of clinical findings can vary within a family. Prenatal testing for pregnancies at increased risk is possible if the ACTG2 pathogenic variant has been identified in an affected family member.
Diagnosis
ACTG2-related disorders are a subset of visceral myopathy with variable involvement of the bladder and intestine.
Suggestive Findings
ACTG2-related disorders should be suspected in individuals with bladder and/or intestinal involvement that can range in a continuum from severe in neonates to more mild in older children and adults.
Bladder involvement can range from neonatal megacystis and megaureter (with its most extreme form of prune belly syndrome) at the more severe end to recurrent urinary tract infections and bladder dysfunction at the milder end. Chronic bladder dysfunction has a high risk of urinary tract infections, dilation of the upper urinary tract, and impaired renal function.
Suggestive bladder findings:
- Prenatal ultrasound revealing megacystis, defined according to trimester [Fievet et al 2014]:
- First trimester: bladder diameter >6 mm
- Second and third trimesters: enlarged bladder with failure to empty within 45 minutes
- In neonates: prune-belly sequence (megacystis with lack of abdominal wall musculature, cryptorchidism in males, and distention of the upper urinary tract) in association with impaired gastrointestinal motility
- Postnatal ultrasound examination or cystogram revealing an enlarged bladder
- In individuals of any age: unexplained chronic functional bladder impairment of voiding without mechanical blockage
Intestinal involvement can range from malrotation, neonatal manifestations of microcolon, and megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) to chronic intestinal pseudoobstruction (CIPO) in neonates, infants, children, and adults.
Suggestive intestinal findings:
- Neonatal bilious emesis, abdominal distention, and feeding intolerance
- Intestinal malrotation and long-term intestinal motility problems often resulting in chronic abdominal pain and constipation
- Neonatal microcolon
- In individuals of any age: chronic intestinal pseudoobstruction (CIPO) (i.e., unexplained chronic functional intestinal obstruction involving small bowel and/or colon without evidence of mechanical blockage).
Suggested specific diagnostic findings [Gabbard & Lacy 2013]:
- Symptoms lasting >6 months, or >2 months from birth
- Evidence of delayed GI transit and/or decreased GI motility
- Imaging studies that do not show mechanical obstruction
- Radiographic documentation of dilated bowel, air fluid levels without fixed obstruction [Rudolph et al 1997]
Establishing the Diagnosis
The diagnosis of an ACTG2-related disorder is established in a proband by the presence of a heterozygous pathogenic variant in ACTG2 (see Table 1).
Between 50% and 70% of individuals with a clinical diagnosis of MMIHS and a significant but unknown fraction of individuals with a diagnosis of CIPO have a heterozygous pathogenic ACTG2 missense variant.
Molecular testing approaches can include single-gene testing and use of a multigene panel:
- Single-gene testing. Sequence analysis of ACTG2 is performed first. Deletion/duplication analysis may be considered if no pathogenic variant is found; however, all pathogenic variants identified to date are missense variants, and no exon or whole-gene deletions/duplications have been identified as a cause of ACTG2-related disorders.
- A multigene panel that includes ACTG2 and other genes of interest (see Differential Diagnosis) may also be used. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in ACTG2-Related Disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant Detectable by Method |
|---|---|---|
| ACTG2 | Sequence analysis 2 | 23/23 3, 4 |
| Gene-targeted deletion/duplication analysis 5 | None detected to date |
- 1.
See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
- 2.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 3.
2/2 probands in Thorson et al [2014], 15/15 probands with ACTG2-related disorders in Wangler et al [2014], 3/3 probands in Tuzovic et al [2015], the case/family reports of Lehtonen et al [2012], Holla et al [2014], and Klar et al [2015]
- 4.
All pathogenic variants identified to date are missense.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, and multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
A number of clinical phenotypes characterized by smooth muscle dysfunction affecting bowel and bladder (including diagnoses such as megacystis-microcolon-intestinal hypoperistalsis syndrome [MMIHS] and chronic intestinal pseudoobstruction [CIPO]) have been described and reported in detail [Puri & Shinkai 2005]. At this time it is not known what percentage of the phenotypes reported before 2012 were caused by mutation of ACTG2 versus other causes.
Molecularly Confirmed ACTG2-Related Disorders
Because ACTG2 pathogenic variants have only recently been identified as a cause of MMIHS, CIPO, and similar phenotypes, the number of affected individuals reported to date is small [Lehtonen et al 2012, Holla et al 2014, Thorson et al 2014, Wangler et al 2014]. (See Table 2.) Thus, current understanding of the breadth of the phenotype and natural history of ACTG2-related disorders is limited, but expected to evolve over time.
Individuals with an ACTG2-related disorder experience functional defects of smooth muscle involving both bladder and bowel. General clinical patterns include neonates with a de novo ACTG2 pathogenic variant who experience severe functional impairment of bowel and bladder consistent with MMIHS, and individuals with an inherited (familial) ACTG2 pathogenic variant who experience later-onset CIPO. Individuals with ACTG2-related disorders usually have normal intellect.
Table 2.
Summary of Bladder and Intestinal Findings in Individuals with Molecularly Confirmed ACTG2-Related Disorders
| Finding | # Reported by Study | |||||
|---|---|---|---|---|---|---|
| Sipponen et al [2009], Lehtonen et al [2012] | Thorson et al [2014] | Holla et al [2014] | Wangler et al [2014] | Klar et al [2015] | ||
| Bladder | Prenatal or postnatal megacystis | Not reported | 2 | Not Reported | 8 | 7 |
| Prune belly syndrome | Not reported | 0 | Not Reported | 1 | 0 | |
| Chronic functional impairment | 2 | 2 | Not Reported | 8 | 7 | |
| Intestinal | Microcolon | Not reported | 1 | Not Reported | 5 | 0 |
| Bilious emesis or inability to tolerate feeds as a neonate | Not reported | 2 | Not Reported | 7 | 0 | |
| History of abdominal surgery | 3 | 2 | 1 | 12 | 7 | |
| Dependent on parenteral nutrition | 2 (intermittent) | 2 | 0 | 7 | 0 | |
| CIPO | 7 | 0 | 1 | 8 | 7 | |
| De novo cases (# of families) | 0 (0) | 2 (2) | 0 (0) | 10 (10) | 0 (0) | |
| Dominant familial cases (# of families) | 8 (1) | 0 (0) | 1 (1) | 9 (3) | 7 (1) | |
| Undetermined inheritance cases (# of families) | 0 (0) | 0 (0) | 0 (0) | 2 (2) | 0 (0) | |
| Total molecularly confirmed cases (total # of families) | 8 (1) | 2 (2) | 1 (1) | 21 (15) | 7 (1) | |
Urologic. From a recent series the majority of individuals with a de novo ACTG2 pathogenic variant had prenatal or postnatal megacystis and approximately one third had had a vesicoamniotic shunt placed prenatally [Wangler et al 2014].
Prune belly syndrome, characterized by lack of abdominal wall musculature, cryptorchidism in males, and distention of the urinary tract, was reported in one male with MMIHS and a de novo ACTG2 pathogenic variant [Wangler et al 2014].
Chronic bladder functional impairment seen in the majority of individuals with an ACTG2 de novo pathogenic variant can require lifelong bladder catheterization.
Gastrointestinal. The majority of neonates with a de novo ACTG2 pathogenic variant are unable to tolerate feedings. Likewise, intestinal malrotation is common and while many undergo a Ladd surgical procedure, many experience persistent symptoms of bowel obstruction after surgical recovery [Wangler et al 2014].
Affected individuals can experience episodic improvement of bowel motility, loss of bowel motility over time, or waxing and waning of reduced bowel motility. Affected individuals may undergo frequent abdominal surgeries (perhaps related to malrotation or presumed adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel.
In many families with a dominantly inherited ACTG2 pathogenic variant and waxing and waning CIPO, affected individuals report lifelong gastrointestinal discomfort and symptoms with episodes resulting in surgery and hospitalization. These individuals can survive to an advanced age.
Long-term survival. Long-term survival in those with a de novo ACTG2 pathogenic variant usually requires total parenteral nutrition and urinary catheterization or diversion. Most long-term survivors have ileostomies.
Large series of individuals with MMIHS reported before the molecular basis of ACTG2-related disorders was known suggested that long-term survival was uncommon because the majority die in childhood or infancy of sepsis, organ failure, and/or malnutrition [Gosemann & Puri 2011]. In contrast, in families with an inherited ACTG2 pathogenic variant, some family members with the pathogenic variant have MMIHS and others with the same variant have milder phenotypes, living into adolescence and early adulthood [Wangler et al 2014].
It is not clear whether differences in prognosis for individuals with an ACTG2-related disorder compared to those with MMIHS of unknown cause reflect advances in medical management of parenteral nutrition or other factors.
Smooth Muscle Dysfunction (including MMIHS and CIPO) of Unknown Cause
Several studies have explored the clinical features of individuals with MMIHS and CIPO, but the proportion due to an ACTG2 pathogenic variant versus other causes is not known. Therefore, these studies may encompass patient populations that combine ACTG2-related disorders and those of other etiologies.
Urologic. Prenatal ultrasound examination is reported to identify megacystis in 88% and gastrointestinal abnormalities in 24% [Tuzovic et al 2014].
Radiographic studies after delivery could reveal megacystis, hydronephrosis, vesicoureteral reflux, and/or the presence of microcolon [Ballisty et al 2013].
Although urinary obstruction and its potential adverse effect on renal function are often a concern in individuals with MMIHS, the long-term consequences for kidney function are not known. In one report of 709 individuals with fetal dilation of the urinary tract of diverse causes (e.g., posterior urethral valves and other types of mechanical obstruction not consistent with MMIHS), 17 instances of MMIHS were identified among 98 individuals with megacystis [Al-Hazmi et al 2012]. In this series, almost 30% (86/289) of those with severe fetal urinary tract dilatation had an abnormal serum creatinine concentration at age two years.
Gastrointestinal. Chronic intestinal pseudoobstruction (CIPO) has been reported at ages ranging from infancy to adulthood. After onset, progression to severe digestive dysfunction can range from one to 46 years [De Giorgio et al 2011].
Some individuals with CIPO may undergo exploratory laparotomy without identification of an obstructive lesion.
Pathology. Numerous histopathologic studies on infants with MMIHS have had variable or inconsistent results [Puri & Shinkai 2005]. Findings have included alterations in ganglion cells (rare), vacuolar degeneration in the smooth muscle layer with connective tissue infiltration between muscle cells in bowel and bladder, excess muscle glycogen, and absent or reduced smooth muscle actin [Puri & Shinkai 2005].
Visceral myopathy reveals the presence of vacuoles or fibrous replacement in the smooth muscle layer (muscularis propria) in a full-thickness intestinal biopsy [Huang et al 2013b].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
To date all reported ACTG2 pathogenic variants have been missense variants, many of which affect arginine residues of the γ-2 actin protein. The same missense variants have been seen across the phenotypic spectrum from neonatal MMIHS to later-onset chronic intestinal pseudoobstruction. Of note, disease caused by a de novo pathogenic variant is often more severe than inherited disease.
Heterozygous null variants may be benign; however, this is not known with certainty.
Penetrance
Thus far, penetrance of ACTG2-related disorders appears to be complete, as no family members heterozygous for a known ACTG2 pathogenic variant have been noted to be completely symptom free. However, the clinical severity can range within a family, and mildly affected individuals may not be aware of the diagnosis. Examples: (1) one individual (in a multi-generation Finnish family) with an ACTG2 pathogenic variant reported episodic mild abdominal pain but no surgery and no signs of visceral myopathy at age 19 years [Lehtonen et al 2012]; (2) one individual diagnosed with "spastic colon" and irritable bowel syndrome had not required surgery or intervention in middle age [Wangler et al 2014].
Nomenclature
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) may also be referred to as familial visceral myopathy or Berdon syndrome.
The broad term "hollow visceral myopathy" includes phenotypically related disorders caused by pathogenic variants in other genes (e.g., ACTA2), and, therefore, should not be used as a synonym for ACTG2-related disorders [Milewicz et al 2010].
Prune belly sequence may also be referred to as Eagle-Barrett syndrome.
Prevalence
To date 47 individuals (from 23 families) have been reported to have a molecularly confirmed ACTG2-related disorder [Lehtonen et al 2012, Holla et al 2014, Thorson et al 2014, Wangler et al 2014]. (See Table 2.)
A total of 227 individuals with MMIHS were reported between 1976 and 2011 [Gosemann & Puri 2011]. The proportion with an ACTG2-related disorder is unknown.
It is estimated that 100 individuals per year in the United States are diagnosed with CIPO [De Giorgio et al 2011]. The proportion with an ACTG2-related disorder is unknown.
Differential Diagnosis
Since many individuals with visceral myopathy with variable involvement of the bladder and intestine do not have an ACTG2 pathogenic variant, mutation of other genes must contribute to the etiology of this phenotype (Table 3). Because mydriasis has been noted in some individuals with MMIHS (megacystis-microcolon-intestinal hypoperistalsis syndrome) [McClelland et al 2013] but not in those with an ACTG2-related disorder, the presence of mydriasis may suggest a differ disorder.
Table 3.
Inherited Disorders in the Differential Diagnosis for ACTG2-Related Disorders
| Gene(s) | MOI | Severe GI or GU Involvement or Both | Distinguishing Clinical Features |
|---|---|---|---|
| MYH11 | AR | Both | Patent ductus arteriosus in 1 individual |
| ACTA2 | AD | Both | Vascular aneurysms & dissections, patent ductus arteriosus, mydriasis |
| FLNA | XL | GI | Periventricular heterotopia in males, seizures in females |
| TYMP | AR | GI | MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy |
| EDNRB, EDN3, or SOX10 | AD or AR | GI | Waardenburg syndrome w/pigmentary abnormalities |
| SGOL1 | AR | GI | CAID: sick sinus syndrome, atrial dysrhythmias |
| RAD21 | AR | GI | Mungan syndrome: Barrett esophagus, megaduodenum, cardiac abnormalities |
| CHRM3 | AR | GU | Posterior urethral valves & prune belly syndrome |
| CHRNA3, CHRNB2, CHRNB4 | NA | GU | Mouse models w/mydriasis & megacystis |
AD = autosomal dominant; AR = autosomal recessive; CAID = chronic atrial and intestinal dysrhythmia; GI = gastrointestinal; GU = genitourinary; MNGIE = mitochondrial neurogastrointestinal encephalopathy; MOI = mode of inheritance; NA = not applicable; XL = X-linked
MYH11. Mutation of this gene was identified in a child with MMIHS and patent ductus arteriosus [Gauthier et al 2015].
ACTA2. This multisystemic smooth muscle dysfunction syndrome due to a de novo ACTA2 pathogenic variant is characterized by dysfunction of smooth muscle cells throughout the body, leading to severe and highly penetrant vascular diseases that include thoracic aortic aneurysms and aortic dissections, patent ductus arteriosus, stenosis and dilatation of cerebral vessels, mydriasis, periventricular white matter hyperintensities on MRI, and pulmonary hypertension, as well as features characteristic of ACTG2-related disorders such as hypotonic bladder and malrotation and hypo-peristalsis of the gut [Milewicz et al 2010]. Prune-belly sequence can also be associated [Richer et al 2012].
FLNA. Pathogenic variants in this X-linked gene have been reported in association with intestinal pseudoobstruction, as well as its commonly recognized phenotypes: X-linked periventricular heterotopia, a neuronal migration disorder with early lethality in affected males and seizures in affected females [Gargiulo et al 2007, Kapur et al 2010].
TYMP. Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by: progressive gastrointestinal dysmotility and cachexia manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea; ptosis/ophthalmoplegia or ophthalmoparesis; hearing loss; and demyelinating peripheral neuropathy manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities. The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades. Direct evidence of MNGIE disease is provided by increase in plasma thymidine concentration >3 µmol/L and increase in plasma deoxyuridine concentration >5 µmol/L.
SGOL1. Chronic atrial and intestinal dysrhythmia (CAID) is the constellation of sick sinus syndrome (SSS) with aberrant sinus node pacing in the heart and intestinal pseudoobstruction [Chetaille et al 2014]. Bladder involvement was not reported. Atrial dysrhythmias have not been observed in ACTG2- related disorders.
RAD21. The combination of CIPO, Barrett esophagus, and cardiac abnormalities caused by biallelic pathogenic variants in RAD21 is called Mungan syndrome [Bonora et al 2015]. Bladder involvement has not been reported. Cardiac abnormalities and Barrett esophagus have not been observed in ACTG2- related disorders.
CHRM3. Prune belly syndrome with megacystis has been reported with mutation of CHRM3, a muscarinic acetylcholine receptor subunit. Gastrointestinal symptoms were not reported [Weber et al 2005, Weber et al 2011].
CHRNA3, CHRNB2, and CHRNB4. Although these nicotinic acetylcholine receptors have not been associated with MMIHS in humans, they may be reasonable candidates based on findings in mouse [Xu et al 1999a, Xu et al