2. Heterotaxy Syndrome: considering malrotation
Isaac Chuang Stein
Seattle Children’s Hospital General Pediatric Surgery
Thursday August 13, 2015

3. Outline Intro to Heterotaxy Epidemiology
Ways to stratify Heterotaxy patients
Clinical Presentation
Implications for intestinal malrotation

4. What is Heterotaxy?
Internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body; broad spectrum
Results in an unusual degree of symmetry between the right and left sides of the body
Can involve the heart, liver, lungs, intestine, and spleen
Associated with mutations of genes that encode proteins that are components of the TGF-B pathway1
NODAL, NKX2-5, CRELD1, LEFTY2, ZIC3, CRIPTC

5. Epidemiology HS occurs in 1 in 10,000-40,000 births2
Equal distribution between male and female
Equal risk across varying ethnic groups
*Within the Heterotaxy population, 32-89% are estimated to have intestinal rotation anomalies8

6. Ways to stratify patients
Atrial appendage isomerism
Right atrial isomerism vs. Left atrial isomerism
Used to describe whether heart has two “right” atria or two “left” atria
Polysplenia syndrome vs. Asplenia syndrome
Situs inversus
Right/left asymmetry remains
Mirror image of normal anatomy
Will only have one spleen

7. Right Atrial Isomerism (RAI)
“Two right sides”
Heart with bilateral right atria and atrial appendages
Absence of left-sided structures (such as coronary sinus)
Consistent heart defects
Absent atrial septum3,4
Anomalous pulmonary venous drainage3,4
Pulmonary outflow tract obstruction3,4
Single ventricle physiology3,4
Absent spleen

8. Left Atrial Isomerism (LAI)
“Two left sides”
Heart with bilateral left atria and atrial appendages
Cardiac abnormalities
*Interrupted IVC – characteristic (80%)5
Highly variable atrial septal anatomy
Commonly show polysplenia

9. Polysplenia vs. Asplenia
Spleen seen on left and right sides of abdomen
Indicative of left atrial isomerism and its associated abnormalities
Spleen absent from abdomen
Indicative of right atrial isomerism and its associated abnormalities

10. How will they present? Antenatal Postnatal
Fetal complete heart block – consider LAI6
AV canal defect with ventricular asymmetry – consider RAI
Postnatal
Cyanosis – due to right-to-left shunting secondary to pulmonary artery outflow obstruction
Respiratory distress – pulmonary congestion due to obstructed pulmonary veins
*Presentation of patients with RAI is much more severe

11. How will they present? Noncardiac presentations
Sepsis – secondary to asplenia in RAI
Jaundice – secondary to biliary atresia (10% of LAI)7
Bilious vomiting – secondary to malrotation

12. Risk of malrotation
Intestinal rotational anomalies have been reported in % of patients with Heterotaxy8
Malrotation has been described in both RAI and LAI
May be asymptomatic; must always consider malrotation in a patient with HS
Evaluation and management of the asymptomatic patient is controversial

13. Malrotation in RAI vs. LAI
Hill et al. 2014, 38 patients with HS identified.
18/38 underwent diagnostic laparoscopy or laparotomy based on upper GI findings or clinical symptoms worrisome for malrotation (bilious emesis, abdominal distension, bloody BM)
Malrotation identified in 8/18 patients (44%) who underwent surgery
Presence of abdominal symptoms predictive of identifying malrotation (80%)
Operative indications in these patients were positive upper GI findings or clinical symptoms worrisome for malrotation.

14. LAI vs. RAI
Likelihood of malrotation in LAI is significantly lower than in RAI (15% vs 72%)10
Especially in an asymptomatic patient with LAI
Malrotation defined in this case as the presence of Ladd’ bands and a narrow mesentery at the time of surgery
Hill et al. 2014

15. Management of the asymptomatic patient
Risks vs. benefits of surgery must be weighed heavily in his patient population
Avoid overtreating, especially in these patients with cardiac anomalies
Papillon et al. in 2013
30 asymptomatic HS patients with upper GI findings indicative of malrotation
0% had true malrotation or a narrow mesentery at time of exploration

16. Treatment algorithm
Hill et al. (2014)

17. Alternative approach
Yu et al retrospective review over (Boston Children’s)
31 HS patients compared to 51 non-HS patients undergoing Ladd’s
No significant difference found in…
Rates of SBO
Hospital stay
Hospital mortality
Routine screening and elective Ladd’s procedure to any patient with HS with positive upper GI given possible catastrophic outcome of volvulus

18. Multicenter Analysis Salavitabar et al. 2015 (NYPB, Columbia)
Inclusion criteria: HS, IRA shown on upper GI, asymptomatic
325 patients at 41 tertiary care children’s hospitals (Pediatric Health Information System database)
Primary outcome: major morbidity or mortality on admissions subsequent to the initial hospitalization
Obstruction including volvulus, gut ischemia, intestinal resection, any subsequent admission.

19. Multicenter Analysis 188/325 (58%) underwent Ladd’s
Remainder managed with observation
Ladd’s procedure on initial hospitalization was associated with a 2.2x increase in odds of major morbidity or mortality (p=0.007)
Suggest that in an asymptomatic patient with HS, even with IRA seen on upper GI, cautious observation is safest.

20. The asymptomatic patient
Multidisciplinary approach with cardiology, cardiac surgery, GI, etc…
Consider patient’s overall health/ability to undergo surgery
Ability to follow-up/social support
Consider isomerism if present
Comfort level of surgeon with Ladd’s procedure

21. References
Kosaki K, Bassi MT, Kosaki R, et al. Characterization and mutation analysis of human LEFTYA and LEFTYB, homologues of murine genese implicated in left-right axis development. Am J Hum Genet 1999; 64: 712.
Lim JS, McCrindle BW, Smallhorn JF, et al. Clinial features, management, and outcome of children with fetal and postnatal diagnoses of isomerism syndromes. Circulation 2005; 112: 2454.
Sapire DW, Ho SY, Anderson RH, Rigby ML. Diagnosis and significance of atrial isomerism. Am J Cardiol 1986; 58: 342.
Stranger P, Rudolph AM, Edwards JE. Cardiac malpositions. An overview based on study of sixty-five necropsy specimens. Circulation 1977; 56: 159
Sharma S, Devine W, Anderson RH, Zuberbuhler JR. Identification and analysis of left atrial isomerism. Am J Cardiol 1987; 60: 1157.
Ho SY, Fagg N, Anderson RH, et al. Disposition of the atrioventricular conduction tissues in the heart with isomerism of the atrial appendages: its relation to congenital complete heart block. J Am Coll Cardiol 1992; 20: 904.
Tanano H, Hasegawa T, Kawahara H, et al. Biliary atresia associated with congenital structural anomalies. J Pediatr Surg 1999; 34: 1687.
Strouse PJ. Disorders of intestinal rotation and fixation (“malrotation”). Pedatr Radiol 2004; 34(11):
Ferdman B, States L, Gaynor JL, et al. Abnormalities of intestinal rotation in patients with congeniral heart disease and the heterotaxy syndrome. Congenit Heart Dis 2007; 2(1): 12-8.
Hill SJ, Heiss KF, Mittal R, et al. Heterotoxy syndrome and malrotation: Does isomerism influence risk and decision to treat. J Pedatr Surg 2014; 49:
Papillon S, Goodhue CJ, Zmora O, et al. Congenital heart disease and heterotaxy; upper gastrointestinal fluoroscopy can be misleading and surgery in an asymptomatic patient is not beneficial. J Pedatr Surg 2013; 48:
Yu DC, Thiagarajan RR, Laussen PC, et al. Outcomes after the Ladd procedure in patients with heterotaxy syndrome, congenital heart disease, and intestinal malrotation. J Pediatr Surg 2009; 44:
Salavitabar A, Anderson B, Aspelund G, et al. Heterotaxy syndrome and intestinal rotational anomalies: Impact of the Ladd procedure. J Pediatr Surg 2015; In press.