Indian J Pediatr DOI 10.1007/s12098-015-1925-x
REVIEW ARTICLE
Cardiac and Non-Cardiac Abnormalities in Heterotaxy Syndrome Smita Mishra 1
Received: 27 May 2015 / Accepted: 14 October 2015 # Dr. K C Chaudhuri Foundation 2015
Abstract Thoraco-abdominal viscera have unique morphological asymmetry, unlike the body’s external organs. Heterotaxy syndrome is a disorder in which there is a loss of normal left to right asymmetry of thoraco-abdominal viscera and their naturally proscribed spatial relationship. It has multiple anatomical alterations, culminating into physiological and hemodynamic consequences. It is divided into two groups on the basis of morphology of the two atrial appendages. These subgroups are - 1) Isomerism of right atrial appendage (asplenia syndrome); 2) Isomerism of left atrial appendage (polysplenia syndrome); Patients from group I, usually have severe cardiac malformations and present early. They may have duct dependent lesions and eventually may undergo Fontan surgery. However, extracardiac anomalies are more common in group II. All the patients must be evaluated in detail to rule out anomalies like gut-malrotation. Patients must be provided with special care for their susceptibility to infection due to absence of spleen or presence of splenic malfunction. Majority of these patients may have genetic link and may present in families. Hence, genetic evaluation is necessary before assuming long term outcome.
Keywords Heterotaxy syndrome . Isomerism of atrial appendage . Asplenia . Polysplenia . Ivemark syndrome . Situs ambiguous . AVSD
Abbreviations HS Heterotaxy Syndrome IRAA Isomerism of Right Atrial Appendage ILAA Isomerism of Left Atrial Appendage CHD Congenital Heart Disease
Introduction Heterotaxy syndrome (HS) is a disorder in which there is a loss of normal left to right asymmetry of thoraco abdominal viscera and their naturally proscribed spatial relationship, secondary to the disruption of the normal sequential embryological development, possibly, at around 5th wk of gestation (streeter’s horizon 13) [1–4] (Fig. 1a and b). HS is a group of complex anatomical alterations leading to diverse physiological as well as hemodynamic consequences. Obviously, body’s exterior shows symmetry of body parts. There are two eyes, ears, hands, legs etc. Factually, the thoraco-abdominal organs do not emulate the body’s exterior as that can be uniquely identified as being right or left sided structure, depending on their gross appearances. For example, right lung is trilobed and left lung is bi-lobed. When both lungs are trilobed or bilobed suggesting that normal asymmetry is lost, we consider the diagnosis of HS (Fig. 1a and b).
Incidence and Genetics [5–7] * Smita Mishra [email protected]; [email protected] 1
Department of Pediatric Cardiology, JAYPEE Hospital, Sector 128, Noida, Uttar Pradesh, India
In general, the incidence of HS is 1 per 10,000–20,000 live births. The reported incidence of HS is around 6.3 % out of those patients who are diagnosed to have primary ciliary dyskinesia (PCD) [5]. The HS has been found to be associated with all possible modes of genetic transmission like sporadic, familial X-linked,
Indian J Pediatr Fig. 1 Line diagram showing salient features of heterotaxy syndrome; a Group I (IRAA) b Group II (ILAA)
autosomal recessive and dominant modes. Though trisomy 21 has not been associated with HS but other genetic disorders like primary ciliary dyskinesia (PCD), trisomy 13, trisomy 18,deletion syndromes like DiGeorge (22q11.2) have been reported to be associated with ambiguity of situs. Environmental factors like maternal cocaine use, maternal diabetes, and monozygotic twinning have all been associated with HS.
Group II: Isomerism of left atrial appendage (ILAA) (Fig. 1b) – Usually it is associated with multiple spleen (Polyspenia syndrome). The other abnormalities of thoraco-abdominal organs showing predilection to one of the groups but may not be sacrosanct to either of them are discussed in Tables 1 and 2.
Approach to Diagnosis
Cardiac Abnormalities in Heterotaxy Syndrome [1–5, 10–14] (Tables 1 and 2)
Heterotaxy syndrome is a morphological diagnosis thus far, it can not be suspected clinically in majority of cases. Essentially, morphology can be analyzed by imaging technology, during surgery or in post-martem specimens. The role of Electrocardiogram, X-Ray chest and Echocardiography will be evaluated. CT angiography or MRI are more helpful and are regularly being used to analyze a case before any intervention.
In general, the group I (IRAA) presents with severe cardiac malformations. Extracardiac malformations are more common in group II (ILAA). a) Cardiac position: Cardiac position in HS is usually abnormal (Dextrocardia or mesocardia), but in many patients levocardia is present (Fig. 2a and b). In HS, due to centrally
Malformations in Heterotaxy Syndrome
Table 1
As it has been discussed, a spectrum of anatomical defects of various thoraco-abdominal organs involving different systems, are seen under the one diagnosis (Fig. 1). Before going for a detailed appraisal of this gamut, one needs to know classification of HS. Classification HS had been classified in two groups based morphology of atrial appendages [8–11]. Group I: Isomerism of right atrial appendage (IRAA) (Fig. 1a) – Usually it is associated with absence of spleen (Asplenia syndrome).
Common terminologies [1–8]
Heterotaxy: Word origin (Greek); Other arrangement Isomerism: Isos (equal) plus meros (part) Situs Ambiguous (SA): Situs ambiguous, therefore, is considered to be present when the thoracic and abdominal organs are positioned in such a way with respect to each other as to be not clearly lateralized and thus have neither the usual, or normal, nor the mirror-imaged arrangements.^ (Nomenclature working group 2007) Isomerism of Right Atrial Appendage (IRAA): When both atrial appendages are morphologically right atrial appendage and cardiac and non cardiac thoraco-abdominal viscera show abundance of right sided morphological features like bilateral trilobed lung, eparterial bronchi or absence of spleen. It is also known as Asplenia or Ivemark syndrome. Isomerism of Left Atrial Appendage (ILAA): When both atrial appendages are morphologically left atrial appendage and cardiac and non-cardiac thoraco-abdominal viscera show abundance of left sided morphological features like bilateral bilobed lung, hyparterial bronchi or presence of multiple spleen. (Also described as Polysplenia syndrome)
Indian J Pediatr Table 2
Synopsis of cardiac and noncardiac anomalies in heterotaxy syndrome
Morphological features
Isomerism of left atrial appendage
Isomerism of right atrial appendage
Abnormal cardiac positions are common in IRAA Any position (Dextrocardia, Mesocardia, Levocardia) patients than normal population. Abnormal cardiac positions are common in 40–50 % patients. Systemic veins Interrupted IVC with azygos venous system continuation IVC drains into one of the atrium. Hepatic veins may to SVC. Hepatic veins, isolated or in confluence drain separately in contralateral atrium drain into either of atrium. (morphological representation of duplication of IVC). Bilateral SVC: Found in 40 % cases and absent coronary Bilateral SVC: Found in 50–60 % cases and absent sinus in 30–55 % cases. coronary sinus in 78 % cases. Obstructed TAPVC is common finding in >50 % cases. Pulmonary veins PAPVC in >50 % patients due to bilateral atrial Unobstructed TAPVC can also be present. connection of ipsilateral PVs or due to mal-aligned septum. Less frequently. TAPVC or TAPVD can be seen (10–12 %). Scimitar syndrome in 1 %. Atrial appendage Both atrial appendages are of left atrial morphology Both atrial appendages are of right atrial morphology (See text) (see text) Common AV valve associated with complete AVSD Atrial septum/AtrioPartial AVSD, ostium primum ASD with two or common atrium is frequently seen. ventricular junction/valve distinct AV orifices and cleft in left component of AV valve is common. Univentricular AV connection Less common (10–40 %) More common (more than 70 %) Pulmonary stenosis/Atresia are common (>80 %) Outflow obstruction Right outflow obstruction: less than 40 %; Left ventricular outflow obstruction are seen more frequently (98 % Conduction system Bilateral absence of sinus node may lead to Two sinus node. The atrial tachyarrhythmias bradyarrhythmias. are common. Bilateral morphological right bronchus and right lung Lungs and bronchi Bilateral morphological left bronchus and left lung (trilobed) (90 %). rally (90 %). Congenital lobar pneumonia and Scimital syndrome can be seen in few cases. The absence of spleen is expected in this group. But in Spleen Multiple spleen are commonly seen. In 5–10 % 10–15 % cases it may be present as a single or cases, it may be absent or present singularly. multiple masses. Spleen may be functionally abnormal. Functional abnormalities are common. Liver and stomach Central liver is common in >70 % cases. It may be Majority patients have central liver. Stomach can be asymmetrical, right or left sided in few cases. central, right or left. Stomach may be central, right or left sided. Bowel malrotation and other Common in ILAA group. Less frequent in this group abnormalities Pancreas Not rare Rare Gall bladder Common Not reported in literature Heart position
ASD: Atrial septal defect; AV: Atrio-ventricular; AVSD: Atrio-ventricular septal defect; V-A (Concordance/Discordance): Ventriculo-Arterial (concordance or discordance); DORV: Double outlet right ventricle; PV: Pulmonary valve; CHD: Congenital heart disease; TGA: Transposition of the great arteries; PS/PA: Pulmonary stenosis or atresia; LVOTO: Left ventricular outflow tract obstruction; SVC: Superior vena cava; IVC: Inferior vena cava; TAPVC/D: Total anomalous pulmonary venous connection/Drainage; PAPVC: Partial anomalous pulmonary venous connection. Adopted with permission, from ref. [13], A comprehensive approach to congenital heart disease, 2013, Publishers JAYPEE Brothers
placed liver, relationship of apex with liver is always abnormal. b) Systemic and pulmonary veins and veno-atrial connection, atrium and atrial septal defect [1–5, 12–16] (Figs. 2, 3a, b, 4a, b and 5a, b). i) Superior Vena Cava : Commonly there are two vena cavae in both of the groups (Fig. 4b). ii) Coronary Sinus : Coronary sinus is absent in majority of cases of group I. It is seen less often in group II patients.
iii) Inferior Vena Cava (IVC) and Hepatic Veins (HV) : Morphologically, atrium is connected to the IVC is the right atrium. IVC and abdominal aorta are present on either side of the spine in a normal person. They are on the same side of spine in Group I patients (Fig. 3a), while in Group II, interrupted IVC with azygus continuation is seen (Fig. 3b). iv) Pulmonary Veins : Pulmonary venous drainage is usually abnormal in HS. In Group I, obstructed total anomalous
Indian J Pediatr
Fig. 2 Chest roentgenogram showing cardiac position: a Mesocardia and central liver in a case from Group II; b Dextrocardia and central liver in a patient from Group I
pulmonary venous drainage (TAPVD) is common. In Group II, usually cardiac type of non-obstructed partial or total anomalous pulmonary venous drainage is seen (Fig. 4). Scimitar syndrome [Partial anomalous pulmonary venous connection (PAPVC) of right pulmonary veins and hypoplasia of right lung, abnormal systemic to pul-
Fig. 3 Visceral situs delineated by echocardiography (subcostal coronal view); a Group 1 (IRAA)–juxtaposed IVC and descending aorta on the left side of spine at the level of diaphragm. b Group II (ILAA)–prominent venous channel (azygus-hemiazygus system) behind the aorta on left side of spine in a case of interrupted IVC
monary collateral and pulmonary sequestration] may be found, in about 1 % cases. v) Atrial Appendages : Morphologically the right atrial appendage (RAA) is muscular, thumb like, broad based structure and has pectinate muscles which extend beyond the junction between RAA with RA cavity. In Group I, both atrium have morphological right atrial appendage (isomerism of right atrial appendage) (Fig. 5a). The left atrial appendage is a finger like, trabecularized structure which lies over the left atrioventricular groove. The pectinate muscles are located almost exclusively within the appendage (Fig. 6). In Group II, atrial appendages on both sides have morphology of left atrial appendage (isomerism of left atrial appendage) (Fig. 5b). vi) Atrial Septum and Atrial Septal Defect (ASD) : The Group I, is usually associated with complete atrio-ventricular septal defect and a large ostium primum ASD (Fig. 7). Atrial septum may be completely absent (common atrium) in many cases. In Group II there may be partial atrio-ventricular septal defect (AVSD) with large ostium primum ASD, sinus venosus ASD or secundum ASD [17]. c) Atrio-ventricular Valve [1–5, 15–17]: Atrioventricular septal defect with common atrio-ventricular valve is commonly seen in HS. Group I patients usually have complete form of AVSD with common atrio-ventricular (AV) valve which frequently associates with the unbalanced ventricles and large inlet ventricular septal defect (VSD). Less commonly, they have only primum ASD and no VSD (partial AVSD). There may be significant regurgitation of AV valve, secondary to presence of a cleft. In Group II, partial AVSD or ostium primum ASD is more common. However, patients from Group II may have absolutely normal tricuspid and mitral valve. d) Ventricular Loop and Ventricles and Outflows [1–5, 15–18] : The ventricular anatomy on two side is never same, therefore ventricular isomerism is unknown. However, a variety of ventricular abnormalities can be seen. The ventricular loop may be abnormal -‘L’ (right ventricle in left side) instead of normal ‘D’ (right ventricle on right side). In Group I, ventricular anatomy usually is such that biventricular repair becomes difficult or impossible. Group I patients usually undergo an early surgery and need Fontan type univentricular repair. In Group II, severity of ventricular malformation is less and many patients may have good biventricular repair. Ventriculo-arterial discordance (D-TGA), double outlet right ventricle (DORV) or corrected transposition physiology, with pulmonary stenosis/pulmonary atresia are usual abnormalities in Group I (IRAA). Any kind of VSD like- inlet, outlet, perimembranous or muscular, can be seen in Group II (ILAA). Left sided abnormalities
Indian J Pediatr Fig. 4 TAPVD (Total anomalous pulmonary venous drainage) due to malaligned atrial septum in patient having ILAA (Group II)
like aortic stenosis and coarctation of aorta are common in these patients. e) Conduction System and Electrocardiogram [1–5, 19–21] : Electrocardiograms in HS must be evaluated for rate, rhythm, accessory pathways and AV conduction. The atrial situs, ventricular hypertrophy patterns can be assessed by evaluating the axis and voltage of P, QRS and T waves. Usual ECG abnormalities are: 1. Abnormal P wave axis suggesting bilateral SA node or absent SA node and position of atria; 2. Bradycardia/Junctional Rhythm/ Block (ILAA); 3. Abnormal left axis deviation (common in AVSD); 4. Abnormal Q waves (single ventricle or ventricular inversion) 5. Accessory pathway. Figure 8a and b show low atrial focus in a patient from Group II
Fig. 5 Atrial appendages (line diagrams) in HS; a Bilateral morphological right atrial appendages; b Bilateral morphological left atrial appendages
(ILAA). Figure 9 shows ECG from a patient having IRAA, showing change in P wave axis. An abnormal cardiac rhythm can also be noticed in fetal life [22]. f) Other Cardio-pulmonary Manifestations [1–5, 14–17, 23] : Pulmonary hypertension with secondary RV pressure overload, association of non-compacted LV, isolated pulmonary sequestration with or without Scimitar syndrome are reported, mostly in Group II. Extra-cardiac Anatomical Abnormalities in Heterotaxy Syndrome a) Bronchial Situs and Lungs [22–28] : In Group I (IRAA), lungs, bronchi and branch pulmonary arteries
Indian J Pediatr
Fig. 6 Bilateral left lung morphology (Group II- ILAA). Bilateral left sided morphological lungs, bronchi and PA branches: Branches of PA (A, B) crossing bronchi before the origin of ULB (upper lobe bronchus- C, D). The distance between carina and ULB (red line E, F) is same on both the sides
show bilateral right sided morphology while in Group II (ILAA) all these structures have bilateral left sided morphology. Hence, in Group I, both lungs are trilobed and have one oblique and one major fissure and have eparterial bronchus (Fig. 10). Both branch pulmonary arteries are morphologically right pulmonary arteries because they run antero-inferiorly to right and left bronchus (Fig. 11). In Group II, both lungs are bilobed and have one major oblique fissure and hyparterial bronchus (Figs. 1a,b and 9). On both the sides, branches of the pulmonary artery are morphologically left PA as they cross the respective bronchi before the origin of first
Fig. 7 Cardiac defect in Group I: Complete atrio-ventricular septal defect, common AV valve and unbalanced ventricles
branch of bronchus. Bronchial anatomy can be recognized in X-ray chest and HRCT and MRI. Three important morphological features of broncho-pulmonary tree with best predictive value for isomeric atrial appendages are : i) Bilaterally lungs have similar number of lobes; ii) Ratio of left to right (L/R) bronchial lengths (12 y: 250 mg BD; 6–12 y: 125 mg BD PO; Phenoxybenzyl Penicillin (Not recommended for patients having H/o previous infection with H. influenzae) < 1 y: 62.5 mg BD, PO; 1–5 y: 125 mg BD,PO; 6 y onwards: 250 mg BD,PO.
B. Allergy to Penicillins 1 mo −2 y
Erythromycin 125 mg OD,PO
Patients above 2 y
Erythromycin 250 mg OD,PO upto 8 y; 500 mg OD, PO Above 8 y
Available at: http://www.ekhuft.nhs.uk/staff/old-antimicrobialguidelines/neutropenia-guidelines/asplenic-prophylaxis/
functional status of spleen. Capsular bacteria and protozoa, both can be detrimental for such a patient. Human and animal bites are also a source of bacterial transmission and must be treated promptly. Streptococcus pneumoniae is the most common pathogen causing septicemia in asplenic children followed by Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus and other streptococci [35]. The recommendations are published for continuous antibiotic prophylaxis atleast upto five years of age for a asplenic child, vaccination against capsular bacteria and prompt use of antibiotics at home or clinic if fever is recorded [34–36] (Tables 3, 4, 5 and 6).
f) Malrotation and Other Gut Abnormalities [1–5, 12–15, 37] (Fig. 13): Malrotation of gut is the result of rotational abnormality of gut secondary to failure of normal counterclockwise rotation of mid gut by 270° [38]. Due to abnormal or absent bowel fixation by the mesenteric bands, these patients have risks of bowel obstruction, acute or chronic volvulus, and bowel necrosis [32]. The cecum does not reach in the right lower quadrant. The mesentery forms a narrow base as the gut lengthens without rotation (Fig. 8a). Routine exclusion of gut malrotation by ultrasound abdomen, Barium examinations under fluoroscopy or CT scanning is recommended to avoid mortality and morbidity related to it (Fig. 13). All gut abnormalities with or without congenital cardiac defects, are common in Group II. Besides the above mentioned abnormalities, there may be jejunal atresia, duplication of bowel or cephalic migration of colon in heterotaxy patients. g) Pancreas in Heterotaxy [1–5, 12–17, 25, 39] (Table 2) : The abnormalities of pancreas are seen in Group II. In many cases tissue from the head of pancreas forms semicircle around the duodenum and is known as annular pancreas; Pancreas is called truncated when only head or head and small body are present (Fig. 12) [13]. Other abnormalities related to pancreas are - pancreatic malrotation, increased incidence of pancreatitis and diabetes mellitus, obstructive jaundice secondary to dorsal agenesis of pancreas and preduodenal portal vein [39]. h) Gall Bladder and Biliary Atresia [1–5, 12–16] : Gall bladder usually shifts to the midline from its usual position, under the surface of right lobe of liver. In
Table 4 Recommendations for additional vaccines besides the national immunization schedule* against capsular bacteria in patients with malfunctioning or absent spleen. (NHS Recommendation) Meningococcal Vaccine
Pneumococcal vaccine Boosters-HIB/MEN-B&C/PCV13/ MMR/PPV23
Influenza vaccine
Diagnosed at
REVIEW ARTICLE
Cardiac and Non-Cardiac Abnormalities in Heterotaxy Syndrome Smita Mishra 1
Received: 27 May 2015 / Accepted: 14 October 2015 # Dr. K C Chaudhuri Foundation 2015
Abstract Thoraco-abdominal viscera have unique morphological asymmetry, unlike the body’s external organs. Heterotaxy syndrome is a disorder in which there is a loss of normal left to right asymmetry of thoraco-abdominal viscera and their naturally proscribed spatial relationship. It has multiple anatomical alterations, culminating into physiological and hemodynamic consequences. It is divided into two groups on the basis of morphology of the two atrial appendages. These subgroups are - 1) Isomerism of right atrial appendage (asplenia syndrome); 2) Isomerism of left atrial appendage (polysplenia syndrome); Patients from group I, usually have severe cardiac malformations and present early. They may have duct dependent lesions and eventually may undergo Fontan surgery. However, extracardiac anomalies are more common in group II. All the patients must be evaluated in detail to rule out anomalies like gut-malrotation. Patients must be provided with special care for their susceptibility to infection due to absence of spleen or presence of splenic malfunction. Majority of these patients may have genetic link and may present in families. Hence, genetic evaluation is necessary before assuming long term outcome.
Keywords Heterotaxy syndrome . Isomerism of atrial appendage . Asplenia . Polysplenia . Ivemark syndrome . Situs ambiguous . AVSD
Abbreviations HS Heterotaxy Syndrome IRAA Isomerism of Right Atrial Appendage ILAA Isomerism of Left Atrial Appendage CHD Congenital Heart Disease
Introduction Heterotaxy syndrome (HS) is a disorder in which there is a loss of normal left to right asymmetry of thoraco abdominal viscera and their naturally proscribed spatial relationship, secondary to the disruption of the normal sequential embryological development, possibly, at around 5th wk of gestation (streeter’s horizon 13) [1–4] (Fig. 1a and b). HS is a group of complex anatomical alterations leading to diverse physiological as well as hemodynamic consequences. Obviously, body’s exterior shows symmetry of body parts. There are two eyes, ears, hands, legs etc. Factually, the thoraco-abdominal organs do not emulate the body’s exterior as that can be uniquely identified as being right or left sided structure, depending on their gross appearances. For example, right lung is trilobed and left lung is bi-lobed. When both lungs are trilobed or bilobed suggesting that normal asymmetry is lost, we consider the diagnosis of HS (Fig. 1a and b).
Incidence and Genetics [5–7] * Smita Mishra [email protected]; [email protected] 1
Department of Pediatric Cardiology, JAYPEE Hospital, Sector 128, Noida, Uttar Pradesh, India
In general, the incidence of HS is 1 per 10,000–20,000 live births. The reported incidence of HS is around 6.3 % out of those patients who are diagnosed to have primary ciliary dyskinesia (PCD) [5]. The HS has been found to be associated with all possible modes of genetic transmission like sporadic, familial X-linked,
Indian J Pediatr Fig. 1 Line diagram showing salient features of heterotaxy syndrome; a Group I (IRAA) b Group II (ILAA)
autosomal recessive and dominant modes. Though trisomy 21 has not been associated with HS but other genetic disorders like primary ciliary dyskinesia (PCD), trisomy 13, trisomy 18,deletion syndromes like DiGeorge (22q11.2) have been reported to be associated with ambiguity of situs. Environmental factors like maternal cocaine use, maternal diabetes, and monozygotic twinning have all been associated with HS.
Group II: Isomerism of left atrial appendage (ILAA) (Fig. 1b) – Usually it is associated with multiple spleen (Polyspenia syndrome). The other abnormalities of thoraco-abdominal organs showing predilection to one of the groups but may not be sacrosanct to either of them are discussed in Tables 1 and 2.
Approach to Diagnosis
Cardiac Abnormalities in Heterotaxy Syndrome [1–5, 10–14] (Tables 1 and 2)
Heterotaxy syndrome is a morphological diagnosis thus far, it can not be suspected clinically in majority of cases. Essentially, morphology can be analyzed by imaging technology, during surgery or in post-martem specimens. The role of Electrocardiogram, X-Ray chest and Echocardiography will be evaluated. CT angiography or MRI are more helpful and are regularly being used to analyze a case before any intervention.
In general, the group I (IRAA) presents with severe cardiac malformations. Extracardiac malformations are more common in group II (ILAA). a) Cardiac position: Cardiac position in HS is usually abnormal (Dextrocardia or mesocardia), but in many patients levocardia is present (Fig. 2a and b). In HS, due to centrally
Malformations in Heterotaxy Syndrome
Table 1
As it has been discussed, a spectrum of anatomical defects of various thoraco-abdominal organs involving different systems, are seen under the one diagnosis (Fig. 1). Before going for a detailed appraisal of this gamut, one needs to know classification of HS. Classification HS had been classified in two groups based morphology of atrial appendages [8–11]. Group I: Isomerism of right atrial appendage (IRAA) (Fig. 1a) – Usually it is associated with absence of spleen (Asplenia syndrome).
Common terminologies [1–8]
Heterotaxy: Word origin (Greek); Other arrangement Isomerism: Isos (equal) plus meros (part) Situs Ambiguous (SA): Situs ambiguous, therefore, is considered to be present when the thoracic and abdominal organs are positioned in such a way with respect to each other as to be not clearly lateralized and thus have neither the usual, or normal, nor the mirror-imaged arrangements.^ (Nomenclature working group 2007) Isomerism of Right Atrial Appendage (IRAA): When both atrial appendages are morphologically right atrial appendage and cardiac and non cardiac thoraco-abdominal viscera show abundance of right sided morphological features like bilateral trilobed lung, eparterial bronchi or absence of spleen. It is also known as Asplenia or Ivemark syndrome. Isomerism of Left Atrial Appendage (ILAA): When both atrial appendages are morphologically left atrial appendage and cardiac and non-cardiac thoraco-abdominal viscera show abundance of left sided morphological features like bilateral bilobed lung, hyparterial bronchi or presence of multiple spleen. (Also described as Polysplenia syndrome)
Indian J Pediatr Table 2
Synopsis of cardiac and noncardiac anomalies in heterotaxy syndrome
Morphological features
Isomerism of left atrial appendage
Isomerism of right atrial appendage
Abnormal cardiac positions are common in IRAA Any position (Dextrocardia, Mesocardia, Levocardia) patients than normal population. Abnormal cardiac positions are common in 40–50 % patients. Systemic veins Interrupted IVC with azygos venous system continuation IVC drains into one of the atrium. Hepatic veins may to SVC. Hepatic veins, isolated or in confluence drain separately in contralateral atrium drain into either of atrium. (morphological representation of duplication of IVC). Bilateral SVC: Found in 40 % cases and absent coronary Bilateral SVC: Found in 50–60 % cases and absent sinus in 30–55 % cases. coronary sinus in 78 % cases. Obstructed TAPVC is common finding in >50 % cases. Pulmonary veins PAPVC in >50 % patients due to bilateral atrial Unobstructed TAPVC can also be present. connection of ipsilateral PVs or due to mal-aligned septum. Less frequently. TAPVC or TAPVD can be seen (10–12 %). Scimitar syndrome in 1 %. Atrial appendage Both atrial appendages are of left atrial morphology Both atrial appendages are of right atrial morphology (See text) (see text) Common AV valve associated with complete AVSD Atrial septum/AtrioPartial AVSD, ostium primum ASD with two or common atrium is frequently seen. ventricular junction/valve distinct AV orifices and cleft in left component of AV valve is common. Univentricular AV connection Less common (10–40 %) More common (more than 70 %) Pulmonary stenosis/Atresia are common (>80 %) Outflow obstruction Right outflow obstruction: less than 40 %; Left ventricular outflow obstruction are seen more frequently (98 % Conduction system Bilateral absence of sinus node may lead to Two sinus node. The atrial tachyarrhythmias bradyarrhythmias. are common. Bilateral morphological right bronchus and right lung Lungs and bronchi Bilateral morphological left bronchus and left lung (trilobed) (90 %). rally (90 %). Congenital lobar pneumonia and Scimital syndrome can be seen in few cases. The absence of spleen is expected in this group. But in Spleen Multiple spleen are commonly seen. In 5–10 % 10–15 % cases it may be present as a single or cases, it may be absent or present singularly. multiple masses. Spleen may be functionally abnormal. Functional abnormalities are common. Liver and stomach Central liver is common in >70 % cases. It may be Majority patients have central liver. Stomach can be asymmetrical, right or left sided in few cases. central, right or left. Stomach may be central, right or left sided. Bowel malrotation and other Common in ILAA group. Less frequent in this group abnormalities Pancreas Not rare Rare Gall bladder Common Not reported in literature Heart position
ASD: Atrial septal defect; AV: Atrio-ventricular; AVSD: Atrio-ventricular septal defect; V-A (Concordance/Discordance): Ventriculo-Arterial (concordance or discordance); DORV: Double outlet right ventricle; PV: Pulmonary valve; CHD: Congenital heart disease; TGA: Transposition of the great arteries; PS/PA: Pulmonary stenosis or atresia; LVOTO: Left ventricular outflow tract obstruction; SVC: Superior vena cava; IVC: Inferior vena cava; TAPVC/D: Total anomalous pulmonary venous connection/Drainage; PAPVC: Partial anomalous pulmonary venous connection. Adopted with permission, from ref. [13], A comprehensive approach to congenital heart disease, 2013, Publishers JAYPEE Brothers
placed liver, relationship of apex with liver is always abnormal. b) Systemic and pulmonary veins and veno-atrial connection, atrium and atrial septal defect [1–5, 12–16] (Figs. 2, 3a, b, 4a, b and 5a, b). i) Superior Vena Cava : Commonly there are two vena cavae in both of the groups (Fig. 4b). ii) Coronary Sinus : Coronary sinus is absent in majority of cases of group I. It is seen less often in group II patients.
iii) Inferior Vena Cava (IVC) and Hepatic Veins (HV) : Morphologically, atrium is connected to the IVC is the right atrium. IVC and abdominal aorta are present on either side of the spine in a normal person. They are on the same side of spine in Group I patients (Fig. 3a), while in Group II, interrupted IVC with azygus continuation is seen (Fig. 3b). iv) Pulmonary Veins : Pulmonary venous drainage is usually abnormal in HS. In Group I, obstructed total anomalous
Indian J Pediatr
Fig. 2 Chest roentgenogram showing cardiac position: a Mesocardia and central liver in a case from Group II; b Dextrocardia and central liver in a patient from Group I
pulmonary venous drainage (TAPVD) is common. In Group II, usually cardiac type of non-obstructed partial or total anomalous pulmonary venous drainage is seen (Fig. 4). Scimitar syndrome [Partial anomalous pulmonary venous connection (PAPVC) of right pulmonary veins and hypoplasia of right lung, abnormal systemic to pul-
Fig. 3 Visceral situs delineated by echocardiography (subcostal coronal view); a Group 1 (IRAA)–juxtaposed IVC and descending aorta on the left side of spine at the level of diaphragm. b Group II (ILAA)–prominent venous channel (azygus-hemiazygus system) behind the aorta on left side of spine in a case of interrupted IVC
monary collateral and pulmonary sequestration] may be found, in about 1 % cases. v) Atrial Appendages : Morphologically the right atrial appendage (RAA) is muscular, thumb like, broad based structure and has pectinate muscles which extend beyond the junction between RAA with RA cavity. In Group I, both atrium have morphological right atrial appendage (isomerism of right atrial appendage) (Fig. 5a). The left atrial appendage is a finger like, trabecularized structure which lies over the left atrioventricular groove. The pectinate muscles are located almost exclusively within the appendage (Fig. 6). In Group II, atrial appendages on both sides have morphology of left atrial appendage (isomerism of left atrial appendage) (Fig. 5b). vi) Atrial Septum and Atrial Septal Defect (ASD) : The Group I, is usually associated with complete atrio-ventricular septal defect and a large ostium primum ASD (Fig. 7). Atrial septum may be completely absent (common atrium) in many cases. In Group II there may be partial atrio-ventricular septal defect (AVSD) with large ostium primum ASD, sinus venosus ASD or secundum ASD [17]. c) Atrio-ventricular Valve [1–5, 15–17]: Atrioventricular septal defect with common atrio-ventricular valve is commonly seen in HS. Group I patients usually have complete form of AVSD with common atrio-ventricular (AV) valve which frequently associates with the unbalanced ventricles and large inlet ventricular septal defect (VSD). Less commonly, they have only primum ASD and no VSD (partial AVSD). There may be significant regurgitation of AV valve, secondary to presence of a cleft. In Group II, partial AVSD or ostium primum ASD is more common. However, patients from Group II may have absolutely normal tricuspid and mitral valve. d) Ventricular Loop and Ventricles and Outflows [1–5, 15–18] : The ventricular anatomy on two side is never same, therefore ventricular isomerism is unknown. However, a variety of ventricular abnormalities can be seen. The ventricular loop may be abnormal -‘L’ (right ventricle in left side) instead of normal ‘D’ (right ventricle on right side). In Group I, ventricular anatomy usually is such that biventricular repair becomes difficult or impossible. Group I patients usually undergo an early surgery and need Fontan type univentricular repair. In Group II, severity of ventricular malformation is less and many patients may have good biventricular repair. Ventriculo-arterial discordance (D-TGA), double outlet right ventricle (DORV) or corrected transposition physiology, with pulmonary stenosis/pulmonary atresia are usual abnormalities in Group I (IRAA). Any kind of VSD like- inlet, outlet, perimembranous or muscular, can be seen in Group II (ILAA). Left sided abnormalities
Indian J Pediatr Fig. 4 TAPVD (Total anomalous pulmonary venous drainage) due to malaligned atrial septum in patient having ILAA (Group II)
like aortic stenosis and coarctation of aorta are common in these patients. e) Conduction System and Electrocardiogram [1–5, 19–21] : Electrocardiograms in HS must be evaluated for rate, rhythm, accessory pathways and AV conduction. The atrial situs, ventricular hypertrophy patterns can be assessed by evaluating the axis and voltage of P, QRS and T waves. Usual ECG abnormalities are: 1. Abnormal P wave axis suggesting bilateral SA node or absent SA node and position of atria; 2. Bradycardia/Junctional Rhythm/ Block (ILAA); 3. Abnormal left axis deviation (common in AVSD); 4. Abnormal Q waves (single ventricle or ventricular inversion) 5. Accessory pathway. Figure 8a and b show low atrial focus in a patient from Group II
Fig. 5 Atrial appendages (line diagrams) in HS; a Bilateral morphological right atrial appendages; b Bilateral morphological left atrial appendages
(ILAA). Figure 9 shows ECG from a patient having IRAA, showing change in P wave axis. An abnormal cardiac rhythm can also be noticed in fetal life [22]. f) Other Cardio-pulmonary Manifestations [1–5, 14–17, 23] : Pulmonary hypertension with secondary RV pressure overload, association of non-compacted LV, isolated pulmonary sequestration with or without Scimitar syndrome are reported, mostly in Group II. Extra-cardiac Anatomical Abnormalities in Heterotaxy Syndrome a) Bronchial Situs and Lungs [22–28] : In Group I (IRAA), lungs, bronchi and branch pulmonary arteries
Indian J Pediatr
Fig. 6 Bilateral left lung morphology (Group II- ILAA). Bilateral left sided morphological lungs, bronchi and PA branches: Branches of PA (A, B) crossing bronchi before the origin of ULB (upper lobe bronchus- C, D). The distance between carina and ULB (red line E, F) is same on both the sides
show bilateral right sided morphology while in Group II (ILAA) all these structures have bilateral left sided morphology. Hence, in Group I, both lungs are trilobed and have one oblique and one major fissure and have eparterial bronchus (Fig. 10). Both branch pulmonary arteries are morphologically right pulmonary arteries because they run antero-inferiorly to right and left bronchus (Fig. 11). In Group II, both lungs are bilobed and have one major oblique fissure and hyparterial bronchus (Figs. 1a,b and 9). On both the sides, branches of the pulmonary artery are morphologically left PA as they cross the respective bronchi before the origin of first
Fig. 7 Cardiac defect in Group I: Complete atrio-ventricular septal defect, common AV valve and unbalanced ventricles
branch of bronchus. Bronchial anatomy can be recognized in X-ray chest and HRCT and MRI. Three important morphological features of broncho-pulmonary tree with best predictive value for isomeric atrial appendages are : i) Bilaterally lungs have similar number of lobes; ii) Ratio of left to right (L/R) bronchial lengths (12 y: 250 mg BD; 6–12 y: 125 mg BD PO; Phenoxybenzyl Penicillin (Not recommended for patients having H/o previous infection with H. influenzae) < 1 y: 62.5 mg BD, PO; 1–5 y: 125 mg BD,PO; 6 y onwards: 250 mg BD,PO.
B. Allergy to Penicillins 1 mo −2 y
Erythromycin 125 mg OD,PO
Patients above 2 y
Erythromycin 250 mg OD,PO upto 8 y; 500 mg OD, PO Above 8 y
Available at: http://www.ekhuft.nhs.uk/staff/old-antimicrobialguidelines/neutropenia-guidelines/asplenic-prophylaxis/
functional status of spleen. Capsular bacteria and protozoa, both can be detrimental for such a patient. Human and animal bites are also a source of bacterial transmission and must be treated promptly. Streptococcus pneumoniae is the most common pathogen causing septicemia in asplenic children followed by Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus and other streptococci [35]. The recommendations are published for continuous antibiotic prophylaxis atleast upto five years of age for a asplenic child, vaccination against capsular bacteria and prompt use of antibiotics at home or clinic if fever is recorded [34–36] (Tables 3, 4, 5 and 6).
f) Malrotation and Other Gut Abnormalities [1–5, 12–15, 37] (Fig. 13): Malrotation of gut is the result of rotational abnormality of gut secondary to failure of normal counterclockwise rotation of mid gut by 270° [38]. Due to abnormal or absent bowel fixation by the mesenteric bands, these patients have risks of bowel obstruction, acute or chronic volvulus, and bowel necrosis [32]. The cecum does not reach in the right lower quadrant. The mesentery forms a narrow base as the gut lengthens without rotation (Fig. 8a). Routine exclusion of gut malrotation by ultrasound abdomen, Barium examinations under fluoroscopy or CT scanning is recommended to avoid mortality and morbidity related to it (Fig. 13). All gut abnormalities with or without congenital cardiac defects, are common in Group II. Besides the above mentioned abnormalities, there may be jejunal atresia, duplication of bowel or cephalic migration of colon in heterotaxy patients. g) Pancreas in Heterotaxy [1–5, 12–17, 25, 39] (Table 2) : The abnormalities of pancreas are seen in Group II. In many cases tissue from the head of pancreas forms semicircle around the duodenum and is known as annular pancreas; Pancreas is called truncated when only head or head and small body are present (Fig. 12) [13]. Other abnormalities related to pancreas are - pancreatic malrotation, increased incidence of pancreatitis and diabetes mellitus, obstructive jaundice secondary to dorsal agenesis of pancreas and preduodenal portal vein [39]. h) Gall Bladder and Biliary Atresia [1–5, 12–16] : Gall bladder usually shifts to the midline from its usual position, under the surface of right lobe of liver. In
Table 4 Recommendations for additional vaccines besides the national immunization schedule* against capsular bacteria in patients with malfunctioning or absent spleen. (NHS Recommendation) Meningococcal Vaccine
Pneumococcal vaccine Boosters-HIB/MEN-B&C/PCV13/ MMR/PPV23
Influenza vaccine
Diagnosed at
