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polysplenia

Polysplenia

Polysplenia also called heterotaxy syndrome or bilateral left‐sidedness, is a congenital disease manifested by multiple small accessory spleens. There are frequent associated congental anomalies all related to deviations in the development of anatomical asymmetries in early embryonic stages. Associated conditions include intestinal malrotation, situs inversus, biliary atresia, and the range of congenital cardiac malformations. Polysplenia is a rare congenital disease initially described by Helwig in 1929 1. Since then, few cases were described in the literature with an incidence of 1‐1.5/10 000 live births with a high mortality rate 2. Most of the patients do not reach adulthood because of serious cardiac anomalies. 5%–10% of patients that lack cardiac involvement reach adulthood.

Heterotaxy syndrome accounts for approximately 3 percent of all congenital heart defects. For reasons that are unknown, the condition appears to be more common in populations in Asia than in North America and Europe. Recent studies report that in the United States, the condition occurs more frequently in children born to Black or Hispanic mothers than in children born to white mothers.

In the normal body, most of the organs in the chest and abdomen have a particular location on the right or left side. For example, the heart, spleen, and pancreas are on the left side of the body, and most of the liver is on the right. This normal arrangement of the organs is known as “situs solitus.” Rarely, the orientation of the internal organs is completely flipped from right to left, a situation known as “situs inversus.” This mirror-image orientation usually does not cause any health problems, unless it occurs as part of a syndrome affecting other parts of the body. Heterotaxy syndrome is an arrangement of internal organs somewhere between situs solitus and situs inversus; this condition is also known as “situs ambiguus.” Unlike situs inversus, the abnormal arrangement of organs in heterotaxy syndrome often causes serious health problems.

The term “heterotaxy” is from the Greek words “heteros,” meaning “other than,” and “taxis,” meaning “arrangement.” Individuals with heterotaxy syndrome have complex birth defects affecting the heart, lungs, liver, spleen, intestines, and other organs. The Nomenclature Working Group defines heterotaxy as “an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left- right axis of the body” 3. Heterotaxy syndrome can alter the structure of the heart, including the attachment of the large blood vessels that carry blood to and from the rest of the body. It can also affect the structure of the lungs, such as the number of lobes in each lung and the length of the tubes (called bronchi) that lead from the windpipe to the lungs. In the abdomen, the condition can cause a person to have no spleen (asplenia) or multiple small, poorly functioning spleens (polysplenia). The liver may lie across the middle of the body instead of being in its normal position to the right of the stomach. Some affected individuals also have intestinal malrotation, which is an abnormal twisting of the intestines that occurs in the early stages of development before birth.

Heterotaxy is generally classified into 2 major syndromes, polysplenia and asplenia syndromes 4.

Polysplenia is defined as an abnormal morphology and position of the thoraco-abdominal organs that do not coexist with the normal arrangement of organs with usual left‐right asymmetry (situs solitus) or reversed/mirrored arrangement of the abdominal and thoracic organs (situs inversus) 5.

Patients with right isomerism (asplenia) have a higher incidence of univentricular circulation, complete atrioventricular septal defect, pulmonary atresia, and total anomalous pulmonary venous return compared to patients with left isomerism (polysplenia). Long‐term outcome of polysplenia heterotaxy syndrome determined by the severity of the cardiac anomalies 6.

There is a high association of congenital gastrointestinal abnormalities, such as varying degrees of malrotation of the bowel, biliary atresia, volvulus, and splenic anomalies that significantly affect the long‐term survival in infants with the heterotaxy syndrome.

Polysplenia is seen predominantly in female patients. It is usually diagnosed in childhood or adulthood, later than asplenia syndrome, since associated congenital heart diseases tend to be less severe than those encountered in the latter.

The severity of heterotaxy syndrome varies depending on the specific abnormalities involved. Some affected individuals have only mild health problems related to the condition. At the other end of the spectrum, heterotaxy syndrome can be life-threatening in infancy or childhood, even with treatment. The prognosis of patients with complex cardiac lesions and heterotaxy is poor. The 1-year mortality is >85% for patients with asplenia and >50% for patients with polysplenia 7. Escobar et al 8 in their studies concluded that the 5‐year survival rate was 86% for polysplenia syndrome compared to 53% for asplenia syndrome where noncardiac anomalies and pulmonary vein stenosis were predictors for death while in the polysplenia syndrome, the presence of univentricular circulation and left ventricular circulation were predictors for the poor outcome.

In patients with heterotaxy syndrome, the spleen is almost always affected, although the reason is not clearly understood. Three types of splenic anomalies have been described: (A) the spleen may be absent; (B) the spleen may be composed of a cluster of smaller splenules, a large spleen may be accompanied by several smaller splenules, or it may be multilobed; and (c) the spleen may be of normal size but located in the right upper quadrant of the abdomen. In a study of 109 autopsies of visceral heterotaxy with congenital heart disease, 58 patients (53%) had asplenia, 46 (42%) had polysplenia, and 5 (5%) had a single right-sided spleen. The polysplenia and asplenia syndromes, each have their own associated characteristic anomalies 9

Isomerism

The word isomerism is also derived from the Greek: iso-meaning equal and meros-meaning part. Isomerism refers to structures that are themselves mirror-imaged. When used in the area of the congenitally malformed heart, the term “isomerism” has become the conventional description for the situation in which morphologically right structures or morphologically left structures are found on both sides of the body in the same individual.

The Nomenclature Working Group 3 offers the following definition for the term “isomerism”: Isomerism in the context of the congenitally malformed heart is defined as a situation where some paired structures on opposite sides of the left-right axis of the body are, in morphologic terms, symmetrical mirror images of each other.

Left Isomerism

Left isomerism in the context of the congenitally malformed heart is defined as a subset of heterotaxy where some paired structures on opposite sides of the left-right axis of the body are symmetrical mirror images of each other, and have the morphology of the normal left-sided structures. Those patients with isomeric left atrial appendages frequently have bilaterally bilobed lungs, each with a long bronchus, and multiple spleens.

In many cases of isomeric left appendages, patients have pulmonary veins connecting to both the atrial chambers as if both atriums were morphologically left atriums. The symmetry, however, is far from complete.

Right Isomerism

Right isomerism in the context of the congenitally malformed heart is defined as a subset of heterotaxy where some paired structures on opposite sides of the left-right axis of the body are symmetrical mirror images of each other, and have the morphology of the normal right-sided structures. Those patients with isomeric right atrial appendages frequently have bilaterally trilobed lungs, each with a short bronchus, and absence of the spleen. Once again, however, examples exist where the sidedness of the atrial appendages is not concordant with the sidedness of the lungs or spleen.

Situs ambiguous

Situs Ambiguus is defined as an abnormality in which there are components of situs solitus and situs inversus in the same person. Situs ambiguus, therefore, can be 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 lateralised and thus have neither the usual, or normal, nor the mirror-imaged arrangements. All patients with heterotaxy should also be considered to have “situs ambiguus” and all patients with “situs ambiguus” also have heterotaxy syndrome.

Polysplenia syndrome

Polysplenia syndrome also known as left isomerism, bilateral left-sidedness or Ivemark syndrome, is a type of heterotaxy syndrome where there are 2 or more multiple spleens as part of left-sided isomerism associated with various congenital visceral and vascular abnormalities 4. Polysplenia syndrome associates multiple spleens to other malformations, most frequently cardiac, vascular, visceral, and biliary malformations 10. However, some cases of polysplenia syndrome have been described with a single bilobed spleen or a single normal splenic gland. In all cases, the spleens are still located on the same side of the stomach along the greater curvature due to the development of embryonic splenic tissue in the posterior mesogastrium (future gastrosplenic ligament) 4.

The hallmark findings of polysplenia syndrome are multiple spleens associated with cardiac anomalies often ventricular or atrioventricular septal defects and outflow tract abnormalities and heart block. Also typical of polysplenia syndrome are bilateral bilobed lungs, a malpositioned stomach, a midline liver, and interruption of the inferior vena cava with the venous return from the lower body occurring over the prominent azygos vein (right to the aorta) or hemiazygos vein (left to the aorta), running parallel to the descending aorta.

In summary, polysplenia syndrome is a complex syndrome with a broad spectrum of abnormalities, the most common of which are multiple spleens and inferior vena cava (IVC) interruption with azygous continuation. As the use of imaging increases, situs anomalies will likely be detected with greater frequency in adults. The finding of splenic cysts should make us think of the possibility of another anomaly related to the polysplenia syndrome.

Polysplenia causes

The exact cause of polysplenia is unknown. However it is suggested that it is caused by various factors 11:

  • Embryogenic
  • Genetic
  • Teratogenic

Heterotaxy syndrome can be caused by mutations in many different genes. The proteins produced from most of these genes play roles in determining which structures should be on the right side of the body and which should be on the left, a process known as establishing left-right asymmetry. This process occurs during the earliest stages of embryonic development. Dozens of genes are probably involved in establishing left-right asymmetry; mutations in at least 20 of these genes have been identified in people with heterotaxy syndrome.

In some cases, heterotaxy syndrome is caused by mutations in genes whose involvement in determining left-right asymmetry is unknown. Rarely, chromosomal changes such as insertions, deletions, duplications, and other rearrangements of genetic material have been associated with this condition.

Heterotaxy syndrome can occur by itself, or it can be a feature of other genetic syndromes that have additional signs and symptoms. For example, at least 12 percent of people with a condition called primary ciliary dyskinesia have heterotaxy syndrome. In addition to abnormally positioned internal organs, primary ciliary dyskinesia is characterized by chronic respiratory tract infections and an inability to have children (infertility). The signs and symptoms of this condition are caused by abnormal cilia, which are microscopic, finger-like projections that stick out from the surface of cells. It appears that cilia play a critical role in establishing left-right asymmetry before birth.

Studies suggest that certain factors affecting a woman during pregnancy may also contribute to the risk of heterotaxy syndrome in her child. These include diabetes mellitus; smoking; and exposure to hair dyes, cocaine, and certain laboratory chemicals.

Some people with heterotaxy syndrome have no identified gene mutations or other risk factors. In these cases, the cause of the condition is unknown.

Polysplenia inheritance pattern

Most often, heterotaxy syndrome is sporadic, meaning that only one person in a family is affected. However, about 10 percent of people with heterotaxy syndrome have a close relative (such as a parent or sibling) who has a congenital heart defect without other apparent features of heterotaxy syndrome. Isolated congenital heart defects and heterotaxy syndrome may represent a range of signs and symptoms that can result from a particular genetic mutation; this situation is known as variable expressivity. It is also possible that different genetic and environmental factors combine to produce isolated congenital heart defects in some family members and heterotaxy syndrome in others.

When heterotaxy syndrome runs in families, it can have an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance, depending on which gene is involved. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. Autosomal recessive inheritance means that both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In X-linked inheritance, the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell.

When heterotaxy syndrome occurs as a feature of primary ciliary dyskinesia, it has an autosomal recessive pattern of inheritance.

Polysplenia symptoms

Polysplenia is characterized by having internal organs that are not arranged as would be expected in the chest and abdomen. This can cause organs such as the heart, lungs, liver, intestines, and spleen to not work correctly. Symptoms of these organs working incorrectly may include breathing difficulties, having a bluish color to the skin (cyanosis, which is due to a shortage of oxygen), an increased risk of infections and problems digesting food. For some people with heterotaxy, the only sign may be a heart defect. The most serious complications are generally caused by critical congenital heart disease, a group of complex heart defects that are present from birth. Biliary atresia, a problem with the bile ducts in the liver, can also cause severe health problems in infancy.Others may have twisting of the intestines (malrotation). People with heterotaxy may have a missing spleen (asplenia) or they may have a spleen that is divided into many smaller parts (polysplenia). If the function of the spleen is affected, this can cause a reduced ability to fight infections. Those who survive present with abdominal complaints or diagnosed because of incidental finding of situs abnormalities.

Most people with heterotaxy are first found to have polysplenia shortly after birth when they have symptoms related to a heart defect. However, other individuals are not diagnosed until later in childhood or adulthood due to problems with the intestines or liver that may cause abdominal pain or vomiting 12. Other adults with heterotaxy are diagnosed because they were receiving imaging for other medical problems. In this case, a diagnosis of heterotaxy is an incidental finding 13.

Symptomatic patients presented with atrioventricular septal defects and may have anomalous of the inferior vena cava (inferior vena cava (IVC) interruption with azygos or hemiazygos continuation) or other gastrointestinal structural abnormalities including partial or complete agenesis of the dorsal pancreas 14. These findings may have clinical relevance with a possible increased risk for intestinal volvulus, diabetes mellitus, or pancreatitis 10. In asymptomatic patients, this congenital anomaly may be found incidentally during abdominal surgery or radiological examination 15.

Other characteristic features include:

  • bilateral hyparterial bronchi
  • bilateral bilobed lungs
  • bilateral pulmonary/left atria
  • midline liver

Polysplenia associated pathology:

  • congenital heart disease (>50%): especially non-cyanotic, and less complex/severe than in asplenia syndrome 14
    • cardiac anomalies include atrial septal defect, endocardial cushion defect, bilateral left atrium, ventricular septal defects, double outlet right ventricle, pulmonary stenosis and interruption of hepatic segment of inferior vena cava with continuation of azygos and hemiazygos is seen in few cases.
    • abnormal pulmonary venous return (70%, partial anomalous pulmonary venous return [PAPVR]/total anomalous pulmonary venous return [TAPVR])
    • dextrocardia (37%)
  • gastrointestinal
    • semi-annular pancreas / congenitally short pancreas 16
    • midgut malrotation (80%) 17
    • gallbladder agenesis (50%) and biliary atresia
    • mobile cecum
    • tracheo-esophageal fistula
  • genitourinary
    • renal cyst
    • renal agenesis
    • ovarian cyst
  • vascular
    • inferior vena cava (IVC) anomalies 17
    • intrahepatic IVC interruption with azygos/hemiazygos continuation
    • portal vein anomalies 17
    • preduodenal portal vein

Asplenia syndrome or right isomerism (bilateral right-sidedness), is characterized by agenesis of the spleen in combination with paired right-sided viscera. Typical findings are right atrial isomerism with bilateral superior vena cava, multiple and more severe cardiac anomalies (including anomalous pulmonary venous connections, often atrioventricular septal defects, and outflow tract abnormalities), bilateral trilobed lungs, and a midline liver. The association of asplenia with cardiovascular anomalies was first described by Ivemark.

Polysplenia diagnosis

Clinical diagnosis of polysplenia can be challenging because of the difficulty detection of the spleen by abdominal ultrasound and during laparotomy due to the abnormal location. Heterotaxy is typically diagnosed by imaging of the internal organs through a CT scan or an MRI. This may suggest the necessity of the CT scan of the abdomen as additional important tool for detection, location, and numbers of spleens and also the determination of possibility of other anomalies in the case of heterotaxy syndrome. Definitive confirmation of polysplenia can be made by a radiocolloid scan using 99mTc‐Sulfur‐colloid taken by the ectopic splenic tissue 5.

More specific imaging of the heart such as an echocardiogram or an electrocardiogram may also be used to diagnose polysplenia 18. If heterotaxy is suspected, further tests may be completed to check for the functioning of the internal organs. For example, blood tests may be done to make sure the spleen is working properly, and an endoscopy may be recommended to determine if the intestines are malrotated. Renal ultrasounds may also determine if the kidneys are in the correct location 12.

Spleens

The splenic mass is usually divided into fairly equalized masses, varying in number from 2 to 6 and ranging from 1 to 6 cm in diameter. The location of the spleens is in either the left or right upper quadrant, along the greater curvature of the stomach 15. Splenic cysts were never reported in the literature.

Venous anomalies

Inferior vena cava (IVC) interruption with azygous continuation is the second most common abnormality observed in polysplenia patients after multiple spleens 4. To understand this anomaly, it should be noted that the embryologic development of IVC is complex, and the normal IVC is composed of 4 segments: hepatic, suprarenal, renal, and infrarenal. The hepatic segment develops from the vitelline vein. The suprarenal segment is formed by the right subcardinal vein and subcardinal-hepatic anastomosis. The renal segment develops from the right supra-subcardinal and postsubcardinal anastomoses. The infrarenal segment derives from the right supracardinal vein 19. Interruption of the IVC results from failure of the right subcardinal-hepatic anastomosis with consequent atrophy of the subcardinal vein (suprarenal IVC) and continuation of the infrarenal IVC as the azygous vein 19. The suprahepatic segment of the IVC is usually present and drains separately into the right atrium 20.

Intestinal malrotation

Polysplenia is commonly associated with anomalies of intestinal rotation, especially in patients with abdominal heterotaxy 4. Intestinal rotation abnormalities include nonrotation (the small bowel is entirely on the right of the spine and the colon on the left), incomplete rotation (the appearance is between normal and nonrotation), and the rare reversed complete or incomplete rotation. In nonrotation and incomplete rotation, the mesenteric attachment is very narrow which predisposes to occurrence of midgut volvulus 21. Radiologic identification of intestinal malrotation is important even if there are no symptoms because prediction of patients who are at risk of midgut volvulus is not possible. Surgical correction is advised by many authorities for all surgically fit patients with malrotation, regardless of age and symptoms 22.

Preduodenal portal vein

A preduodenal portal vein was reported as one of the anomalies in association with polysplenia. Embryologically, the portal venous system is derived from the vitelline veins which drain the primitive gastrointestinal tract. The 2 vitelline veins are connected by 3 interconnecting veins, cranial (in the liver), middle (behind theduodenum), and caudal (in front of the duodenum), simulating a figure of 8. Preduodenal portal vein occurs due to variation in this process where the middle and cranial interconnecting veins and the left vitelline vein atrophy resulting in an L-shaped preduodenal portal vein 23. This anomaly is usually an incidental finding of no clinical importance except if biliary or hepatic surgical procedures are planned 24.

Pancreas anomalies

Anomalies of the pancreas have been described in polysplenia syndrome. Normal pancreas formation occurs from fusion of ventral and dorsal pancreatic buds. The ventral pancreatic bud gives rise to the uncinate process and the head, while the dorsal pancreatic bud gives rise to the body and tail. The development of both dorsal pancreatic bud and spleen occur in the dorsal mesogastrium. Consequently, anomalies in both these organs can be expected in patients with polysplenia syndrome 25. Most case series report a high incidence of short or truncated pancreas, where only the pancreatic head with or without a small portion of the pancreatic body is present. The clinical relevance includes an increased incidence of pancreatitis and diabetes mellitus 4.

Cardiac anomalies

Heterotaxy syndromes are known to be associated with increased incidence of complex cardiac anomalies. Cardiac anomalies are generally less common in polysplenia syndrome than asplenia 26. The various cardiovascular anomalies that may be encountered are atrial septal defect, ventricular septal defect, bilateral superior vena cava, right-sided aortic arch, partial anomalous pulmonary venous return, transposition of the great arteries, pulmonary valvular stenosis, and subaortic stenosis 27.

Note that with increased use of cross-sectional imaging, the number of reported patients with polysplenia and normal hearts who are incidentally discovered during adulthood has increased.

Visceroatrial situs

The relationship between polysplenia and visceroatrial situs is not well described in the literature. The classic term (bilateral sidedness) implies the presence of bilateral bilobed lungs with hyparterial bronchi and bilateral pulmonary atria. However, it should be noted that these findings were not consistently described in association with polysplenia. In fact, the incidence of bilateral left-sidedness is much less in adult patients with polysplenia who usually have no cardiac anomalies, and therefore are not expected to show bilateral left-sidedness which is commonly associated with cardiac anomalies such as partial anomalous pulmonary venous return or atrial septal defect 4.

Polysplenia treatment

The treatment for polysplenia depends on the specific organs that are affected in each individual and should be determined by the nature and severity of the associated cardiac and extracardiac lesions. In infants diagnosed with polysplenia, heart surgery may be necessary to correct any heart defects. For some individuals, this may require multiple procedures to correct the defect. One common procedure is known as a Fontan procedure, which creates a single ventricle of the heart that is responsible for pumping blood both throughout the body and to the lungs. Other surgical procedures such as the Ladd procedure may be necessary to correct an intestinal malrotation 28.

Most cardiac operations for patients with polysplenia are palliative in nature, since normal anatomy is rarely achieved. Not surprisingly, then, mortality rates remain high for patients with heterotaxy syndrome. Factors that have historically been associated with increased operative risk include abnormalities of the systemic venous connection, a partial or total anomalous pulmonary venous connection, a common atrioventricular valve that is incompetent, and a morphologic right ventricle supporting the systemic circulation 29.

Other treatment options include inserting a pacemaker to control the rhythm of the heart. Some individuals may require medications to lower blood pressure to reduce stress on the heart. Vaccinations or antibiotics that are taken even when there isn’t an infection (prophylactic antibiotics) may be recommended to make up for a spleen that isn’t functioning properly. In some cases, a heart transplant may be necessary when individuals who had surgical corrections as infants get older. A multidisciplinary team of doctors may be recommended to follow a person who is diagnosed with heterotaxy 12.

Any patient with heterotaxy/polysplenia syndrome with acute abdomen should be aggressively investigated for structural and biochemical abnormalities that could potentially contribute to the condition. The finding of a surgically correctable cause of acute abdomen can lead to curative surgery.

Other abnormalities associated with the polysplenia should be corrected early in life which are difficult to manage later because it can lead to significant morbidity and mortality.

Polysplenia prognosis

The long-term outlook for people affected by heterotaxy depends on the specific organs that are affected in each individual. When children are diagnosed with heterotaxy soon after birth, it is typically because there are heart defects that require immediate surgery. Although the Fontan procedure may allow affected children to survive infancy, people who have had the procedure typically require a heart transplant later in life 12. If people with heterotaxy pass away, it is typically due to heart defects or complications from the Fontan procedure 30.

There is limited data available about the long-term outlook for adults who are diagnosed with heterotaxy. Because most people who are diagnosed in adulthood have less severe symptoms, they may have a better prognosis than children who are diagnosed before birth or during infancy 28.

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