Heterotaxy syndrome

Heterotaxy also called heterotaxy syndrome, is a rare condition characterized by internal organs that are not abnormally arranged in the chest and abdomen. The term “heterotaxy” is from the Greek words “heteros,” meaning “other than,” and “taxis,” meaning “arrangement” ¹⁾. Organs are expected to be in a particular orientation inside of the body, known as “situs solitus”. Heterotaxy occurs when the organs are not in this typical orientation, but are instead in different positions in the body. Individuals with heterotaxy syndrome have complex birth defects affecting the heart, lungs, liver, spleen, intestines, and other organs. This most commonly causes complications with the heart, lungs, liver, spleen, and intestines. Specific symptoms include not getting enough oxygen throughout the body, breathing difficulties, increased risk for infection, and problems digesting food.

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.

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.

Depending on the organs involved, signs and symptoms of heterotaxy syndrome can include a bluish appearance of the skin or lips (cyanosis, which is due to a shortage of oxygen), breathing difficulties, an increased risk of infections, and problems with digesting food. 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.

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.

Heterotaxy may be caused by genetic changes (mutations), exposures to toxins while a woman is pregnant causing the baby to have heterotaxy, or the condition may occur sporadically. The prevalence of heterotaxy syndrome is estimated to be 1 in 10,000 people worldwide with a male to female ratio of 2:1 ²⁾. However, researchers suspect that the condition is underdiagnosed, and so it may actually be more common than this. 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.

Heterotaxy is typically diagnosed through imaging of the internal organs through a CT scan or an MRI. More specific imaging of the heart such as an echocardiogram or an electrocardiogram may also be used to diagnose the condition ³⁾. 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 ⁴⁾.

Treatment for heterotaxy depends on the specific symptoms of each person including the severity of the heart defects and other organ abnormalities, but typically includes heart surgery and monitoring by a team of specialists ⁵⁾. Most patients with left atrial isomerism will require surgical procedures or catheterization to repair holes in the heart or other problems. Some patients will require implantable pacemakers or defibrillators to control abnormal heart rhythm. In rare cases, patients with left atrial isomerism won’t require any treatment, though they will need to visit a pediatric cardiologist regularly for checkups.

Nearly all patients with right atrial isomerism, and some patients with left atrial isomerism, will require a series of major heart surgeries. Surgeons will reconfigure the heart and circulatory system so that the heart functions with one ventricle (pumping chamber), instead of two. This is called Fontan circulation and requires three open heart surgeries, called staged reconstruction. The procedures include the Norwood procedure, hemi-Fontan or Glenn operation, and the Fontan procedure.

All children with heterotaxy syndrome will require lifelong care by a cardiologist. In many cases, children with this condition will have many needs and will require care from different specialist doctors for many years.

Heterotaxy syndrome types

There are different forms of heterotaxy syndrome. All usually involve heart defects of varying types and severity. In addition, organs such as the stomach, intestines, liver and lungs may be in abnormal places in the chest and abdomen.

• Right atrial isomerism: Children with this condition have multiple heart defects. They may have septal defects (holes between the tissue dividing the two sides of the heart) and problems with heart valves, particularly the pulmonary valve. They may also have abnormalities of the blood returning from the lungs to the heart (anomalous pulmonary venous connection). The spleen may be absent (asplenia), and the liver and other organs may be on the wrong side of the body.
• Left atrial isomerism: Children with this condition may have septal defects (holes between the tissue dividing the two sides of the heart) as well as problems with heart valves and the heart’s electrical system. Some children with this problem have complete heart block, which is when the upper-chamber electrical system does not communicate with the lower-chamber electrical system. Most children require pacemakers for this problem. The spleen may be absent, or there may be several small spleens (polysplenia), instead of one spleen.
• The intestines may have malrotation, which is when the loops of bowel are lined up incorrectly. With this problem the bowel can twist on itself (volvulus). Many children with malrotation need abdominal surgery to correct it.
• Some children with heterotaxy syndrome can have a very serious condition of the liver called biliary atresia. This also may require surgical intervention.
• There may also be irregularities with the skeleton, central nervous system and urinary tract.
• In some cases of heterotaxy syndrome, the spleen may not work correctly or may be missing entirely. This can cause many problems, because the spleen helps the body fight infections. When the spleen is missing or doesn’t work correctly, patients have a more difficult time recovering from surgeries or infections (patients with heterotaxy may require multiple surgeries). In some cases, there may be a functioning spleen, but it may be divided into several smaller spleens (polysplenia).
• Sometimes children with heterotaxy syndrome have dextrocardia syndrome. This means the heart is in the right chest instead of the left chest.

Heterotaxy syndrome causes

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.

Heterotaxy 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.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Heterotaxy syndrome signs and symptoms

Heterotaxy 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 heterotaxy syndrome vary widely and depend on the organs affected. Symptoms of these organs working incorrectly may include breathing difficulties, having a bluish color to the skin (cyanosis), and problems digesting food. For some people with heterotaxy, the only sign may be a heart defect ⁶⁾. 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 ⁷⁾.

The heart is almost always involved in cases of heterotaxy syndrome. What type of defects are found depends on a number of things, including the type of heterotaxy syndrome (eg bilateral right sidedness or left-sidedness). Listed below are the most common heart anomalies associated with heterotaxy:

• Dextrocardia (the heart is located in the right side of the chest instead of the left)
• Single atrium (single top chamber of the heart)
• Single ventricle (single bottom chamber of the heart)
• Transposition of the great arteries (the aorta and the pulmonary artery have switched positions)
• Total or partial anomalous pulmonary venous return (the pulmonary veins enter into the heart in the incorrect location)
• Atrioventricular canal defect (large hole in the center of the heart with a single common valve)
• Coarctation of the aorta (narrowing of the aorta)
• Pulmonary valve atresia (absence of the pulmonary valve)
• Pulmonary stenosis (narrowing of the pulmonary valve)
• Double outlet right ventricle (where both main arteries of heart arise from the right ventricle)
• Complete atrioventricular block (no electrical signal from the top chambers of the heart reaches the bottom chambers of the heart resulting in a slow heart rate)
• Multiple sinus nodes or absent sinus node (the sinus node is the impulse-generating tissue of the heart)

In nearly all cases of right atrial isomerism and some cases of left atrial isomerism, symptoms will appear at birth or a few days after because the heart defects are severe. In these cases, symptoms include:

• Blue or purple tint to lips, skin and nails (cyanosis)
• Difficulty breathing
• Difficulty feeding
• Lethargy: baby is abnormally sleepy or unresponsive

Sometimes patients with left atrial isomerism don’t have any symptoms and the condition isn’t diagnosed until the child is older or an adult.

Most people with heterotaxy are first found to have the condition 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 ⁸⁾. 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 ⁹⁾.

Heterotaxy syndrome diagnosis

In many cases, heterotaxy syndrome is diagnosed before birth. After the child is born, diagnosis of heterotaxy syndrome may require some or all of these tests:

• Electrocardiogram (EKG or ECG): a record of the electrical activity of the heart
• Echocardiogram (also called “echo” or ultrasound): sound waves create an image of the heart
• Chest x-ray
• Cardiac MRI: a three-dimensional image shows the heart’s abnormalities

Sometimes, cardiac catheterization will be required. In cardiac catheterization, a thin tube is inserted into the heart through a vein and/or artery in either the leg or through the umbilicus (“belly button”).

Other diagnostic tests on other areas of the body will also be required, including renal ultrasound and abdominal ultrasound.

Heterotaxy syndrome treatment

The treatment for heterotaxy depends on the specific organs that are affected in each individual. In infants diagnosed with heterotaxy syndrome, 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 ¹⁰⁾.

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 ¹¹⁾.

Heterotaxy syndrome 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 ¹³⁾. In a retrospective, single-center study (1997-2014) of 35 children with heterotaxy syndrome, the reported survival was 83% over a median follow-up of 65 months ¹⁴⁾. Of the 12 patients with poor outcomes (34.3%), 6 died, 1 underwent cardiac transplantation, and 5 had a New York Heart Association heart failure classification above 3.

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 ¹⁵⁾.