What are the other Names for this Condition? (Also known as/Synonyms)

• Ivemark’s Syndrome
• Situs Ambiguous
• Visceral Heterotaxy

What is Heterotaxy Syndrome? (Definition/Background Information)

• Heterotaxy Syndrome is defined as the abnormal arrangement of organs inside the chest and abdomen of an individual
• The term is derived from the Greek language, in which “hetero” means ‘other than’ and “taxis” translates to ‘arrangement’. Thus, the name of the condition signifies “other than normal arrangement”
• Approximately, 3% of all congenital heart defects are reported to occur as a result of Heterotaxy Syndrome. The condition is more common among the Asian, African-American, and Hispanic populations
• In most cases, the syndrome develops sporadically, with no family history of the condition. In about 10% of cases, those with Heterotaxy Syndrome may have an immediate family member with the disorder. In addition, exposure to environmental toxins has also been reported to cause the syndrome
• Mutation(s) in over 60 genes have been described in individuals with the syndrome, which may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner
• The symptoms of Heterotaxy Syndrome may include the absence of spleen, heart defects, breathing difficulties, and issues with digestion. Generally, a diagnosis of the condition is made through imaging of internal organs to identify abnormalities
• The treatment is determined by the organ affected and extent of malformation. The treatment of Heterotaxy Syndrome may include medications and/or surgery to correct malformations
• The prognosis of Heterotaxy Syndrome is dictated by the severity of malformations. Typically, those diagnosed before birth or in early childhood have poorer outcomes than those who are diagnosed with the condition into adulthood

Who gets Heterotaxy Syndrome? (Age and Sex Distribution)

• A diagnosis of Heterotaxy Syndrome occurs most often before birth or during infancy or childhood. However, the condition may be diagnosed in adults too
• The syndrome is seen in individuals of both genders worldwide, at a frequency of approximately 1:10,000
• Although all races and ethnicities may be affected, more cases are reported from Asia than continents such as Europe or North America
• In the US, children of Hispanic or African-American heritage are more likely to be diagnosed with Heterotaxy Syndrome than Caucasian children

What are the Risk Factors for Heterotaxy Syndrome? (Predisposing Factors)

The following are some reported risk factors for Heterotaxy Syndrome:

• A family history of the condition (about 10% of cases are inherited)
• Individuals with primary ciliary dyskinesia; approximately, 12% of such individuals are diagnosed with Heterotaxy Syndrome
• The following factors in a pregnant woman:
  • Diabetes mellitus
  • Exposure to hair dyes
  • Smoking habit
  • Cocaine use
  • Household or occupational exposure to some toxic chemicals

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Heterotaxy Syndrome? (Etiology)

Heterotaxy Syndrome may be caused by mutations in over 60 genes, which may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner.

• Autosomal dominant type of inheritance: A single copy of the mutated gene is sufficient to cause the condition. Having one parent with the condition may cause Heterotaxy Syndrome in children
• Autosomal recessive type of inheritance: In this type of inheritance, an individual must inherit both copies of a causative gene in the defective form for the condition to manifest itself. The affected individual inherits one defective copy of the gene from each parent. The parents themselves are carriers of the condition and generally do not show symptoms
• X-linked inheritance pattern: This occurs when the causative gene is located on the X chromosome. Females carry two X-chromosomes (denoted as XX), whereas males carry one X and one Y chromosome (denoted as XY). In the males, therefore, any gene mutation carried on the X-chromosome is more likely to be expressed and manifested

The following have been associated with an X-linked inheritance pattern:

• Having been diagnosed with primary ciliary dyskinesia; observed in about 1 in 8 cases
• Exposure to toxic chemicals during pregnancy, which may affect the developing fetus. Such chemicals may include hair dyes, cigarette smoke, cocaine, and other chemical compounds via occupational exposure
• Diabetes mellitus in the pregnant mother
• Unknown causes, which may include hitherto undiscovered genetic mutations

Irrespective of the cause of Heterotaxy Syndrome, the following organs may be altered, causing symptoms:

• Heart: Structure and blood vessel arrangement, including septal defects, abnormalities of the pulmonary valve and heart’s electrical system owing to non-communication between the upper and lower chambers of the heart
• Lungs: Number of lobes in each lung, shape of lobes, length of bronchi may be affected
• Duodenum (part of small intestine): Abnormal narrowing known as duodenal atresia
• Pancreas: Malformation of the organ, or a condition called “annular pancreas,” which results in constriction of the duodenum
• Liver: Change of position to the center of the abdomen; abnormalities in bile ducts
• Spleen: Absence of the organ (asplenia), or presence of many dysfunctional ones (polysplenia)
• Intestines: Abnormal twisting of the organ (malrotation)

Based on the abnormalities, Heterotaxy Syndrome is classified into two types, namely

• Right atrial isomerism, which is characterized by major structural defects in the heart, such that blood flow between the chambers is affected. The spleen may be missing in this type of Heterotaxy Syndrome
• Left atrial isomerism, with abnormalities involving the heart walls and electrical conductivity. The spleen may either be absent, or be present as polysplenia

However, it must be noted that it may not be possible to classify many affected individuals into one category, as their symptoms may overlap between the two types.

What are the Signs and Symptoms of Heterotaxy Syndrome?

The signs and symptoms of Heterotaxy Syndrome may vary in type and severity, and may depend on the affected organ. Some individuals with left atrial isomerism may be asymptomatic too.

The following are some known symptoms of Heterotaxy Syndrome in newborns and infants:

• Breathing difficulties
• A bluish tinge to the skin, lips, and nails (cyanosis)
• Inability to feed properly
• Frequent infections
• Listlessness
• Enlarged liver
• Jaundice and dark urine, if there is bile duct obstruction (biliary atresia)
• Abdominal swelling, because of enlarged liver
• Irritability
• Weight loss

In many cases, children with left atrial isomerism (when the electrical conductivity of heart is affected) may not show symptoms till later in life

How is Heterotaxy Syndrome Diagnosed?

The diagnosis of Heterotaxy Syndrome is made on the basis of the following tests and exams:

• A thorough physical examination and an assessment of symptoms
• A complete evaluation of personal and family medical history
• Imaging of internal organs through computed tomography (CT) and magnetic resonance imaging (MRI) scans
• Echocardiography, to procure moving pictures of the heart
• Electrocardiography, to check electrical conductivity of the heart
• Endoscopy to check for abnormal twisting of intestines
• Blood tests to evaluate functioning of spleen
• Ultrasound scan to check for position of the kidneys

Note: Owing to the structural defects, it may be possible to diagnose Heterotaxy Syndrome before birth, with a fetal echocardiogram.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Heterotaxy Syndrome?

The potential complications from Heterotaxy Syndrome include:

• Heart problems, including blockage and heart attack, which may be fatal
• Susceptibility to infections
• Deteriorating digestive functions
• Malnutrition

How is Heterotaxy Syndrome Treated?

The treatment options for Heterotaxy Syndrome depend on the affected organ and severity of an affected individual’s symptoms. A cooperative effort by professionals of different medical specialties is often required. The treatments may include one or more of the following:

• Medication to regulate blood pressure such as beta blockers and angiotensin-converting enzyme (ACE inhibitors)
• Medication to regulate heart rhythm such as beta blockers and calcium channel blockers
• Insertion of a pacemaker or implantable cardiac defibrillator to regulate heart rhythm
• Placement of a cardiac stent to regulate blood flow
• Surgery to correct structural abnormalities in the heart
  • Fontan procedure may be used in children who are born with a single ventricle. This procedure allows the ventricle to pump blood to the lungs, as well as to the whole body by re-routing the circulatory system of the heart
  • Heart transplantation, for severe cases
• Vaccinations
• Prophylactic use of antibiotics (if needed on a daily basis), to avoid infections and overcome a dysfunctional or ‘absent’ spleen
• Surgical repair of abnormal intestinal twisting, called the Ladd procedure, to correct and prevent recurrence of malrotation
• Liver transplantation, in case of severe blockage of bile duct (biliary atresia)

How can Heterotaxy Syndrome be Prevented?

• At the present time, there are no definitive methods or guidelines for the prevention of Heterotaxy Syndrome
• Smoking cessation and avoidance of drugs by pregnant women may aid in decreasing the risk for Heterotaxy Syndrome in the developing fetus
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired disorders such as Heterotaxy Syndrome
• Regular medical screening at periodic intervals with tests and physical examinations are advised

What is the Prognosis of Heterotaxy Syndrome? (Outcomes/Resolutions)

• The prognosis of Heterotaxy Syndrome is dictated by the organ affected, as well as the type and severity of symptoms in an individual
• Generally, children diagnosed before birth or in infancy have a poorer prognosis than when the condition is diagnosed during adulthood
• Individuals with left atrial isomerism may be asymptomatic and get diagnosed as adults. Such individuals may lead a fairly normal life
• Children born with severe heart defects generally require a surgery for a better prognosis. Many children with severe heart anomalies may not survive beyond the first year
• Continuous monitoring is required in those with severe symptoms, even after surgery and medication to correct abnormalities
• Children, who have undergone the Fontan procedure, may require heart transplantation later in their life

Additional and Relevant Useful Information for Heterotaxy Syndrome:

• The normal arrangement of organs in the chest and abdomen of a human being is known as “situs solitus”
• “Situs inversus” occurs when the arrangement is a mirror image of the normal state. This condition does not typically cause any major health issues