Ivemark Syndrome

NORD gratefully acknowledges Anastasia Konstantinidou, MD, PhD, Associate Professor of Pathology,
Medical School, National Kapodistrian University of Athens, Greece, for assistance in the preparation of
this report.

Synonyms of Ivemark Syndrome

asplenia syndrome
asplenia with cardiovascular anomalies
bilateral right-sidedness sequence
right isomerism sequence
General Discussion

Ivemark syndrome is a rare disorder that affects multiple organ systems of the body. It is characterized by
the absence (asplenia) or underdevelopment (hypoplasia) of the spleen, malformations of the heart and the
abnormal arrangement of the internal organs of the chest and abdomen. The symptoms of Ivemark
syndrome can vary greatly depending upon the specific abnormalities present. Many infants have
symptoms associated with abnormalities affecting the heart including bluish discoloration to the skin due
to a lack of oxygen in the blood (cyanosis), heart murmurs, and signs of congestive heart failure. Ivemark
syndrome often causes life-threatening complications during infancy. The exact cause of Ivemark
syndrome is not known.

The medical terminology used to describe Ivemark syndrome and related disorders is extremely
complicated and confusing. Ivemark syndrome is classified as a heterotaxy disorder or a laterality
disorder. These terms refer to the failure of the internal organs of the chest and abdomen to be arranged in
the proper location within the body. Additional terms used when discussing Ivemark syndrome may
include situs solitus (which refers to the normal positioning of these organs); situs inversus (which refers
to the complete reversal of the organs so that those normally on the left side are on the right and vice
versa); and situs ambiguous (which refers to the random positioning of the organs, with some in the
correct place and others in the wrong location). Ivemark syndrome is usually referred to as a specific form
of situs ambiguous.

Signs & Symptoms

The symptoms of Ivemark syndrome are due to the abnormal arrangement and malformation of certain
internal organs. The organs of the chest and abdomen normally develop with specific left-right
asymmetry, which means that the internal organs on the left side of the body are different than those on
the right. In Ivemark syndrome, there are several characteristic findings involving the internal organs of
the chest and abdomen including misplacement of the liver near the center of the body, abnormal
positioning of the intestines (intestinal malrotation), and severe underdevelopment (hypoplasia) or
absence (asplenia) of the spleen. Ivemark syndrome may also be known as right isomerism sequence
because the left side of the body is identical to the right. For example, the right and left sides of the heart
and lungs, which normally are distinct, may not be clearly defined.

Infants with Ivemark syndrome often have several heart defects that are present at birth (congenital heart
defects) due to the failure of normal right-left asymmetry. The heart is normally located in the middle of
the chest. The right and left sides of the heart are different and have different functions. The normal heart
has four chambers. The two upper chambers are known as atria; one is located on the left side of the heart
and one on the right side. They are separated from each other by a fibrous partition known as the atrial
septum. The two lower chambers are known as ventricles; one is located on the left side and the other on
the right. They are separated from each other by the ventricular septum. Valves connect the atria (left and
right) to their respective ventricles. The valves allow for blood to be pumped through the chambers.
Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen.
The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle
sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood
throughout the body.

Heart defects commonly associated with Ivemark syndrome include double outlet right ventricle, in
which the main artery of the body (aorta) and the main artery of the lungs (pulmonary artery) both arise
from the upper right chamber of the heart (ventricle) instead of the left; transposition of the great vessels,
in which the aorta and the pulmonary artery are reversed; and ventricular or atrial septal defects, which
are “holes” in the thin membrane (septum) that separates the chambers of the heart.

These various heart defects may cause a moderate or significant bluish discoloration to the skin of an
affected infant due to a lack of oxygen in the blood (cyanosis). Some infants may develop heart murmurs
or signs of congestive heart failure such as lack of energy and shortness of breath. The heart abnormalities
associated with Ivemark syndrome can cause life-threatening complications early during infancy.

Infants with Ivemark syndrome may have an underdeveloped spleen, or the spleen may be missing
altogether (asplenia). The spleen is an organ located in upper left part of the abdomen that filters out worn
out blood cells. A missing or poorly functioning spleen may leave individuals more susceptible to
repeated infections including infection of the blood (sepsis).

In some cases, additional findings have been reported including sudden, severe pain in the abdomen
(acute abdomen) often due to abnormal twisting or the intestines (volvulus), narrowing (atresia) of the
ducts that carry bile from the liver to the gallbladder (biliary atresia) and kidney abnormalities.
Alterations of form, size and position of the pancreas may also be anticipated, and, in the rare instance of
absence of the pancreas (pancreatic aplasia), total pancreatic insufficiency would be an additional
complication of the affected neonate. The pancreas is a small organ located behind the stomach that
secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other
hormones such as insulin, which helps break down sugar.

Causes

The exact cause of Ivemark syndrome is unknown. Most cases seem to occur randomly for no apparent
reason (sporadic cases). Researchers believe that multiple factors (e.g., genetic and environmental) play a
role in the development of the disorder. Ivemark syndrome has occurred in multiple members of the same
family suggesting that an inherited genetic predisposition may have been a factor in the development the
disorder in these cases.

During embryonic development, the internal organs normally develop and are finally positioned either on
the right or left side of the body. In Ivemark syndrome and related disorders, there is a failure to establish
this normal left-right asymmetry. Researchers believe that mutations in certain genes essential for the
development of normal left-right asymmetry are most likely involved in heterotaxy disorders.

Although some genes are known to be involved with heterotaxy, no specific gene(s) have been
conclusively linked to Ivemark syndrome. In 1995, researchers identified mutations of the connexin43
gap junction gene in a group of individuals with Ivemark syndrome. However, several other researchers
failed to identify this gene mutation in other individuals with Ivemark syndrome. More research is
necessary to locate which genes are involved in Ivemark syndrome and to determine the specific,
complex factors that cause Ivemark syndrome and other similar disorders.

Affected Populations

According to the medical literature, Ivemark syndrome affects boys more often than girls. The exact
incidence of Ivemark syndrome is unknown. The incidence of laterality disorders taken together is
estimated to be 1 in 15,000 people in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of Ivemark syndrome. Comparisons may be
useful for a differential diagnosis.

Polysplenia syndrome is a form of heterotaxy that is characterized by congenital heart defects, the
presence of multiple, usually underdeveloped, spleens and the location of organs normally found on the
left side of the chest and abdomen on the right. Polysplenia syndrome is also known as bilateral left-
sidedness sequence or left isomerism sequence and is often grouped with Ivemark syndrome as
“heterotaxy syndrome”. As with individuals with Ivemark syndrome, intestinal malrotation may also
occur in individuals with polysplenia syndrome. Signs of congestive heart failure such as a moderate or
significant bluish discoloration to the skin of an affected infant due to a lack of oxygen in the blood often
occur early during infancy and may be the presenting sign of polysplenia syndrome. Some affected
infants may develop yellowing of the skin or the whites of the eyes (jaundice) because of narrowing
(atresia) or blockage of the tubes that carry bile from the liver to the gallbladder. The multiple spleen
found in polysplenia syndrome are usually underdeveloped and do not function properly. Consequently,
affected individuals are at risk of developing repeated infections. The exact cause of polysplenia
syndrome is unknown. Multiple different factors are believed to cause the development of the disorder.

Kartagener syndrome is a rare disorder characterized by chronic inflammation of the sinuses (sinusitis),
complete reversal of the internal organs of the chest and abdomen (situs inversus) and bronchiectasis, a
condition in which the respiratory passages become enlarged due to mucus build up. Brochiectasis can
result in damage and scarring to the respiratory tubes, which allows more mucus and potentially bacteria
to build up eventually resulting in chronic respiratory infections. Additional symptoms associated with
Kartagener syndrome including underdevelopment or lack of a spleen (asplenia), chronic middle ear
infections (otitis media), inflammation of the nasal passages (rhinitis), and improper location of the heart
on the right side of the chest (dextrocardia). Kartagener syndrome is caused by defects affecting the cilia,
the thin hair-like structures that cover most of the cells in the body. The cilia of cells in the respiratory
tract are defective and fail to clear the respiratory passages of mucus and other secretions. Kartagener
syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose
“Kartagener” as your search term in the Rare Disease Database.)

X-linked visceral heterotaxy is a rare genetic disorder characterized by various heart defects including the
improper location of the heart on the right side of the chest (dextrocardia), complete reversal of the
internal organs (situs inversus viscerum) so that they are the opposite side of the body than normal, and
the absence of the spleen (asplenia) or the presence of multiple spleens (polysplenia). X-linked visceral
heterotaxy is caused by disruptions or changes (mutations) to the zinc finger protein of cerebellum 3
(ZIC3) gene located on the X chromosome.
Diagnosis

A diagnosis of Ivemark syndrome is made based upon a detailed patient history, a thorough clinical
evaluation, identification of characteristic symptoms and a variety of specialized tests. Blood samples
may be taken to detect the presence of Howell-Jolly bodies, which are small fragments of DNA found in
red blood cells that indicate problems with the function of the spleen (or the lack of a spleen). In addition,
a test that uses sound waves to make a picture of the heart (echocardiogram) can confirm the presence and
severity of heart defects.

Ivemark syndrome can be detected before birth through a fetal ultrasound, a test that uses high-frequency
sound waves to create a picture of a developing fetus. A fetal ultrasound can detect specific abnormalities
associated with Ivemark syndrome including the lack of a spleen and the presence of heart defects.

Standard Therapies

Treatment

The treatment of Ivemark syndrome is directed toward the specific symptoms that are apparent in each
individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons,
pediatric cardiologists, pediatric gastroenterologists, and other healthcare professionals may need to
systematically and comprehensively plan an affected child's treatment.

Affected infants may need heart surgery to correct the various heart defects that are often present at birth.
The specific procedures required will vary depending upon the specific heart defect present. (See the
Resources section below for organizations that can provide more information on pediatric heart disease).

Because of the absence or poor function of the spleen, individuals with Ivemark syndrome may receive
prophylactic antibiotic therapy to reduce the incidence of infection. When infection does occur, it should
be aggressively treated and infants should receive the proper immunizations.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies
receiving U.S. government funding, and some supported by private industry, are posted on this
government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact
the NIH Patient Recruitment