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.
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.
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.
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.
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.
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.
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.
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 Office:
Tollfree: (800) 411-1222
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Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Elsevier Saunders, Philadelphia, PA; 2006:698-699.
Britz-Cunningham SH, Bailey LL, Fletcher WH. Ivemark Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:205-206.
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:1460-1461.
Konstantinidou A, Sifakis S, Koukoura O, et al. Pancreatic aplasia in a fetus with asplenia – cardiovascular defect – heterotaxy (Ivemark syndrome). Birth Defects Res A Clin Mol Teratol. 2008;82:601-604.
Ferdman B, States L, Gaynor JW, Hedrick HL, Rychik J. Abnormalities of intestinal rotation in patients with congenital heart disease and the heterotaxy syndrome. Congenit Heart Dis. 2007;2:12-18.
Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxias. Eur J Hum Genet. 2006;14:17-25.
Bartram U, Wirbelauer J, Speer CP. Heterotaxy syndrome – asplenia and polysplenia as indicators of visceral malposition and complex congenital heart disease. Biol Neonate. 2005;88:278-90.
Fulcher AS, Turner MA. Abdominal manifestations of situs anomalies in adults. Radiographics. 2002;22:1439-1456.
Applegate KE, Goske M, Pierce G, Murphy D. Situs revisited: imaging of the heterotaxy syndrome. Radiographics. 1999;19:838-852.
Debrus S, Tuffery S, Matsuoka R, et al. Lack of evidence for connexin 43 gene mutations in human autosomal recessive laterization defects. J Molec Cell Cardiol. 1997;29:1423-1431.
Britz-Cunningham SH, Shah MM, Zuppan CW, Fletcher WH. Mutations of the connexin43 gap-junction gene in patients with heart malformations and defects of laterality. N Engl J Med. 1995;332:1323-1329.
FROM THE INTERNET
Shannon KM. Heterotaxy, Asplenia. Emedicine Journal, April 17 2006. Available at: http://www.emedicine.com/PED/topic2513.htm Accessed on: May 12, 2008.
Hernanz-Schulman M. Asplenia/Polysplenia. Emedicine Journal, February 28 2008. Available at: http://www.emedicine.com/Radio/topic58.htm Accessed on: May 12, 2008.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:208530; Last Update:03/11/2008. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=208530 Accessed on: May, 2008.
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