Laterality sequence refers to a variable group of developmental anomalies in which some or all of an affected individual's internal organs form on the opposite side of the body than is standard. The heart, stomach, and spleen may form on the right side of the body, instead of the left. The liver and gallbladder may form on the left side of the body, instead of the right. Laterality refers to a side of the body. A sequence is a chain of events that occurs as a result of a single abnormality or problem.
All humans display a characteristic placement of internal organs with the heart, stomach, and spleen towards the left, and the liver and gallbladder on the right. This placement of organs is called situs solitus. Very early in fetal development, the embryo forms a left-right axis that determines which side is left and which side is right. The axis can then instruct the body to form organs towards one side or the other. When the left-right axis does not form correctly, all or some of the organs form in the wrong location and result in a laterality sequence defect.
The first documented cases of laterality sequence occurred in the 1600s with Fabricus' description of an individual's symptoms of reversed liver and spleen, and Marco Severino's recognition of dextrocardia. Laterality sequence defects range in features and descriptions. Features of laterality sequence anomalies include abnormal placement of all or some organs, dextrocardia (heart on the right side of the body), asplenia (no spleen), polysplenia (multiple spleens), complex congenital heart defects, intestinal malrotation, abnormal lung formation, symmetrical liver, midline abnormalities, and neural tube defects . Other terms for laterality sequence defects include situs inversus, situs inversus viscerum, situs transverses, heterotaxy, situs ambiguous, isomerism sequence, asplenia syndrome, Ivemark syndrome, polysplenia syndrome, partial situs inversus, and dextrocardia.
Laterality sequence defects can occur due to genetic or multifactorial causes. Most cases of laterality sequence defects are sporadic and multifactorial. Multifactorial conditions result from the combination of environmental and genetic factors that contribute to the development of laterality sequence defects. First-degree relatives of an individual affected by a multifactorial condition have an increased risk that is based on family studies. A family who has one child with an isolated case of a laterality sequence, with no other affected children, runs a 3–5% risk of having a future child being affected by a laterality sequence defect.
Although all of the genes that are known to be involved in laterality sequence defects encode proteins that help determine the laterality of an individual, the inheritance pattern of inherited laterality sequence defects depends on the specific gene defect. New genetic mutations that cause laterality defects are still being discovered. Current genes associated with laterality defects include ZIC3 (also known as HTX1, zinc finger protein ZIC 3, Xq26.2), CRELD1 (Cysteine-rich with EGF-like domains located at 3p25.3), DNAH11, LEFTB (formerly LEFTY2), CRC (CRYPTIC located on chromosome 2), EBAF (transforming growth factor beta 1q42.1), NKX2 (homeobox protein Nkx-2.55 5q34), and ACVR2B (encoding activin receptor IIB located at 3p22-p21.3).
Most cases of inherited laterality defects travel through the family in an autosomal recessive manner. In an autosomal recessive condition, two copies of the mutant, or nonworking, gene are needed to develop the symptoms of laterality sequence. In these cases, both parents each carry one copy of a mutant gene. Individuals with only one copy of a nonworking gene for a recessive condition are known as carriers, and have no problems related to the condition. In fact, each person carries between five and 10 nonworking genes for harmful, recessive conditions. However, when two people with the same mutant recessive gene have children together, there is a 25% chance, with each pregnancy, for the child to inherit two mutant copies, one from each parent. That child then has no working copies of the gene and, therefore, has the signs and symptoms associated with genetic defects. Gene mutations that result in autosomal recessive forms of laterality defects include DNAH11. DNAH11, located on the short arm of chromosome 7 (7p21), is expressed in the node of the embryo at day 7.5, and is involved in left-right axis determination of the organs. Mutations in the coding region of DNAH11 account for situs inversus totalis.
Additional autosomal recessive laterality defects can also be a feature of other inherited conditions, such as Kartagener syndrome and Ivemark syndrome. Kartagener syndrome is an autosomal recessive disorder characterized by bronchiectasis, sinusitis, dextrocardia, and infertility that can be caused by several different genetic locations and mutations. Approximately 25% of individuals affected by situs inversus have Kartagener syndrome. Ivemark syndrome refers to the congenital absence of the spleen, usually accompanied by complex cardiac malformations, malposition and maldevelopment of the abdominal organs, and abnormal lobation of the lungs.
Some cases of laterality sequence defects are inherited in an autosomal dominant pattern. In an autosomal dominant inheritance pattern, the genes that cause laterality sequence are carried on one of the 22 pairs of numbered autosomal chromosomes, rather than on the X or Y sex chromosomes. Furthermore, in autosomal dominant conditions, only one copy of the mutant, or nonworking, gene is necessary for the development of laterality sequence. An individual who inherits a normal gene copy from one parent and an abnormal gene copy from the other parent is likely to have a lateral sequence anomaly. The children of an individual with one normal gene copy and one mutated copy have a 50% chance of inheriting laterality sequence. One known form of laterality sequence that is found inherited in an autosomal dominant manner occurs in patients with a nonworking copy of CFC1. CFC1 is located on chromosome 2 and is involved in the formation of the left-to-right axis in human development. Accordingly, individuals who have one nonworking copy of CFC1 have randomized organ positioning (heterotaxia).
Some cases of laterality sequence defects are inherited in an X-linked recessive pattern. As opposed to genes that are carried on one of the 22 pairs of numbered autosomal chromosomes, X-linked genes are found on the sex chromosomes called X. Females have two X chromosomes, while males have a single X chromosome and a single Y chromosome. When a female inherits a mutated gene on the X chromosome, she is known as a carrier. She often has no problems related to that condition, because the gene on her other chromosome continues to function properly. However, males only inherit one copy of the information stored on the X chromosome. When a male inherits a mutated copy of the gene that causes an X-linked recessive condition, he will experience the symptoms associated with the disease. The chance for a carrier female to have an affected son is 50%, while the chance to have an unaffected son is 50%. The chance for a carrier female to have a daughter who is also a carrier for the condition is 50%, while the chance for her to have a daughter who is not a carrier is 50%. An affected male has a 100% chance of having carrier daughters and a 0% chance of having affected sons. In 1997, an X-linked recessive form of laterality sequence caused by mutations in HTX1 located on the long arm of the X chromosome (Xq26.2) was described. In the same year, it was determined that the gene is a zinc finger protein, and was named ZIC3. Currently, the gene is known as both ZIC3 and HTX1. ZIC3 is involved in the development of the left-right axis, and mutations account for approximately 1% of individuals affected by heterotaxy. Accordingly, mutations in ZIC3 cause inability of the embryo to establish normal left-right asymmetry.
Laterality sequence defects occur in about one in 8,500–25,000 live births. It occurs in individuals of all ethnic backgrounds. An equal number of males and females are affected by laterality sequence defects.
Signs and symptoms
Different laterality sequence defects can be described by the positioning of the various organs and associated malformations.
Complete situs inversus or situs transversus is a laterality defect resulting in a mirror image of the normal organ formation with heart, spleen, and stomach on the right, and the liver and gallbladder on the left side, respectively. The normal pulmonary anatomy is reversed so that the left lung has three lobes and the right lung has two lobes. The remaining internal structures also are a mirror image of the normal.
Heterotaxy or situs ambiguous refers to random positioning of individual organs that can result in multiple malformations with severe heart defects, livers found in the middle of the body, spleen abnormalities, and intestines turned in the opposite direction than is standard (gastrointestinal malrotation). Often, structures normally found on one side of the body are duplicated or absent. Two primary subtypes of heterotaxy are based on the presence or absence of certain organs. In classic right isomerism, or asplenia, patients have a right atrium on both sides of the body, a centrally located liver, no spleen, and both lungs have three lobes. In left isomerism, or polysplenia, patients have left atria on both sides, multiple spleens, and both lungs have two lobes.
Dextrocardia refers to right-sided positioning of the heart. There are various forms of dextrocardia, ranging from a normally configured heart that is positioned further to the right than normal to mirror-image dextrocardia in which the positions of the heart chambers and major vessels are exactly the reverse of the standard arrangement.
Laterality sequence defects caused by mutations in DNAH11 are characterized by situs inversus viscerum, intrauterine growth retardation, congenital heart defects, such as transposition of the great vessels, ventricular septal defect, atrial septal defect, truncuscommunis, and dextrocardia, right pulmonary isomerism, and right spleen. Mutations in DNAH11 may also be associated with Kartagener syndrome that includes bronchiectasis, sinusitis, dextrocardia, and infertility.
Laterality sequence defects caused by mutations in CFC1 result in visceral heterotaxy including a variable group of congenital anomalies that include complex cardiac malformations and situs inversus or situs ambiguous.
Laterality sequence defects caused by mutations in ZIC3 include a variable group of congenital anomalies that include complex cardiac malformations (corrected transposition of great arteries, ventricular septal defect, and patent ductus arteriosus ), dextrocardia, situs inversus, asplenia, polysplenia, situs inversus viscerum, pulmonic stenosis, and poor growth (intrauterine growth retardation). Some individuals with mutations in ZIC3 have been found to have isolated heart defects only. Female carriers have been described with uterine septums and hypertelorism (wide-spaced eyes).
Laterality defects may be discovered before birth and in infancy because of associated heart defects or other health problems. Laterality defects also may remain asymptomatic in childhood and are discovered by chance in adult life as affected individuals seek medical attention for an unrelated condition. Clinical testing for several genes associated with laterality defects (ACVR2B, CFC1, CRELD1, EBAF, NKX2-5, and ZIC3) is available; however, diagnosis is still primarily based on imaging through means such as ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) scan.
Some symptoms of laterality sequence defects such as heart defects, poor growth (intrauterine growth retardation), and possibly organ reversal may be identified through a screening ultrasound around 18 weeks gestation of pregnancy. Accuracy of diagnosis of laterality sequence defects depends on the position, size, and maturity of the fetus, as well as an adequate volume of amniotic fluid and mother's size. A fetal echocardiogram can also help characterize a heart defect or placement before birth. If there is a known gene mutation present in an affected family member, prenatal diagnosis may be available through tests, such as amniocentesis .
Diagnosis of a laterality sequence defect in infancy is most often made as a result of a heart defect or other serious medical issue related to the organ positioning and/or number of organs. Laterality sequence defects can be verified through use of x rays, ultrasound, or CT scan. The location and relationships of the abdominal organs, veins of the liver, heart arteries and veins, heart chambers, and heart valves should be reviewed carefully.
Diagnosis in adulthood is based on clinical manifestations and exams such as abdominal and thoracic radiography and electrocardiogram. CT is the preferred examination for definitive diagnosis of situs inversus with dextrocardia because it provides good detail for confirming visceral organ position, cardiac position, and great vessel branching. MRI is usually reserved for difficult cases or for patients with associated cardiac anomalies. The features of laterality sequence defects are variable and require thorough evaluation of the internal organs for full diagnosis.
Treatment and management
The treatment and management of laterality sequence defects depend on the type of defect. Infants and children with laterality defects can have congenital heart defect and other associated birth defects that require surgery. Many adults with incidental detection of their laterality sequence anomalies will not need special treatment or management unless they are ill or need surgery. The recognition of situs inversus is important for preventing surgical mishaps that result from the failure to recognize reversed anatomy or an atypical history. The reversal of the organs may lead to some confusion, as many signs and symptoms will be opposite from the standard side. Laterality sequence defects can also complicate organ transplantation operations as donor organs will most likely come from normal individuals whose organs and vessels are a mirror image of the transplanted patients. Accordingly, in the event of a medical problem, the knowledge that the individual has a laterality defect can increase the time and accuracy of diagnosis and increase the safety of surgery.
Many patients with laterality sequence defects such as total situs inversus present with no significant medical problems and have normal life expectancy. Total organ reversal results in normal relationships between the left-right positions of the organs and their blood supplies. In other forms of laterality sequence defects, such as those associated with Kartagener's syndrome, issues such as chronic respiratory problems and infertility can occur. Infants affected by complex cardiac defects may die as a result of their congenital heart defects. Prognosis in isolated dextrocardia depends on the congenital cardiac defects present. Women have been described with a uterine septum that can result in difficulties maintaining a pregnancy.
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