Trisomy 18 syndrome is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in cells of the body. In some cases, the chromosomal abnormality may be present in only a percentage of cells, whereas other cells contain the normal chromosomal pair (mosaicism).
Depending on the specific location of the duplicated (trisomic) portion of chromosome 18--as well as the percentage of cells containing the abnormality--symptoms and findings may be extremely variable from case to case. However, in many affected infants, such abnormalities may include growth deficiency, feeding and breathing difficulties, developmental delays, mental retardation, and, in affected males, undescended testes (cryptorchidism). Individuals with trisomy 18 syndrome may also have distinctive malformations of the head and facial (craniofacial) area, such as a prominent back portion of the head; low-set, malformed ears; an abnormally small jaw (micrognathia); a small mouth with an unusually narrow roof (palate); and an upturned nose. Affected infants may also have narrow eyelid folds (palpebral fissures), widely spaced eyes (ocular hypertelorism), and drooping of the upper eyelids (ptosis). Malformations of the hands and feet are also often present, including overlapped, flexed fingers; webbing of the second and third toes; and a deformity in which the heels are turned inward and the soles are flexed (clubfeet [talipes equinovarus]). Infants with trisomy 18 syndrome may also have a small pelvis with limited movements of the hips, a short breastbone (sternum), kidney malformations, and structural heart (cardiac) defects at birth (congenital). Such cardiac defects may include an abnormal opening in the partition dividing the lower chambers of the heart (ventricular septal defect) or persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus). Congenital heart defects and respiratory difficulties may lead to potentially life-threatening complications during infancy or childhood.
The symptoms and findings associated with trisomy 18 syndrome may be extremely variable. In addition, if only a percentage of cells contains the chromosomal abnormality (mosaicism), associated symptoms may tend to be less severe. However, certain findings before birth (prenatally) and during infancy are considered characteristic of trisomy 18 syndrome. In many cases, there is abnormally decreased movement during fetal development. In addition, many affected newborns are born abnormally early or late (altered gestation). Additional characteristic findings typically include poor suckling ability and associated feeding difficulties, failure to grow and gain weight at the expected rate (failure to thrive), mental retardation, and distinctive malformations of the head and facial (craniofacial) area. In many infants with trisomy 18 syndrome, other physical abnormalities may also be present, such as undescended testes in affected males (cryptorchidism), malformations of the hands and feet, additional skeletal defects, and structural abnormalities of the heart (congenital heart defects).
A “full-term” infant is born anywhere from 37 to 42 weeks of gestation. (Gestation refers to the period of development from fertilization of the egg [ovum] to birth.) However, about one third of newborns with trisomy 18 syndrome are born prior to 37 weeks’ gestation (premature infant), and approximately one third are born after 42 weeks (postmature infant). Affected infants also tend to have a low birth weight, growth delays, and severe feeding difficulties. In addition, at birth, skeletal muscles and underlying connective and fatty tissues (subcutaneous and adipose tissue) may be underdeveloped (hypoplastic). Additional characteristic abnormalities during infancy may include diminished muscle tone (hypotonia) followed by unusually increased tone (hypertonia) and muscle stiffness (rigidity); an abnormally weak, feeble cry; a decreased response to environmental sounds; and/or repeated episodes in which there is a temporary cessation of breathing (apneic episodes).
Many infants with trisomy 18 syndrome also have distinctive malformations of the craniofacial region. These may include a small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent back region of the head (occiput); a small mouth (microstomia); incomplete closure of the roof of the mouth (cleft palate) and/or an abnormal groove in the upper lip (cleft lip); a small jaw (micrognathia); or a short, webbed neck. Affected infants may also have an upturned nose; low-set, malformed ears; widely spaced eyes (ocular hypertelorism) with slanted or narrow eyelid folds (palpebral folds); and vertical skin folds covering the eyes’ inner corners (epicanthal folds).
Trisomy 18 syndrome may also be characterized by additional eye (ocular) abnormalities. For example, there may be drooping of the upper eyelids (ptosis) and an inability to completely close the eyes. Some affected infants also have clouding of the normally transparent front regions of the eyes (corneas); loss of transparency of the lenses (cataracts); absence or defects of tissue (colobomas) affecting the colored regions of the eyes (irides); or unusual smallness of the eyes (microphthalmia). Additional ocular abnormalities may include abnormal deviation of one eye in relation to the other (strabismus); inequality in the diameter of the pupils (anisocoria); rapid involuntary eye movements (nystagmus); and/or a decreased response to visual stimuli.
Many infants with trisomy 18 syndrome also have characteristic malformations of the hands and feet. The hands are typically clenched, with overlapping of the index finger (second finger) over the third finger and the “pinky” (fifth finger) over the fourth. Frequent findings also include unusual skin ridge patterns (dermatoglyphics) on the fingers and palms; underdeveloped (hypoplastic) nails, particularly those of the fifth fingers and toes; and abnormal deviation of the great toes (hallux) in an upwardly bent position (dorsiflexion). In some cases, additional malformations may be present, such as the presence of extra fingers or toes (polydactyly); webbing (syndactyly) of certain toes; or a deformity in which the feet appear shaped like the rocker of a rocking chair (“rocker-bottom feet”) with abnormal prominence of the heel bones (calcaneus). Some infants also have a foot deformity in which the heels are turned inward and the soles are flexed (clubfeet [talipes equinovarus]).
Many infants with trisomy 18 syndrome also have additional skeletal deformities, such as a short breastbone (sternum); a small pelvis with limited outward movements (abduction) of the hips; or abnormalities of the ribs. In addition, in some cases, there may be defects of certain bones of the spinal column (vertebrae), including sideways curvature of the spine (scoliosis); underdevelopment of one half of certain vertebrae (hemivertebrae); or abnormal fusion of vertebrae.
As mentioned above, in males with the disorder, the testes fail to descend into the scrotum (cryptorchidism). Trisomy 18 syndrome may also be associated with additional genital abnormalities. In some affected males, there may be division of the scrotum into two parts (bifid scrotum) and/or abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis. In some females with the disorder, there is underdevelopment (hypoplasia) of the outer skin folds (labia majora) surrounding the vaginal opening and abnormal prominence of the relatively small, sensitive protrusion (clitoris) that forms part of the female external genitalia.
Trisomy 18 syndrome is also often characterized by structural heart (cardiac) defects that are present at birth (congenital heart defects). Many affected infants have an abnormal opening in the fibrous partition (septum) that separates the lower chambers of the heart (ventricular septal defect). Another common finding is abnormal persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) that emerge from the heart (patent ductus arteriosus). In some cases, additional cardiac defects may be present. These may include narrowing (stenosis) of the opening between the right ventricle and the artery that carries oxygen-deficient blood to the lungs (pulmonary artery); narrowing of the major artery that transports oxygen-rich blood from the heart to all parts of the body (coarctation of the aorta); and/or abnormalities of certain heart valves.
In some instances, infants with trisomy 18 syndrome have additional physical defects, such as malformations of the abdominal wall and the kidneys. For example, there may be protrusion of portions of the intestine through an abnormal opening in muscles of the groin (inguinal hernia) or the abdominal wall near the navel (umbilical hernia). Some infants with trisomy 18 syndrome have an omphalocele, a birth defect in which varying amounts of intestines or other abdominal organs (viscera), covered by a membrane-like sac, protrude through an opening in the abdominal wall near the navel. In addition, in some affected infants, the kidneys may be abnormally positioned (ectopic) or joined together (horseshoe kidneys) or contain multiple cysts (polycystic kidneys). There may also be swelling of the kidneys with urine due to narrowing or blockage of the tubes that carry urine from the kidneys to the bladder (hydronephrosis).
Some affected infants may also have malformations of the brain and spinal cord (central nervous system [CNS]). These may include absence (agenesis) or underdevelopment (hypoplasia) of the thick band of nerve fibers connecting the two hemispheres of the brain (corpus callosum); protrusion of part of the spinal cord and its surrounding membranes (meninges) through an abnormal opening in the spinal column (myelomeningocele); or other malformations. Trisomy 18 syndrome is also typically characterized by mental retardation, with severely impaired intellectual, verbal, and motor development.
In many cases, congenital heart defects, respiratory difficulties (e.g., apneic episodes, aspiration), or other abnormalities associated with the disorder may lead to potentially life-threatening complications during infancy or childhood.
In individuals with trisomy 18 syndrome, all or a particular region of chromosome 18 is present three times (trisomy) rather than twice in cells. In approximately 10 percent of cases, only a percentage of cells contains the extra 18th chromosome (mosaicism).
Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.
Trisomy (or “duplication”) of a certain region or regions of chromosome 18 is responsible for the symptoms and findings that characterize the disorder. The severity and range of symptoms may depend on the length and location of the duplicated portion of the chromosome as well as the percentage of cells that contain the abnormality. In individuals with partial trisomies of chromosome 18 who have characteristic symptoms of the disorder, evidence suggests that a critical region associated with trisomy 18 syndrome is duplication at band 18q11.
In most individuals with the disorder, duplication of chromosome 18 is caused by spontaneous (de novo) errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). Reports suggest that the risk of such errors may increase with advanced parental age. In cases in which only a percentage of cells contains the trisomy 18 abnormality (mosaicism), errors may also occur during cellular division after fertilization (mitosis).
In some cases, trisomy 18 may result from a translocation involving chromosome 18 and another chromosome. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of a “balanced” translocation. (If a chromosomal rearrangement is balanced–i.e., consists of an altered but balanced set of chromosomes–it is usually harmless to the carrier. However, balanced translocations are sometimes associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. Chromosomal testing may determine whether a parent has a balanced translocation.)
Trisomy 18 syndrome was originally known as Edwards syndrome, after one of the investigators (JH Edwards) who initially recognized the condition as a distinct disease entity in 1960. The syndrome appears to affect females more frequently than males by a ratio of approximately three or four to one. Large population surveys indicate that it occurs in about one in 5,000 to 7,000 live births. The frequency of trisomy 18 syndrome increases with advancing age of the mother. Reports indicate that the mean maternal age is 32.5 years.
A diagnosis of trisomy 18 syndrome may be suggested before birth (prenatally) based upon specialized testing, such as fetal ultrasonography, certain blood studies, amniocentesis, and/or chorionic villus sampling (CVS).
During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal disorder or other abnormalities. In addition, screening tests that reveal abnormal levels of certain "markers" in the mother's blood may suggest an increased risk of trisomy 18 syndrome or other chromosomal abnormalities (e.g., Down syndrome). Such tests measure the levels of specific substances in the blood, including alpha-fetoprotein (AFP); human chorionic gonadotropin (hCG); unconjugated estriol; or other markers. If such screening studies reveal abnormal levels of these markers, additional testing may be recommended, such as amniocentesis with chromosome analysis.
Prenatal tests, such as amniocentesis or CVS, may also be offered to all pregnant women who are aged 35 or older; for known translocation carriers; and/or due to other factors. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on the fluid or tissue samples may confirm the presence of trisomy 18.
The diagnosis of trisomy 18 syndrome may also be made or confirmed after birth (postnatally) based upon a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. For infants diagnosed with the syndrome, careful monitoring and specialized testing may be conducted to ensure early detection and appropriate management of certain conditions that may be associated with trisomy 18 syndrome.
The treatment of trisomy 18 syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a multidisciplinary team of medical professionals.
For many affected infants, supportive measures may be required to improve feeding and the intake of necessary nutrients. Such measures may include the delivery of liquid nutrients to the stomach through a tube inserted through the nose (nasogastric tube feeding). In addition, oxygen therapy may be required to ensure sufficient oxygen supply to bodily tissues.
In some cases, recommended treatment may include surgical correction of certain abnormalities associated with the disorder. The surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors.
A supportive team approach for children with this disorder may be of benefit and may include special education, physical therapy, and/or other medical or social services. Genetic counseling will also be of benefit for families of affected children. Other treatment for this disorder is symptomatic and supportive.
The Tracking Rare Incidence Syndromes (TRIS) project is designed to raise awareness and provide support for families and professionals involved in the care of children and adults with rare trisomy conditions. The TRIS project seeks to increase the knowledge base on rare incidence trisomy conditions, and to make this information available to families and interested educational, medical and therapeutic professionals. For more information, contact:
Tracking Rare Incidence Syndromes (TRIS) project
Phone: (618) 453-2311
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FROM THE INTERNET
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LEARN ABOUT TRISOMY 18
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