Trisomy 18

Definition

Trisomy 18 is a genetic syndrome of multiple congenital anomalies and severe to profound mental retardation. It is caused by the presence of an extra chromosome 18 in some or all of the cells of the body. Babies with the condition usually do not survive past several months of age. Trisomy 18 in the embryo/fetus is also a common chromosomal cause of pregnancy loss.

Description

Chromosomes are the microscopic structures inside cells that carry the genes . The genetic material inside each cell contains all of the instructions the body needs to develop and function normally. Humans have 23 different pairs of chromosomes. Chromosomes 1-22 are numbered from largest to smallest, and as a group are known as the autosomes. The last pair of chromosomes are designated X and Y, and are known as the sex chromosomes—females have two X chromosomes and males have one X and one Y. Other than sperm and eggs, each cell in the body normally has 46 chromosomes—a pair of each of the autosomes plus two sex chromosomes. In order for normal development and functioning to occur, chromosomes and genes must be present in the correct quantity and in the correct proportion to each other. Too much or too little genetic material usually causes serious problems.

The term euploid means "good set," and is used to designate a full set of 46 chromosomes. A cell is aneuploid ("not a good set") if it has any number of chromosomes other than 46. A trisomy is one type of aneuploidy, and refers to a cell that contains three of the same chromosome. Trisomy 18, then, refers to three chromosomes 18. After Down syndrome (trisomy 21), trisomy 18 is the most common autosomal aneuploid condition seen in live-born babies. Trisomy 18 is also known as Edwards syndrome.

Edwards syndrome is comprised of a specific but broad pattern of multiple congenital anomalies and mental retardation. Babies with Edwards syndrome tend to have similar physical features and medical problems because they all have the same genetic imbalance—an extra copy of the genes on chromosome 18. The physical anomalies associated with Edwards syndrome involve nearly every organ and system of the body. However, some anomalies occur more often than others, such as those of the heart, kidney, brain, skeleton, and craniofacial (head and face) area. The birth defects are typically serious and, combined with the large number of anomalies possible, result in a high mortality rate. About 60% of newborns with Edwards syndrome die within the first week, and 80% do not survive past one month of age. Even those with Edwards syndrome who live longer will have severe to profound mental retardation and chronic medical problems, necessitating involved care and monitoring throughout their lives.

Genetic profile

Edwards syndrome occurs in three different forms: full trisomy 18, mosaic trisomy 18, and partial trisomy 18. Before each of these is described, however, it is helpful to review the basics of normal reproduction and early embryonic development. As noted, cells in the body normally contain 46 chromosomes in 23 pairs, except sperm in males and eggs in females, which contain one chromosome of each pair, or 23 total. Meiosis is the process by which sperm and eggs, collectively known as gametes, are produced. In normal meiosis, the 46 chromosomes line up in pairs in the middle of a cell, and the cell divides down the middle separating each pair of chromosomes. When a sperm fertilizes an egg at conception, the 23 chromosomes from each gamete combine. A process of repeated chromosome duplication followed by cell division, known as mitosis, then begins. A cell that goes through mitosis produces two new cells, each with 46 chromosomes. A developing human is called an embryo during the eight weeks after conception, and a fetus for the remainder of pregnancy.

Full trisomy 18

Occasionally, chromosomes of a single pair do not separate during meiosis, an abnormal process known as nondisjunction. The result is one gamete with 24 chromosomes and another with 22. If a gamete with 24 chromosomes results in conception with a normal counterpart, an embryo with 47 chromosomes is produced. In most cases, all cells in the body will then have 47 chromosomes, a condition known as full trisomy 18 (when referring to an individual with the disorder, unless otherwise specified, the term "trisomy 18" implies a full trisomy, whereas Edwards syndrome may refer to any of the forms).

Nondisjunction of two chromosomes 18 during the formation of an egg or sperm is by far the most common cause of Edwards syndrome. Nondisjunction is a chance occurrence, with no known causative or preventive factors. The incidence of nondisjunction does increase, however, as men and women age. For anyone who has a fetus or child diagnosed with trisomy 18, the risk for a chromosomal disorder of any type in subsequent offspring is about 1%, the exception being women over age 35, who face their age-related risk.

Mosaic trisomy 18

If the body contains a mixture of cells, some with trisomy 18 and some with a normal chromosome count, the condition is called mosaic trisomy 18. A small percentage of Edwards syndrome cases are due to mosaic trisomy 18.

Mosaic trisomy 18 occurs in one of two ways. The first involves mitotic (rather than meiotic) nondisjunction of chromosomes 18, in which a cell undergoing mitosis in a chromosomally normal embryo produces one cell with trisomy 18 and another with monosomy 18. The cell with monosomy 18 cannot survive, but if the trisomic cell survives, all cells in the body derived from it will have trisomy 18. These trisomic cells, combined with the normal cells that continue to develop, result in mosaic trisomy 18. The other cause of mosaicism involves an embryo with full trisomy 18. In this case, however, one cell loses its extra chromosome during mitosis. The result is a euploid cell, which in turn produces a euploid cell line in addition to the original trisomic cell line. Since mitotic nondisjunction appears to be the cause in most cases, and is due purely to chance, the recurrence risk for subsequent offspring after the diagnosis of mosaic trisomy 18 is less than 1%.

Because they have some normal cells, individuals with mosaic trisomy 18 tend to be less severely affected than those with full trisomy 18, but not always. Much of the prognosis depends on the total percentage of trisomic cells in the body and/or the proportion of trisomic cells in specific tissues and organs. There is no way to determine exact percentages of cells, and therefore no way to provide an accurate prognosis.

Partial trisomy 18

A third cause of Edwards syndrome is a rearrangement, or translocation, of genetic material between chromosome 18 and another chromosome. An unbalanced chromosome translocation (extra and/or missing genetic material) may result in an embryo that has an extra piece of chromosome 18, known as partial trisomy 18. If cells are trisomic for a portion of chromosome 18, the result could be a form of Edwards syndrome. However, translocations between chromosomes can be complicated, and some cases of partial trisomy 18 may result in a pattern of anomalies that does not resemble Edwards syndrome.

Unbalanced translocations can occur in an embryo for the first time (de novo), or they can be inherited from a healthy parent who is a carrier of the translocation in a balanced state (no missing or extra genetic material). Normal blood chromosome tests on both parents implies the translocation was de novo, which means no increased risk for subsequent offspring. Detection of a balanced translocation in one parent, however, presents an increased risk for unbalanced translocations in subsequent offspring, as well as an increased risk for pregnancy loss. In cases of partial trisomy 18, genetic counseling is critical to help determine risks and available options. Chromosome translocations resulting in partial trisomy 18 make up a small percentage of Edwards syndrome cases.

Demographics

The incidence of Edwards syndrome is about one in 5,000 births. Two-thirds of all newborns with the condition are female, probably because males with trisomy 18 are more likely to be miscarried. The condition is not known to occur more frequently in any ethnic group or in any part of the world. Increased parental age is the only factor known to result in a greater risk for trisomy 18. In the United States, parents of babies with trisomy 18 average about 32 years of age, while 26 is the average age for parents of children without a chromosomal disorder. The risk increases with age in both sexes, but begins earlier and is more pronounced in women.

Increasing maternal age elevates the risk for chromosomal disorders due to nondisjunction in general, not just trisomy 18. For instance, a 20-year-old woman has about a 1 in 10,000 chance of having a child with trisomy 18, while the risk of having a child with any chromosomal disorder at that age is 1 in 800. By age 35, those same risks have risen to 1 in 2,000 and 1 in 200 respectively, and increase to 1 in 600 and 1 in 65 at age 40. Other common chromosomal disorders caused by nondisjunction that result in live birth include trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome ), and several conditions caused by aneuploidy of the sex chromosomes.

Signs and symptoms

Many physical anomalies and medical complications are associated with Edwards syndrome. In fact, well over 100 different anomalies have been reported in the medical literature. The more common findings are categorized and described below.

Prenatal anomalies

The majority of pregnancies in which the embryo/fetus has trisomy 18 will result in miscarriage or stillbirth. Some physical anomalies of the heart, skeleton, brain, kidneys, and body walls have the best chance of being detected by prenatal ultrasound. Other, pregnancyrelated findings include intrauterine growth restriction (IUGR) of the fetus, a single umbilical artery (also called two vessel cord), and too much (polyhydramnios) or too little (oligohydramnios) amniotic fluid. While detection of fetal anomalies by ultrasound may lead to suspicion of Edwards syndrome, the diagnosis can only be confirmed by chromosome testing. Women carrying a fetus with Edwards syndrome sometimes report they feel little movement. Cesarean sections are more common due to abnormal fetal position or fetal distress near term.

General anomalies

Of those babies with Edwards syndrome that are live-born, two-thirds are delivered several weeks earlier or later than their expected due date. Low birth weight is common, as are low Apgar scores (measurements of a newborn's activity just after birth). Newborns are frail, and tend to have a weak cry and difficulty feeding. Muscles may be poorly developed, and often become tight and contracted (hypertonic). Extra hair (hirsutism) on the forehead and back is sometimes seen, as is loose, redundant skin.

Abnormalities of the lungs, kidneys, pancreas, spleen, and gastrointestinal system are associated with Edwards syndrome. The thyroid, thymus, and adrenal glands may be affected. Anomalies of the breastbone, radius (bone in the forearm), ribs, pelvis, and the spine (scoliosis ) are the more frequent skeletal findings. An abdominal wall defect (omphalocele ) or hernia in the abdominal region may be present. Genital (sex organ) anomalies in both males and females have been described.

Heart anomalies

Ninety percent of babies with Edwards syndrome have one or more heart defects. Ventricular septal defects (VSD) and atrial septal defects (ASD), holes between the lower and upper chambers of the heart respectively, are the most common cardiac problems. Patent ductus arteriosis (open connection between the pulmonary artery and aorta) and abnormal heart valves are also typical.

Craniofacial anomalies

Small head size (microcephaly) and a prominent occiput (back of the skull) are variations in skull shape typical of Edwards syndrome. Common facial features include widely spaced and/or slanted eyes, skin folds at the inner eyelid (epicanthal folds), ptosis (drooping) of the eyelids, low-set malformed ears, a small oral opening, narrow palate or cleft lip/palate, and a small jaw (micrognathia).

Hand and foot anomalies

A specific pattern of hand and foot anomalies is seen in most infants with Edwards syndrome. Clenched hands, with the index finger overlapping the third and the fifth finger overlapping the fourth, are a classic sign. Abnormal dermatoglyphics (finger print pattern), underdeveloped nails, outward or inward deviation of the hand, underdeveloped or absent thumbs, and a single crease across the palm are other frequent anomalies of the hands. Abnormalities affecting the feet include so-called "rocker-bottom feet" and clubfoot .

Central nervous system anomalies

Probably the most medically significant abnormal development that occurs in Edwards syndrome involves the brain. Some anomalies, such as a small cerebellum or hydrocephalus (increased fluid within the brain), can be visualized by ultrasound or other imaging techniques. However, some neurologic problems may only be noticed through their physical effects. For example, difficulties in feeding and breathing, hypertonic muscles, a diminished response to sound, seizures, and severe mental retardation all indicate serious neurologic deficits. Spina bifida (open spine) is an infrequent but serious problem affecting the spinal cord. Babies with spina bifida usually have some degree of paralysis below the point on the back where the spine failed to close.

Diagnosis

Prenatal

Two screening and two diagnostic procedures for trisomy 18 are available to women during pregnancy. Following are brief explanations of each of the prenatal testing alternatives.

Maternal serum alpha-fetoprotein (MSAFP)-Plus, also known as the "triple screen," is a routine maternal blood test offered to women at 15-20 weeks of pregnancy. It screens for open defects (such as spina bifida), Down syndrome, and trisomy 18. However, the screen's sensitivity for trisomy 18 is not as well established as it is for the other conditions. Test results provide a risk adjustment only, not a diagnosis of any condition in the fetus. Any woman who has a result showing an increased risk for trisomy 18 in the fetus is offered follow-up testing such as amniocentesis or a detailed (level II) ultrasound.

Ultrasound, also called sonography, visualizes structures inside the body using high frequency sound waves. During a prenatal ultrasound, a technician or doctor moves an instrument (transducer) back and forth across the skin of a pregnant woman's lower abdomen. The transducer emits and receives harmless high frequency sound waves, which the ultrasound machine then converts into images of the fetus. Today's sophisticated ultrasound machines, used by skilled technicians and doctors, can detect a number of different physical anomalies in the fetus. An ultrasound screen for trisomy 18 has good (but not absolute) sensitivity, and presents no risk to the mother or fetus. Ultrasound becomes more sensitive for trisomy 18 the later in pregnancy it is performed. A level II ultrasound is performed after 20 weeks of pregnancy by a specialist (perinatologist). An abnormal ultrasound suggesting trisomy 18 would lead to the option of amniocentesis to confirm the diagnosis.

Chorionic villus sampling (CVS) is a method used to obtain tissue (chorionic villi) from the edge of the developing placenta. CVS is typically performed at 10-12 weeks of pregnancy. Chorionic villi come from the fetal side of the placenta, and thus are chromosomally the same as cells in the fetus. Guided by ultrasound, a physician inserts a needle through either the abdomen or the cervix, into the placenta, and removes a small sample of tissue. Cells from the sample are analyzed under the microscope and a chromosome count is obtained. CVS carries a risk for miscarriage of approximately 1 in 150, and appears to have a very small risk of causing certain types of limb defects in the fetus as well. In about 3% of cases, CVS produces results that are difficult to interpret, which may lead to a follow-up amniocentesis.

Amniocentesis is the most widely used procedure to obtain fetal cells for genetic testing . The procedure can be performed anytime after about 15 weeks of pregnancy. Under ultrasound guidance, a physician passes a thin needle through the lower abdomen into the amniotic sac and removes a small amount of amniotic fluid. Fetal skin cells that normally float in the fluid are then extracted for genetic analysis. Diagnosis of chromosomal disorders by this method is highly accurate. Amniocentesis causes a miscarriage in about 1 in 300 women who have the procedure, but poses no other serious risk to the fetus.

The benefit of CVS and amniocentesis is their accuracy at detecting trisomy 18, while the drawback is their risk to the pregnancy. The procedures are typically not offered unless the risk for a chromosomal disorder in the fetus is greater than the risk of the procedure, such as in pregnant women who are 35 or older, a couple with a previous child with trisomy 18, and any woman who carries, or whose partner carries, a balanced chromosome translocation. Detection of fetal anomalies by ultrasound or an abnormal MSAFP-Plus screen would lead to the option of amniocentesis.

The benefit of ultrasound and MSAFP-Plus is their lack of risk to the pregnancy, while the drawback is that neither procedure is diagnostic. Women who wish to first modify their risk for a fetal chromosomal disorder (and spina bifida) may choose screening. In any case, prenatal testing, whether screening or diagnostic, is never mandatory. Careful consideration must always be given to what action might be taken after an abnormal result, and how reassuring a normal result might be.

Postnatal

A newborn with typical signs of Edwards syndrome can sometimes be diagnosed from a physical examination alone, especially by a physician who is familiar with the condition such as a geneticist or neonatologist. However, chromosome testing is the only method to confirm the diagnosis, and should always be performed if Edwards syndrome is suspected. Chromosome analysis helps to determine whether the underlying cause is full, mosaic, or partial trisomy 18, and may exclude other syndromes with similar signs and symptoms. Fetuses and newborns with Edwards syndrome sometimes die before chromosome analysis can be performed. In those cases, the diagnosis unfortunately cannot be confirmed, and an accurate cause and recurrence risk cannot be given.

Chromosome testing will detect full trisomy 18 with near 100% accuracy. Likewise, a translocation of chromosome 18 that produces signs of Edwards syndrome should be detected in virtually every case. Mosaic trisomy 18 presents more of a problem for chromosome analysis. The likelihood of confirming mosaic trisomy 18 depends on the percentage of trisomic cells in the particular tissue examined. Mosaicism, if present, can be confirmed by chromosome testing, and usually is. However, normal chromosome tests do not rule out the possibility of trisomic cells elsewhere in the body.

Treatment and management

Medical management of an infant with Edwards syndrome depends on the number and severity of anomalies present. In order to make the best-informed and most appropriate decisions for their child, parents must establish a close working relationship with the treating physicians.

Regardless of the medical procedures that might be performed, most babies with Edwards syndrome will not survive. Nearly all will be transferred to the neonatal intensive care unit (NICU) after birth. In some cases, parents elect not to have any life-prolonging, heroic measures taken should their child experience cardiac or respiratory failure. They may also elect not to have certain types of surgery performed if other complicating medical problems make it unwise.

A more medically stable, less severely affected infant with Edwards syndrome will likely require various medical procedures and treatments. Surgical repair of certain physical anomalies, ventilator (breathing) support, medications, and/or placement of a feeding tube into the stomach are common. A baby may go home and remain there after some length of hospital stay, or may need to be readmitted one or more times. For those children that show some possibility of longer-term survival (more than six months), a plan for their medical care, both in the hospital and at home, must be established. Parents should also be informed of the various educational and support services available to them, including the Support Organization For Trisomy 18, 13, and Related Disorders (S.O.F.T.). Genetic counseling, to discuss the cause, prognosis, and recurrence risks for their child's type of trisomy 18, can be of great help to parents.

There is no way to prevent the occurrence of trisomy 18. The technology now exists to test multiple embryos conceived by in vitro fertilization for certain chromosome anomalies, but this is very expensive and is only performed at several centers in the world.

Prognosis

The prognosis for a baby born with trisomy 18 is poor. On average, about 40% of newborns with trisomy 18 survive the first week, 20% are alive at one month, 6% at six months, and about 5% live past their first birthday. Survival rates are somewhat higher for children with mosaic or partial trisomy 18. As is the case before birth, males with trisomy 18 have a higher mortality rate than females, with about one-third as many males as females surviving infancy.

The outlook for trisomy 18 is not likely to change much in the coming years. Surgery to repair various birth defects has improved dramatically over the years. However, most babies with trisomy 18 do not die from repairable anomalies. For those parents whose babies are expected to survive some length of time, connecting them with support groups and providing them with accurate information as soon as possible is important.

Resources

PERIODICALS

Baty, Bonnie J., Brent L. Blackburn, and John C. Carey. "Natural History of Trisomy 18 and Trisomy 13: I. Growth, Physical Assessment, Medical Histories, Survival, and Recurrence Risk." American Journal of Medical Genetics 49 (1994): 175-88.

Baty, Bonnie J., Brent L. Blackburn, and John C. Carey. "Natural History of Trisomy 18 and Trisomy 13: II. Psychomotor Development." American Journal of Medical Genetics 49 (1994): 189-94.

Matthews, Anne L. "Chromosomal Abnormalities: Trisomy 18, Trisomy 13, Deletions, and Microdeletions." Journal of Perinatal and Neonatal Nursing 13 (1999): 59-75.

ORGANIZATIONS

Chromosome 18 Registry and Research Society. 6302 Fox Head, San Antonio, TX 78247. (210) 567-4968. <http://www.chromosome18.org>.

National Society of Genetic Counselors. 233 Canterbury Dr., Wallingford, PA 19086-6617. (610) 872-1192. <http://www.nsgc.org/GeneticCounselingYou.asp>.

Support Organization for Trisomy 18, 13 and Related Disorders (SOFT). 2982 South Union St., Rochester, NY 14624. (800) 716-SOFT. <http://www.trisomy.org>.

Scott J. Polzin, MS, CGC