Triploidy is a rare lethal chromosome abnormality caused by the presence of an entire extra set of chromosomes. A fetus with triploidy has 69 chromosomes, rather than 46. The majority of fetuses with triploidy are spontaneously miscarried during pregnancy. Those that survive until birth will have severe growth retardation and multiple birth defects. This condition is incompatible with life.
Triploidy is a devastating condition caused by having a full extra set of chromosomes. This extra set of chromosomes causes a variety of serious birth defects, placental problems, and severe growth problems in a fetus. In fact, most pregnancies in which the fetus has triploidy end in a spontaneous miscarriage. Very few infants with triploidy survive to term. Of those that do, most are stillborn and those that are born alive usually die shortly after birth. Infants with this lethal condition are generally small due to severe intrauterine growth retardation (IUGR) and they have multiple birth defects, including facial abnormalities, such as cleft lip, heart defects, neural tube defects (spina bifida ), and other serious birth defects. The exact pattern of abnormalities depends on whether the extra set of chromosomes was inherited from the mother or from the father. Unfortunately, there is nothing that can be done to treat or cure triploidy.
Triploidy is a chromosomal disorder. Chromosomes are the structures that contain all of the body's genes (the basic unit of inheritance ). Humans have 46 chromosomes in every cell of their body, with the exception of their sperm and eggs cells, which contain only 23 chromosomes. When a sperm and an egg unite at conception, the resulting fertilized egg will have 46 chromosomes: half from the mother and half from the father. This fertilized egg will continue to develop and grow into a fetus and, eventually, into a live-born infant with 46 chromosomes in every cell of their body.
Of these 46 chromosomes, 22 pairs (or 44 chromosomes) are called autosomes (or non-sex chromosomes) and the twenty-third pair is the sex chromosomes. Women have two X chromosome (46,XX) and men have an X and Y chromosome (46,XY). Fetuses with triploidy can be 69,XXX (female), 69,XXY (male), or 69,XYY (male). Twenty-three chromosomes (or one set) is referred to as a haploid set of chromosomes, 46 chromosomes (or two sets) is referred to as a diploid set of chromosomes, and 69 chromosomes (or three sets) is referred to a triploid set of chromosomes. A fetus with triploidy has three haploid sets of chromosomes.
Triploidy occurs in several different ways. The extra set of chromosomes can be inherited from the father (paternal inheritance) or they can be from the mother (maternal inheritance). The most common mechanism for triploidy is the fertilization of a single egg by two sperm. This results in a triploid egg with two sets of paternal chromosomes and one set of maternal chromosomes. This accounts for about 60% of cases of triploidy. The other mechanism is an error in cell division in which an egg cell ends up with 46 chromosomes instead of 23. This egg with 46 chromosomes is fertilized by a sperm with 23 chromosomes, resulting in a fertilized egg with 69 chromosomes, which then has two sets of maternal chromosomes and one set of paternal chromosomes. This mechanism is responsible for about 40% of cases of triploidy. The physical effects of triploidy differ depending on whether the extra set of chromosomes was inherited from the mother (maternally inherited) or from the father (paternally inherited).
In pregnancies in which the extra set of chromosomes is maternally inherited, the fetuses tend to be well-formed, with a small head (microcephaly). The placenta in these pregnancies is generally enlarged and cystic (filled with cysts). This type of placenta is often referred to as a hydati-form mole and the pregnancy as a whole may be referred to as a partial molar pregnancy. In pregnancies in which the extra set of chromosomes is paternally inherited, the fetuses have severe growth retardation, a large head, and a small, non-cystic placenta.
The physical birth defects seen in triploidy are variable. All fetuses will have some of these birth defects, but very few will have all of them. The birth defects most commonly seen are heart defects, cleft lip, neural tube defects, kidney malformation, abnormal genitalia (males), and defects in the abdominal wall. Regardless of the presence or absence of these birth defects, triploidy is incompatible with life.
Triploidy is a sporadic (or accidental) event. It is not caused by anything that a parent may or may not have done. Unlike some other chromosome abnormalities (trisomy 21 or Downs syndrome), triploidy is not associated with a mother's age. This means that there is not an increased risk for triploidy for an older mother to have a pregnancy. Because triploidy is an accidental event, there is no increased recurrence risk in future pregnancies. A woman who has had one triploid pregnancy is not at any increased risk to have a second one.
Triploidy occurs in about 1–2% of all conceptions, but most of these pregnancies end in early spontaneous miscarriage. Very few pregnancies with a triploid infant go to term. Only one in 10,000 infants is born with triploidy, and it is estimated that for every live-born infant with triploidy, 1,200 have been lost as miscarriages. Most infants with triploidy are either stillborn or die shortly after birth. The longest recorded lifespan of an infant with full triploidy is 10 months, although this length of survival is extremely rare.
There is a milder form of triploidy that is the result of mosaicism, which is the presence of two separate types of cells within the same individual. Infants with mosaic triploidy have both a normal cell line (46,XX or 46,XY) and a triploid cell line (69,XXX or 69,XXY or 69,XYY). These infants can survive to be live born, but they generally have growth retardation, growth asymmetry (their limbs may be different sizes), some of the other birth defects seen in full triploidy, and severe mental retardation. It is thought that the presence of the normal cell line aids in survival.
Signs and symptoms
Triploidy manifests itself in many different ways. It can be diagnosed both prenatally and at birth.
The diagnosis of triploidy is often made prenatally or during the course of a pregnancy. The diagnosis is often suspected because of an abnormal sonogram or because of an abnormal maternal serum screening test.
A sonogram, or ultrasound, is a common test done during pregnancy that uses sound waves to examine the fetus. There is no known risk to the fetus from an ultrasound. However, a fetus affected with triploidy will often show abnormalities that will warrant further testing to confirm the diagnosis of triploidy. Some of the most common abnormalities seen on a sonogram of a fetus with triploidy include severe growth problems or intrauterine growth retardation (IUGR), an abnormal placenta, and limb abnormalities.
Not every fetus with triploidy will have all of these findings, but most will show some signs that can be detected by sonogram. Abnormal sonogram findings include:
- severe early-onset intrauterine growth retardation (detected as early as 12–14 weeks)
- brain abnormalities, including isolated ventriculomegaly (enlarged ventricles), Arnold-Chiari malformation , holoprosencephaly , and agenesis of the corpus callosum
- cleft lip and possible cleft palate
- limb abnormalities, such as clubfoot or syndactyly (webbing of the fingers and toes)
- heart defects
- kidney abnormalities
- abdominal wall defects, such as an omphalocele (an opening in the abdominal wall, which causes the intestines to be located outside the body)
- neural tube defects, such as spina bifida (an opening in the spinal cord)
- oligohydramnios (a decrease amount of amniotic fluid)
- placental abnormalities, including an enlarged placenta or a cystic placenta
In addition to detection by prenatal sonogram, many fetuses with triploidy are detected by an abnormal maternal serum screening test. A maternal serum screening test is a voluntary blood test usually performed in the second trimester of pregnancy. It is not specifically designed to detect triploidy, but often does because of some of the abnormalities seen in triploidy. The blood test measures the amount of certain proteins in the mother's blood. These proteins, alpha-fetoprotein, human chorionic gonadotropin (hCG), and estriol, are all made either by the fetus or by the placenta. These proteins cross the placenta and get into the mother's blood system. By looking at the amount of these proteins present in the mother's blood system, it is possible to screen for certain genetic abnormalities. Because fetuses with triploidy often have abnormal placentas, too much or too little of these proteins are leaked into the mother's system and the blood test results are often abnormal. If a maternal serum screening test is abnormal, the patient should be offered a detailed ultrasound and amniocentesis .
Both prenatal sonograms and maternal serum screening testing are screening tests. They can pick out individuals with a higher risk to have a fetus with a specific disorder, but they cannot actually give a specific diagnosis. Because of this, if an individual has an abnormal screening test, further diagnostic testing is indicated.
The only way to definitively diagnose triploidy is to have a chromosome analysis (karyotype ) done and actually count the number of chromosomes present. In order to do a chromosome analysis during pregnancy, it is necessary to obtain some tissue from the fetus. This is commonly done through either a chorionic villi sampling (CVS) test or through an amniocentesis. During a chorionic villi test, a catheter is used to remove a small piece of tissue from the placenta. Since the placenta and fetus have come from the same fertilized egg, the chromosomes in the placenta are the same as the chromosomes in the fetus. A CVS test is usually done between 10 and 12 weeks of pregnancy. If a patient is further along in the pregnancy when an abnormality is suspected, an amniocentesis may be performed. This test is usually done between 15 and 20 weeks of pregnancy. It involves using a needle to remove some of the amniotic fluid from around the fetus. The amniotic fluid contains fetal skin cell, which can then be cultured (grown) and analyzed. The results from these tests can take between one and two weeks. By doing a fetal karyotype (counting the number of chromosome the fetus has), it is possible to definitely diagnose triploidy. A newer technique, fluorescent in situ hybridization (FISH), is available in some laboratories and results may be available in as little as 24 hours. It is always wise to do a complete karyotype in addition to FISH testing.
Very few fetuses survive to be born to term with triploidy. Those infants that survive do show a very specific pattern of birth defects. Almost all of these infants will have growth retardation and characteristic facial features, including wide-set eyes (hypertelorism), low-set ears, and limb abnormalities, such as clubfoot and syndactyly (webbing of the fingers and toes). Other anomalies include heart defects, kidney malformations, and genital malformations (particularly in males). Once triploidy is suspected in an infant, a blood chromosome analysis (a karyotype) should be performed to confirm the diagnosis. Additionally, the newer technique, FISH, is advised.
The diagnosis is often suspected in pregnancies due to abnormal growth parameters, abnormalities seen on a sonogram, an abnormal screening test, or an abnormal CVS or amniocentesis result.
The diagnosis in infants is made by physical examination shortly after birth. Severe growth retardation, an abnormal placenta and physical birth defects first raise the suspicion of triploidy. This diagnosis is then confirmed through a chromosome analysis (karyotype) which is blood test performed on the infant. A karyotype is a picture of an individuals chromosomes and in this case will show an abnormal number of chromosomes (69 instead of 46).
The diagnosis in infants with the rare mosaic form of triploidy (one normal cell line and one abnormal cell line) may be suspected shortly after birth due to the presence of growth retardation, asymmetrical growth of the limbs, and other physical birth defects. The diagnosis is then confirmed through a chromosome analysis (karyotype), which, in this case, will show the presence of two cell lines: one normal cell line with 46 chromosomes and an abnormal cell line with 69 chromosomes.
Treatment and management
There is no cure and no treatment for triploidy. Infants that survive to term should receive palliative care, including warmth, nourishment, and comfort, until the parents have a chance to incorporate the diagnosis and make decisions about care options. Surgical correction of birth defects is not indicated given the lethal nature of this diagnosis.
If triploidy is detected during a pregnancy, patients have the option to terminate a pregnancy based upon the lethality of this condition. This is a very personal decision and should be made following complete counseling about the nature and outcome of this diagnosis. If the pregnancy continues, then the mother should be monitored for pre-eclampsia and hyperthyroidism. There is no need for special interventions, such as fetal monitoring or a caesarean section, based solely on the diagnosis of triploidy given the inevitability of the outcome.
Once the diagnosis has been firmly establish, there is no need for heroic measures given the established lethality of the conditions. Infants should be provided with basic supportive care until the family can make decisions.
This diagnosis is devastating for families. The bleak prognosis and lack of treatment can be very shocking. Families should be reassured that there is nothing that they did or did not do that could have prevented the outcome. While grieving is inevitable and appropriate, the family needs time to incorporate the information about the diagnosis. Many families find it helpful to have reminders of their baby, including footprints, photographs, and locks of hair, and the neonatal staff can aid in collecting these materials following the birth of the infant. Parents also need to understand the genetic diagnosis and its implications for future pregnancies. It is important to make sure that they understand the sporadic nature of this diagnosis and that it is unlikely to recur in a future pregnancy.
The prognosis for a fetus or infant with full (nonmosaic) triploidy is very bleak. Many pregnancies end in spontaneous abortion, and those that go to term often result in a stillborn infant or one that dies shortly after birth. The longest recorded survival of an infant with triploidy is 10 months, although this length of survival is exceedingly rare.
Infants with mosaic triploidy (two cell lines: one normal and one with triploidy) often survive pregnancy but generally have multiple birth defects, severe growth abnormalities, and severe mental retardation. Their life expectancy is often dependant on the severity of their associated birth defects.
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Kathleen A. Fergus, MS, CGC