One simple, widely accepted mechanism for generating an aberrant chromosome number, or aneuploidy, is through nondisjunction — a chromosome distribution error that occurs during mitosis when both copies of a duplicated chromosome are deposited into one daughter cell and none into the other. Shi and King 1 challenge this view, concluding that nondisjunction does not yield aneuploid cells directly, but instead gives rise to tetraploid cells that may subsequently become aneuploid through further division.
Here we show that the direct result of chromosome nondisjunction is gain or loss of a single chromosome, which results in near-diploid aneuploidy, not tetraploidy. We suggest that chromatin trapped in the cytokinetic cleavage furrow is the more likely reason for furrow regression and tetraploidization.
Shi, Q. Nature , — Weaver, B. Cell Biol. Babu, J. Matsuura, S. A , — Article Google Scholar. Hanks, S. Nature Genet. Limwongse, C. Mullins, J. Andreassen, P. Cell 12 , — Uetake, Y. Wong, C.
BMC Cell Biol. We report a case of a patient with double aneuploidy—a combination of trisomy 21 and triple X syndrome. The proband had typical features of Down syndrome and did not manifest any symptoms of polysomy X. The patient had hypotonia, a cardiac defect, and an annular pancreas. A clinical diagnosis of Down syndrome was established, but the cytogenetic analysis found two free full trisomies—trisomy 21 Down syndrome and triple X.
Cases of double aneuploidy, combining trisomy 21 and trisomy of a sex chromosome, could be challenging because the patients manifest only symptoms, typical for Down syndrome. The discovery of a second complete free trisomy X in our case was an incidental finding.
This illustrates the importance of the cytogenetic analysis, despite the evident phenotype of trisomy Double aneuploidy DA is a rare genetic phenomenon in humans, and the majority of cases are found in abortive material [ 1 ]. It usually involves an autosomal trisomy such as trisomy 21, 18, or 13 and aneuploidy of the sex chromosomes. The last one could be Klinefelter, Turner syndrome, polysomy X, or polysomy Y [ 2 ].
There are also reported mosaic cases of DA, which may include other autosomes such as chromosome 8 or 14 [ 3 , 4 ]. The clinical presentation of every case would be different, depending on the cytogenetic finding. In this study, we present a case of a full free double aneuploidy, combining both trisomy 21 and triple X syndrome, described for the first time in Bulgaria. The patient was a preterm girl, born in 37 gestational weeks per vias naturales after a second uneventful pregnancy.
The pregnancy was not followed-up by an obstetrician. The birth weight of the patient was g Apgar score was 5 points in 1 min and 6 points in 5 min. The baby girl presented with upslanting palpebral fissures, and the ears were low set and with abnormal outer morphology Fig. She also showed a tendency for tongue protrusion.
The patient had hypotonia. The above described dysmorphic features were suspicious for the presence of Down syndrome. The X-ray showed a normal-sized cardiac silhouette and a dislocated to the right shadow of the right ventricle.
A ventricular and an atrial septal defect were diagnosed after a transthoracic ultrasound of the chest. The patient had tachypnea, two-sided vesicular breathing with crepitations. The child needed a constant supply of oxygen. Every time after the baby was fed, it vomited stomach content, and it could not gain weight. A barium X-ray examination of the abdomen was done, and it was diagnosed with a possible stenosis of the pylorus or the duodenum.
On the 7th day after birth, the girl underwent a surgical correction for annular pancreas, which was constricting the duodenum. The other internal organs, bone, and soft tissues were normal. A blood sample for cytogenetic analysis was collected to prove the clinical diagnosis of trisomy The patient was discharged from the hospital and was clinically improved.
The family was referred to genetic counseling. Cytogenetic analysis of peripheral lymphocytes was performed using Giemsa staining in the Laboratory of Medical Genetics, Varna. An informed consent was received from the family. The proband was diagnosed with double aneuploidy and two free full trisomies—trisomy 21 Down syndrome and triple X syndrome.
Cytogenetic analysis of the parents was not performed. Circles indicate the additional copies of chromosome 21 and X chromosome. The first published case of the same type of double aneuploidy—trisomy 21 together with triple X syndrome was in by Breg et al. We summarized 12 other reported cases through the years Table 1. Even though the individual frequency of the described aneuploidy is not clear, it is estimated that the frequency of DA in general is around 0.
Despite this, the incidence of these cases could be higher than expected, if it is multiplied by the individual frequency of each of these aneuploidies [ 12 ]. The clinical presentation of patients with DA could be different, depending on the cell line, which prevails, the degree of mosaicism, and the type of affected chromosomes.
There could be a combination of symptoms, typical for both observed chromosomal aberrations [ 1 , 16 ]. However, DA of trisomy 21 and a sex chromosome aneuploidy is an exception since there are usually phenotypic traits only of Down syndrome.
This is because trisomies of the sex chromosomes generally do not manifest with facial dysmorphism or congenital anomalies [ 17 ]. This is also observed in our case due to the fact that triple X syndrome is not associated with any clinical severe features [ 18 ].
The main symptoms of our patient are due to the additional copy of chromosome Nevertheless, in cases of triple X syndrome, there may be a developmental delay, learning disabilities, speech problems, behavioral, emotional disorders, and delayed motor skills. Also, there could be menstrual disturbances and early menopause [ 19 ]. This illustrates the importance of regular follow-up of our patient with DA not only for complications due to trisomy 21, but also because of the additional copy of the X chromosome.
In contrast to polysomy X, dysmorphic features of monosomy X could be present right after the birth of the baby—for example, lymphedema of hands and feet [ 20 ].
However, in cases of mosaicism for the Turner syndrome, the dysmorphic features of Down syndrome would be the main reason for genetic testing [ 21 ]. That is why cytogenetic analysis is always required to check for other chromosomal aberrations. Double aneuploidies are the result of nondisjunction of the chromosomes during the meiotic or mitotic division, but the last one would lead to somatic mosaicism. Down syndrome is the most common chromosomal abnormality in humans with an incidence of one in live births.
Although it is the most intensively studied human chromosomal abnormality, little is known about its cause and only advanced maternal age is confirmed as a risk factor [ 17 ]. On the other hand, Klinefelter syndrome is the most common disorder of sex chromosomes in humans, with prevalence of one in males. The classic form is the most common chromosomal disorder, in which there is one extra X chromosome resulting in the karyotype of 47,XXY [ 18 ]. This is also the most commonly described double aneuploidy.
The karyotype is shown on Figure 3 [ 19 ]. The coincidence rate of both Down and Klinefelter syndromes in the same individual is estimated to lie in the range 0. On the other hand, lower values of XXY pattern recorded in older boys and men with Down syndrome suggest that there might be an increased selection against these individuals after birth [ 21 ]. Several cases of double aneuploidy of XXY and trisomy 21 have been published since the first report by Ford et al.
Table 5. However, in children diagnosed with Klinefelter syndrome, a chronic heart disease has only rarely been reported. The phenotypic characteristics of the 4-month-old child had showed the presence of features typical of mongoloid slant. Also, Doppler echocardiogram detection has been showed atrial septal and ventricular septal defects with patent ductus arteriosus, pulmonary hypertension and mild tricuspid regurgitation [ 22 ].
Similarly, a month-old boy was reported with double aneuploidy and a double aortic arch suffered from frequently recurrent severe feeding and respiratory problems [ 23 ]. Some examples of double aneuploidy in patients affected with Down and Klinefelter Syndrome.
Shu et al recently presented a neonate with a double aneuploidy associated with congenital heart defect suffered from cyanosis after birth. The patient had typical features of Down syndrome including hypertelorism, slightly lowest ears with protruding pinna Figure 4.
Doppler echocardiography has been indicated complex congenital heart disease with an ostium secundum atrial septal defect, enlarged right ventricle, and mild tricuspid valve regurgitation. Until now, only eight cases of double aneuploidy associated with CHD defect has been reported [ 24 ]. This abnormality has also been described in a pair of monozygotic twins [ 25 ]. In six sex chromatin surveys of the newborn This was 18 times higher than the indirect estimate for the general population and 30 times higher than the expected frequency based on chance association.
These figures suggested that there was a much higher incidence of double trisomics at birth than would be expected by chance; the most satisfactory explanation for the reduced incidence among older groups was that double trisomics had a much higher mortality during the early years of life than the primary trisomics. The association of Klinefelter Syndrome and Down syndrome in the same siblings has already been referred to and would be expected by chance although this is more difficult to establish.
In particular, three of them, trisomy 21, trisomy 18 and trisomy 13 are the most frequently seen autosomal aneuploidies. Other commonly seen gonosomal aneuploidies are Turner syndrome, Klinefelter syndrome and its variants, poly X syndromes and poly Y syndromes. However, neonatal survey data has revealed that the incidence of XXY and trisomy 21 double trisomy at birth is higher than expected from the incidence of either alone [ 28 ]. The prenatal mortality rate of Downs-Klinefelter syndrome has not been extensively studied.
Compared with either condition alone, the survival rate for the combination of XXY and trisomy 21 appears to be intermediary [ 30 ].
Forrester and Merz reported 1 death in utero 3. Bojesen et al reported no intrauterine deaths in 49 fetuses with prenatally diagnosed Klinefelter syndrome [ 32 ]. These data excluded terminations of pregnancies. Triple X syndrome, also called trisomy X or 47,XXX, is characterized by the presence of an additional X chromosome in each of a female's cells. The frequency of 47,XXX in newborn females is about 1 in and is associated with maternal age.
Most XXX females are clinically normal with normal gonadal function and fertility. Although females with this condition may be taller than average, this chromosomal change typically causes no unusual physical features. Most females with triple X syndrome have normal sexual development and are able to conceive children.
However, there is an increased risk for learning disabilities, reduction in performance IQ, menstrual problems and early menopause Table 1. Triple X syndrome is associated with an increased risk of learning disabilities and delayed development of speech and language skills.
Delayed development of motor skills such as sitting and walking, weak muscle tone hypotonia , and behavioral and emotional difficulties are also possible, but these characteristics vary widely among affected girls and women Figure 5.
Seizures or kidney abnormalities occur in about 10 percent of affected females. Trisomy and triple-X in the same individual has been reported earlier [ 45 , 46 ] and more recently [ 47 - 52 ] and phenotypic features of classical Down syndrome were only seen. However, strabismus, periorbital swelling, scanty eyebrows and microganthia have not been observed in these reports Table 6. Sheth et al reported a case of double aneuploidy showing trisomy 21 and triple-X chromosome in a case of Down syndrome born to young non-consanguineous parents.
The child presented with strabismus, periorbital swelling, scanty eyebrows and microganthia in addition to Down features. Molecular characterization had shown the maternal origin of double aneuploidy with trisomy 21 at meiosis-II and triple-X at meiosis-I [ 51 ]. Approximately 1 in newborn males have a 47,XYY karyotype. Although most 47,XYY patients are clinically normal, they tend to be taller than normal and have an increased tendency for behavioral and learning problems as children and young adults.
Y-chromosome aneuploidy results from paternal meiotic nondisjunction and is not associated with maternal age. Although males with this condition may be taller than average, this chromosomal change typically causes no unusual physical features. Most males with 47,XYY syndrome have normal sexual development and are able to father children. Delayed development of motor skills such as sitting and walking, weak muscle tone hypotonia , hand tremors or other involuntary movements motor tics , and behavioral and emotional difficulties are also possible Table 1.
These characteristics vary widely among affected boys and men. A small percentage of males with 47,XYY syndrome are diagnosed with autistic spectrum disorders, which are developmental conditions that affect communication and social interaction. Most cases of 47,XYY syndrome are not inherited. The chromosomal change usually occurs as a random event during the formation of sperm cells.
An error in cell division called nondisjunction can result in sperm cells with an extra copy of the Y chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra Y chromosome in each of the body's cells. Unlike Down syndrome, the XYY is not associated with increased parental age.
The only consistent phenotypic feature associated with the XYY syndrome is tall stature, which becomes evident at about years of age. These children may have learning difficulties, attention deficits, hyperactivity and increased aggressiveness. However, the behavioral changes appear to be variable and may be modified by the environment in which these children live.
Therefore, it is important to recognize the XYY abnormality at the earliest so that these children can be evaluated periodically and given appropriate care and interventions for learning and behavioral needs. Reddy observed only 22 cases of double aneuploidy, such as XXY and 21 trisomy among spontaneous abortuses that the frequency even less than expected if the two aneuploidy events were independent of each other. They also occurred at an older mean maternal age [ 58 ].
Koken et al presented the patient had typical features of Down syndrome, however, phenotypic features of XYY was not present Figure 6. In addition, the patient also had atrial septal defect, multiple trabecular small ventricular septal defect, and moderate degree of pulmonary hypertension [ 60 ]. Parihar et al reported a 5-year-old boy with the clinical features of Down syndrome.
Cytogenetic analysis has been showed a mosaicism for a double aneuploidy, Down syndrome and XYY. In the intervening half-century, the importance of numerical chromosome abnormalities to human disease pathology has been well-documented. Taken together, these studies established aneuploidy as the leading known cause of congenital birth defects and miscarriage and demonstrated that most aneuploid conceptuses perish in utero.
The occurrence of double aneuploidy i. Although aneuploidies are common structural chromosomal abnormalities, double aneuploidies involving chromosomes 21 and sex and autosomal chromosomes are very rare. Trisomy 21 and numerical sex chromosome anomalies are common chromosomal disorders, with a birth incidence of to , respectively [ 30 ].
The chances of two chromosomal anomalies occurring in a single conceptus are a rare event and the reported incidence varies from 0. Various double aneuploidy associations are summarized in Tables above. In general, the double aneuploidies which involve the sex chromosomes as well as trisomy have phenotypic features representative of both aneuploidy conditions.
These usually have the features of both conditions although the more serious condition usually masks the less serious. The presence of an associated sex chromosome abnormality in children with Down syndrome may not be clinically evident until puberty. The existence of two chromosomal abnormalities in the same individual is relatively a rare phenomenon. Both these aneuploidies could have the same or different parental origin [ 62 ].
Both aneuploidies arise as a result of nondisjunction in maternal meiosis II [ 47 ] and these results support the hypothesis that a segregation defect at the cellular level may cause nondisjunction involving more than one chromosome. Most reported cases of double aneuploidy are presented in the form of spontaneous abortions. Most cases of double aneuploidies in live births involve the sex chromosomes combined with either trisomy 13, 18 or 21, i.
Double aneuploidies are observed in 0. For women 35 years and older, the rate of trisomy 21 is increased to 1 per pregnancies when data from 2 sources are combined. The rate of Klinefelter syndrome in pregnancies carried by women 35 years or older is 1 per The nonrandom aspect of double aneuploidy provides evidence that a hereditary predisposition to nondisjunction exists, with one chromosomal imbalance increasing the risk of another to occur, which suggests that both events arise from the same parent.
Nondisjunction in cases of double trisomy has been found to be entirely maternal in origin, entirely paternal in origin, and both maternal and paternal in origin.
In such cases in which the additional chromosomes originate from different parents, the two errors may be coincidental and unrelated to a genetically determined nondisjunction. Abnormal separation of chromosomes may occur in older individuals because of dysfunction of structures related to chromosome separation, such as the spindle apparatus and kinetochore.
Trisomy 21, resulting in Down Syndrome DS , is the most common autosomal trisomy among live-born infants and is caused mainly by nondisjunction of chromosome 21 within oocytes. Risk factors for nondisjunction depend on the parental origin and type of meiotic error.
For errors in the oocyte, increased maternal age and altered patterns of recombination are highly associated with nondisjunction. Studies of normal meiotic events in humans have shown that recombination clusters in regions referred to as hotspots. The results from early studies demonstrated that most aneuploidies are due to errors in maternal meiosis and that increasing maternal age is a powerful contributor to the occurrence of aneuploidy. However, studies during the past years have also implicated events that occur at the onset of female meiosis in the fetal ovary and during the protracted dictyate arrest.
The duration of the division 10 to 50 years and beyond provides ample opportunity for errors to occur and to accumulate, which is a feature that has been the basis of a number of hypotheses to explain the maternal age effect. Indeed, the emerging picture indicates that aneuploidy is not due to a single causal factor but involves a complex constellation of effects that begins in utero, continues throughout the reproductive lifespan of the woman, is exacerbated by age and is facilitated by the unique features of cell cycle control in the oocyte.
The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Increased maternal age and altered number and location of recombination events have been found to be associated with maternal meiotic errors involving chromosome 21 [ 65 ].
The overwhelming majority of trisomy 21, or Down syndrome, is caused by the failure of chromosomes to separate properly during meiosis, also known as chromosome nondisjunction.
0コメント