Trisomy 21 Down syndrome. II. Structural chromosome rearrangements in the parents.

In a series of 374 families with Down syndrome progeny, structural chromosome rearrangements were detected in the parents of six children with regular trisomy. The aberrations were reciprocal translocations and inversions. In all three informative families, the parent who transmitted the extra chromosome was not the one with the structural rearrangement. Among the three non-informative families there was one in which both parents carried different reciprocal translocations. In two other families a chromosome aberration was detected: a triple X mother and a father with a Philadelphia chromosome. Omitting the four parents with possible biased ascertainment, 0.4% had a chromosome rearrangement. When the parents with constitutional chromosome aberrations and those with mosaicism, described previously, are combined, the frequency of chromosomally abnormal parents lies between 1.9% and 3.2%. When correlated with parental transmission of the extra chromosome, mosaicism rather than structural rearrangements appears to be of etiologic significance.

The fragile X in cattle.

In search of an animal model for the human fragile X syndrome, the chromosomes of Holstein cows were examined. This breed was chosen because of previous studies on the baldy calf syndrome. An achromatic gap was observed at a specific site on the X chromosome closer to the centromere than that identified in humans. This unstained gap was found in 3%-4% of cells of the following four animals: an affected calf, her sister, their mother, and an unrelated Holstein cow. The bovine fragile X may not be analogous to the human fragile X but its location may be important as a genetic marker in linkage studies involving the loci for hypoxanthine phosphoribosyltransferase (HPRT) and glucose-6-phosphate dehydrogenase (G-6-PD).

Detection and interpretation of two different cell lines in triploid abortions.

Among a series of 98 triploid abortions, there were four specimens with two cells lines. The detection of two clones was by Q-banding of chromosomes. Two of these four specimens were dizygotic twins, the third was either a mosaic or monozygotic twins with loss of a sex chromosome from one twin and the fourth was best explained as a chimaera which arose by fertilization of two female pronuclei by three sperms. These two unusual specimens had XYY sex chromosome complements which is rare among triploids. Two additional specimens were diagnosed clinically as possible twin pregnancies but only one cell line was identified from tissue culture. The frequency of twins was of the order of 1/33.

Trisomy 21 Down syndrome. Parental mosaicism.

The lymphocyte chromosomes of trisomy 21 Down syndrome patients and their parents in a random series of 374 families were analyzed, the objective being the identification of parental mosaicism. The numbers of parents in whom at least two trisomy 21 cells were detected were seven mothers and three fathers, a frequency of 2.7% of families. Confirmation of mosaicism was by identification of parental transmission of the extra chromosome to the progeny, by repeat chromosome analysis, and/or by the presence of more than one affected child. If to these are added six others in whom only one trisomic cell was detected, but with no other supporting evidence, the frequency could be as high as 4.3%. Differences in parental age at the birth of Down syndrome progeny may be accounted for by differences in frequencies of mosaicism in germ cells and somatic tissue. Mosaicism was found more frequently in the mothers than in the fathers, but more data are required for confirmation of a real difference.

Triploidy and chromosomes.

In a total sample of 105 triploid spontaneous abortions and live-born and stillborn infants, the parental origin could be determined in 77%. Dispermy was the most common cause of this abnormality. Among the digynic triploids 69% resulted from retention of the second polar body. Parental ages did not differ from those of the general population except for 10 aneuploid triploids with significantly elevated parental ages. In five sibships, simple aneuploidy in another pregnancy was observed, four of them being potentially viable. Two sisters had triploid conceptions. There were four twin pregnancies, a frequency of one in 26. Only two triploids had an XYY sex chromosome complement, one of which was mosaic with loss of an autosome and the other was a chimera. A frequency of almost 50% of mothers exposed to preconception abdominal radiation is suggestive of an association between radiation and triploidy and requires further investigation.

Additional evidence for fragile X activity in heterozygous carriers.

The result of a previous study showing an association between mental development and fragile X activity in heterozygous females is given further support by similar investigations of three additional kindreds. The increased frequency of demonstrable fragile X chromosomes in mentally retarded females appears to be due to an increase in the active fragile X while the inactive marker X remains at a similar low frequency in all heterozygotes whether retarded or not. The frequencies of the active fragile X separated the normal and abnormal subjects into two distinct populations. The suggested inverse correlation between the number of lymphocytes with detectable fragile X chromosomes and advancing age can be attributed to ascertainment biases.

Twinning rate in spontaneous abortions.

An unselected series of spontaneous abortions and their mothers were karyotyped with Q-bands to obtain a frequency of twin conceptions lost during the first trimester. Among 661 spontaneous abortions, 15 twin pairs were identified including two sets of conjoined twins. Analysis of Q-band variants permitted the exclusion of cases with two cell lines that could be attributed to maternal contamination or mosaicism. The twinning rate among spontaneous abortions was 1/44 compared with 1/103 live births and stillbirths in the Ontario population. If Weinberg's differential method is applied to these data, the frequency would be as high as 1/30 under the assumption that the incidence of monozygotic twins among abortions is the same as that for live births.

45,X/46,XX mosaicism in discordant monozygotic twins.

Monozygotic twins discordant for Turner's syndrome were both mosaic for 45,X/46,XX in the blood with the same low frequency of 2% to 3% 45,X cells. However, the fibroblasts of the abnormal girl were all uniformly 45,X whereas her normal twin had only 46,XX cells. Monozygosity was confirmed by genetic markers, chromosome variants, and a single monochorionic placenta with a shared vascular circulation. The mechanism by which this disparate pair developed from a single zygote is suggested.

Birth weight and placental proximity in like-sexed twins.

In addition to zygosity, the type of placentation has proven to be an important variable in twin studies. A number of quantitative traits in human twins have been found to be influenced by chorion type. Our study confirms an earlier finding that there is larger within-pair birth weight variability in dichorionic twins with fused placentas than in those with separate placentas. This finding emphasizes the importance of detailed twin placental examinations to help identify traits that may be influenced by prenatal environmental influences.

Two children with deletion of the long arm of chromosome 4 with breakpoint at band q33.

A 10-year-old boy with developmental delay, craniofacial dysmorphia, malformations of the hands and feet and a cardiac malformation was found to have a small deletion of the distal region (q33 leads to qter) of the long arm of a chromosome 4. The clinical findings in this case are compared with those of a 17-week-old girl recently found to have the same deletion. Two additional patients with similar small deletions have been described in the literature. The similarity among the cases suggests the possibility of a deletion (4) (q33) syndrome. The major features of the syndrome are similar to those of larger deletions of the long arm of chromosome 4 and include mental and growth retardation, craniofacial dysmorphia including upslanting palpebral fissures, depressed nasal bridge, anteverted nares, abnormally shaped ears and micrognathia, and cardiac defects.

Activity of the fragile X in heterozygous carriers.

Chromosome analyses with conventional stain, Q- and G-banding, and R-banding with 5-bromodeoxyuridine (BrdU) incorporation were performed on the lymphocytes of two sisters who are heterozygous for the fragile X chromosome and clinically diagnosed as slow learners. Two heterozygous relatives with normal intelligence were used as controls. The frequencies of the active fragile X for the "slow" females were 100/129 (77.5%) and 85/120 (70.8%) compared with 40/78 (51.3%) and 10/32 (31.3%) for controls, the difference being highly significant. These observations are consistent with the Lyon hypothesis: activity of the abnormal X could account for the reduction in mental ability of some heterozygous females. Similar to retarded males with the fragile X chromosome, our slow learners had verbal scores that were lower than performance scores.

Partial 11q trisomy syndrome.

The syndrome caused by partial trisomy for 11q is reviewed on the basis of a patient of our own and 20 cases (including a stillbirth) from the literature. The main symptoms are presented in Tables 1 and 2. The syndrome can be suspected when, in addition to mental retardation, the following characteristics are present: short nose, long philtrum, micrognathia, retracted lower lip, and micropenis in males. In 15 families, the mother was a balanced translocation carrier and in four the father. The translocation had arisen de novo in two patients. The chromosome number was 46 in 13 affected individuals (including the stillbirth) and 47 in eight. In seven of the latter patients the other translocation chromosome was 22, and in one, chromosome 9. The breakpoints on 11q ranged from 11q121 to 11q232 (Fig. 5). There is no apparent correlation between the length of the trisomic segment and the number or severity of the symptoms (Table 2). This could be explained by assuming that most, if not all, symptoms are caused by trisomy for the Q-dark region distal to 11q232, whereas trisomy for the rest of the 11q up to q121 has few phenotypic effects. These observations support the idea that Q-dark segments, and especially certain hot spots, have a high gene density in contrast with Q-brighter regions.

A rare case of mosaic Down syndrome 46,XY/46,XY, -21, +i(21q).

Detailed studies were carried out on a patient with a rare type of mosaicism which gave rise to an effective 21 trisomy. The clinical signs of Down syndrome were minimal. The cytogenetic interpretation is that the abnormal clone had an isochromosome derived from a maternal No. 21. The normal cell line appears to be replacing the abnormal clone.

Radiation-induced nondisjunction.

The methodology and results of epidemiological studies of the effects of preconception diagnostic x-rays of the abdomen on chromosome segregation in humans are described. Many studies have been conducted in a number of different countries. The vast majority show the same positive, though not significant, trend to increased nondisjunction among the offspring of irradiated women. The results of the various studies, however, cannot be pooled because of differing methodologies used. A worldwide co-operative project with standardized methodology is recommended. Such a study should identify the parental origin of the nondisjunctional event before etiological factors are investigated. Abnormal chromosome segregation during mitotic division has been inducted experimentally by the in vitro exposure of human lymphocytes to a low dose of 50 R gamma irradiation. First meiotic nondisjunction has been successfully induced by whole body exposure of female mice to a low dose of radiation. Further experiments are being conducted to try to induce abnormal segregation during second meiotic division. Because of difficulties encountered in trying to estimate total gonad doses resulting from differing techniques employed by radiologists and other health personnel, no attempt has been made to estimate the doubling dose nor minimum safe dose regarding the effects of radiation on chromosome segregation in humans. The question of time-related repair of the mechanism involved in chromosome segregation is raised.

Comparisons of dermatoglyphic patterns in monochorionic and dichorionic monozygotic twins.

The data presented here indicate that different influences affect dermatoglyphic pattern development in MC-MZ and DC-MZ twins. Only five of 84 variables had significant mean differences but their clustering suggested a real difference in mean placement of the atd angle. Nineteen of 84 variables had significantly different within-pair mean squares for the two twin types. Larger numbers of twins will be required to obtain accurate estimates of the magnitude of the dermatoglyphic differences between MC-MZ and DC-MZ twins. Studies of dermatoglyphics in MC-MZ and DC-MZ twins are important to the understanding of factors which influence early embryonic development and when better documented may provide a mechanism for retrospectively diagnosing placental type of MZ twins.