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Introduction
Parents of trisomy 21 children (proband) address questions not only
about the risk of recurrence of the disease for other future children (sibship
of proband) but as well for second degree relatives (nephews of probands) or
third degree (first cousins of probands). After excluding cases due to
translocations, the risk of recurrence for sibships has been estimated from
prenatal diagnoses done for women with a previous trisomy 21 child. In a sample
of 297 women this risk was approximately 1 per cent without considering the
mother's age at the birth of the proband (Daniel et al., 1982). This risk
differed according to mothers' ages at amniocentesis in a study based on 2890
prenatal diagnoses from 12 European countries (Steve et al., 1984). The
estimated risk was 1.3 per cent when the mother's age is 34 years or less at
amniocentesis and 1.8 per cent if the mother is older. The risk is not clearly
estimated for distant relatives.
In a case-control study, we compared the occurrence of Down syndrome
in families of trisomy 21 and of healthy children. Since the frequency of
miscarriages is also important, the reproductive histories of mothers was
ascertained.
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Material and methodsHaut
Population
As described by Berr et al. (1989), we conducted our study in the
outpatients department of Hôpital Necker-Enfants Malades (Paris), on a group
of children with classical cytogenetically confirmed trisomy 21 (n = 188) and a
control group of normal children affected by ordinary diseases, mostly asthma
and allergy (n = 185). All familial relationships were defined in reference to
the child.
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Questionnaire
Demographic and detailed medical characteristics of the children,
their parents (mother and father), uncles and aunts and their first cousins
were provided by the children's parents. The existence of any important
malformation or mental retardation in the families was recorded. The occurrence
of Down syndrome in a relative was based on information provided by the
proband's family, but was not documented cytogenetically.
The total number of first cousins was ascertained for each family.
The obstetrical history of the proband's mother was recorded: total number of
pregnancies births and miscarriages. Mothers provided information which allowed
us to distinguish early miscarriages (before 3 months of amenorrhea) from late
miscarriages (after 3 months of arnenorrhea). We did not register maternal age
at the time of miscarriage.
Parents of patients and controls were similarly interviewed at the
hospital by two of us (Claudine Berr and Elsa Borghi). A form was used to
record, at hone, information that was not available at the time of the
interview. Parents were encouraged to obtain data from other family members
whenever possible.
Nearly all the parents approached agreed to participate. Children
whose parents were separated or the father unknown were excluded.
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Analysis
The rates of recurrence were obtained for each kinship category as
the ratio of reported Down syndrome cases to the total number of relatives. The
frequency of Down syndrome among the different kinship categories was
calculated for age of the proband's mother at birth (< 35 and >= 35
years) to determine if risk values differed from relatives of probands whose
mothers were younger than 35 in comparison with those whose mothers were older
than 35.
Variance analysis was used to compare quantitative items.
Statistical analysis of categorical data was performed using the chi-square
test or the one-tailed Poisson test.
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ResultsHaut
Sample characteristics
The mean age of the children was similar in the two groups : 7.4
years for trisomy 21 group, 7.9 years for controls. Birth rank was higher for
trisomy 21 children than for controls : 2.33 versus 1.59 (p <
10-4). Maternal age at time of birth was significantly higher in the
trisomy 21 group as shown in figure 1. There were 118 trisomic children and 167
controls whose mother's age was less than 35 at the time of birth.
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Recurrence risks of Down syndrome in
relatives
Among the 314 sibs of probands (table I), there was no case of
trisomy 21. Fifteen Down syndrome cases were reported in 14 families of
trisomic probands, five of these affecting close relatives (uncles or aunts and
first cousins) and ten more distant. Six cases were described in five control
families, two of which afflicting close relatives.
The incidence of Down syndrome in close relatives of trisomic
children was similar to that in the control families, whatever the maternal age
at birth. Other cases were reported for more distant relatives (great uncles or
aunts, first cousins of parents and their descendants), ten within trisomy 21
families and three within controls. It was not possible to perform comparisons
for more distant relatives, for which the total number of subjects was not
known.
TABLE I. - Occurrence of Down syndrome in different kinship
categories.
| Age of probant's mother at time of birth |
< 35 years old | > 34 years old | Total |
Prop with DS | ‰
affected | Prop with DS | ‰
affected | Prop with DS | ‰
affected |
Sibs | T21 | 0/155 | | 0/159 | | 0/134 | |
| C | 0/185 | | 0/23 | | 0/208 | |
uncles/Aunts | T21 | 1/669 | 1.5 | 1/374 | 2.7 | 2/1043 | 1.9 |
| C | 1/826 | 1.2 | 0/83 | | 1/909 | 1.6 |
First
cousins | T21 | 3/1095 | 2.7 | 0/780 | | 3/1875 | 1.6 |
| C | 1/1189 | 0.9 | 0/125 | | 1/1314 | 0.8 |
Prop with DS: stands for proportion with Down
syndrome
T21: stands for family members of trisomy 21 probands.
C : stands for family members of control probands. |
TABLE II. - Reproductive history reported by mothers of the
two groups.
| Age of probant's mother at time of birth |
< 35 years old | > 34 years old | Total |
N | mean | N | mean | N | mean |
Mean age of mothers at time of
study | T21 | 118 | 34.6 | 70 | 47.1 | 188 | 39.2*** |
| C | 167 | 34.6 | 18 | 45.9 | 185 | 35.7 |
Total
pregancies | T21 | 329 | 2.79* | 284 | 4.06** | 613 | 3.26*** |
| C | 408 | 2.44 | 60 | 3.33 | 468 | 2.53 |
| | N | % total
pregancies | N | % total pregancies | N | % total
pregancies |
Miscarriages | T21 | 39 | 11.8* | 36 | 12.6 | 75 | 12.2* |
| C | 30 | 7.3 | 9 | 15.0 | 39 | 8.3 |
T21: stands for family members of trisomy 21 probands.
C : stands for family members of control probands.
P value for comparison between T21 and C : * P
= 0.05, ** P =
0.01, *** P = 0.001 |
 Fig. 1. - Distribution of maternal age at birth
of proband
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Miscarriages
Mothers of probands reported more pregnancies than in the control
group (table II) whatever their age at the time of the proband's birth. The
trisomy 21 mothers' group reported more miscariages (12.2 %) than the mothers
in the control group (8.3%, p=0.05). This increase is significant for maternal
ages less than 35 years at the time of proband's birth. It cannot be attributed
to differences in mean age at the time of the study. The distinction between
early and late miscarriages did not show any substantial differences between
the trisomy 21 group and the controls.
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Discussion
Our data show that the occurrence of Down syndrome among close
relatives of trisomy 21 children is not elevated when compared with the
incidence of the disease in control families. The low sibling number does not
allow us to estimate the risk for sibs but our results do not support an
increased incidence of Down syndrome among second and third degree relatives of
trisomy 21 children.
Although our sample size was not very large, we must point out that
our study was designed to try to protect us against biases which may have
interfered in previous reports. In order to establish the risk of Down syndrome
in relatives of trisomy 21 patients, studies starting from unselected Down
syndrome probands and unbiased controls are required. Furthermore,
underreporting of Down syndrome cases appears to be greater for distant than
for close relatives. Moreover, omissions are more frequent in controls than in
trisomy 21 families. We restricted our analyses to close relatives and we
ascertained children not referred for genetic counselling. Down syndrome
children included in our study when at the hospital for medical and
psychological follow up. Control children were referred to the hospital for
benign diseases, not related to genetic problems. Total number of Down syndrome
cases was 7 out of 5,663 subjects. The rate observed was close to the rate of 1
per 800 liverbirths observed in the general population.
Tamaren et al. (1983) reported in 219 families of trisomy 21 children
compared to 247 control families, an increased recurrence of trisomy 21 among
second and third degree relatives of probands. Several factors interfere with
the interpretation of their data (Ten Kate et al., 1984 ; Hook, 1985). The
families under study initially requested genetic counselling for Down syndrome
and may represent a biased sample with more Down syndrome cases than usual.
Control families requested genetic counselling for non-chromosomal disorders,
including pregnant women who were seen for amniocentesis to screen for possible
chromosome anomalies due to advanced maternal age. Abuelo et al. (1986), using
a similar study design for 296 families of trisomy 21 children and 336 control
families, did not confirm an increased risk for second or third degree
relatives of trisomic children. In 141 families of Down syndrome children,
Eunpu et al. (1986) did not demonstrate an increased occurrence of trisomy 21
for uncles and aunts of probands, as compared with the general population.
Several mechanisms have been proposed to explain a possible recurrence of
trisomy 21(Ferguson-Smith, 1983). One is the existence of a predisposing factor
to non-disjunction. To test this hypothesis, different markers which may be
implicated in non-disjunction have been examined. DNA polymorphism haplotypes
were studied in families of trisomic 21 children without conclusive results
(Antonorakis et al.,1985). Silver-staining variants of the nucleolar organizer
region (NOR) were reported to be more frequent among parents of children with
trisomy 21 (Jackson- Cook et al.,1985). On the other hand, Spinner et al.
(1989) did not find an elevated risk for non disjunction of chromosome 21 in
individuals with silver-staining variants.
Another hypothesis to explain the recurrence of trisomy 21 is loss,
with aging, of the women's ability to eliminate selectively aneuploid fetuses
(Giraud et al., 1975). This failure night explain the increase in frequ-ency of
trisomy 21 with advanced maternal age. It is difficult to propose a similar
mechanism explaining the recurrence of trisomy 21 among "young " women at the
tine of birth of the first affected child. Moreover, Lippman and Aymé (1984)
have found an increased rate of miscarriages in groups of " young " women,
especially those under 24 years. Spontaneous abortions are related to
chromosomal abnormalities in at least 50 °/o of the cases (Scrimgeour et
Cockburn, 1979). In our study, mothers under 35 at the birth of the proband
have a higher incidence of miscarriages in the trisomy 21 group than in the
control group. The slight increase observed might be subject to memory bias and
does not allow us to propose new arguments in favor of or against one or the
other hypothesis. Only a prospective study which would require a very large
sample and long follow-up could help to answer this question. The elevated
maternal age remains the only identi-fied risk factor for trisomy 21. Our study
suggests that the risk of trisomy 21 among second and third degree relatives of
an affected child is not increased. This is to be taken into consideration at
genetic counselling.
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References
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