Risk of down syndrome in relatives of trisomy 21 children

Claudine BERR1, Elsa BORGHI2, Marie-Odile RETHORÉ2, J. LEJEUNE2, Annick ALPEROVITCH1

BERR Claudine, BORGHI Elsa, RETHORE Marie-Odile, RETHORÉ Marie-Odile, LEJEUNE J., ALPEROVITCH Annick. - Risk of Down syndrome in relatives of trisomy 21 children. A case-control study. Ann Génét, 1990, 33, n° 3, 137-140.

Résumé :

We conducted a case-control study in families of Down syndrome children with classical trisomy 21 (n =188) and in a control group of families of children referred to the same hospital for benign diseases (n -185). The low sibling number does not allow any conclusion about the risk for sibs but our results do not support an increased incidence of des Down syndrome among second and third degree relatives of trisomy 21 children. The choice of the control group and the restriction to close relatives risque protect us against biases which nay have interfered in previous studies reporting recurrence in families.




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.


Material and methods



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.



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.



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.




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.


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 oldTotal
Prop with DS‰ affectedProp with DS‰ affectedProp with DS‰ affected
First cousinsT213/10952.70/7803/18751.6
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 oldTotal
Mean age of mothers at time of studyT2111834.67047.118839.2***
Total preganciesT213292.79*2844.06**6133.26***
N% total preganciesN% total preganciesN% total pregancies

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



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.



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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