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Projekt - Trisomie 21

Im Jahr 2004 ergab sich aus den Daten des Geburtenregisters Mainzer Modell der Verdacht einer überzufälligen Häufung von Neugeborenen mit Trisomie 21 (Morbus Down, Mogolismus).

 

 
In einem Zeitraum von drei Monate wurden mehr als 5 mal soviel Kinder wie zu erwarten und letztendlich mehr als 3 mal soviel Kinder unter Zugrundelegen eines Möglichen Zufalls konzipiert (beginn der Schwangerschaft). Weiterführende Studien (Ursachenforschung) sind geplant.

 


Hier eine kurze englische Zusammenfassung des bisherigen Studienansatzes

 

 

Report on a cluster of Trisomy 21 (Tri21) cases in the region of
Rheinhessen, Germany, in 2004

Abstract

Since 1990 the population-based Birth Registry Mainz Model monitors all livebirths, stillbirths and abortions of Rheinhessen/Germany. Trisomy 21 (Tri21) is the most important genetic cause of mental retardation The baseline risk for trisomy 21 is 0.6/month. Until July 2004, 18 cases of Tri21 were recorded as conceived in 2003, a threefold increase (RR 3.1) over previous years. Eleven of these cases occurred between June and August, demonstrating a highly significant (p<0,0001) raise. This increase suggests a transient exogenous cause. Hypotheses include the extreme climate between June and August 2003 (>40°C; extremely low ground-water). Planned molecular and case-control studies may shed light on the causation of the temporal cluster of trisomy 21.  

Backround

At a prevalence rate of approximately one in 500, trisomy 21 (Tri21) is the most important genetic cause of mental retardation. Although the chromosomal basis has been known for 40 years, there is still a lack of knowledge regarding the causal factors of non-disjunction in chromosome 21.1 Environmental factors may play a role and exert a deleterious effect during meiosis II, a sensitive period shortly after conception.2,3,4

 

Following the suspicion of a cluster of newborns with Tri21 after the 1987 Chernobyl disaster5, the Mainz Birth Defect Registry was founded in 1990. Its main objective is to monitor the prevalence of congenital abnormalities, including chromosomal aberrations. Comparable to other registries worldwide, it serves as an early warning system for known or suspected teratogens. 

Subjects and methods

The population-based Birth Registry Mainz Model actively registers all live births, induced abortions, stillbirths, and spontaneous abortions after the 16th week of gestation in Rheinhessen, a region with approximately 400000 inhabitants.6 Since February 1990, a total of 48303 newborns (approximately 3500 per year) have been screened, covering about 90% of all infants born in the region of Rheinhessen. Information on 579 abortions has been obtained during the study period. Statistical analysis were carried out by 2x2 tables and by Poisson distribution.  

Results

Between January and June 2004, eight live births with Tri21 were observed, which  exceeds the expected number of about three to four live births within a six-month period. A total number of eight stillbirths and abortions with Tri21 were recorded up to June 2004 . Based on the calculated time of conception, the comparison of the two groups showed that 11 infants were conceived within a  period of three months (June to August 2003). These data led to the suspicion of a cluster, and the month of conception was used as the basis for further analysis.

From April 1989 until today, a total of 102 newborns and fetuses with trisomy 21 were recorded, resulting in an average annual prevalence rate of 6.8, at a ratio of 1:474 (Table 1). Between April 1989 and December 2002, 84 cases of Tri21 were diagnosed, corresponding to an average annual prevalence ratio of 1:538. In 2003, a total of 18 cases were observed (estimated annual prevalence ratio 1:173 based on the assumption of 3150 conceptions). The prevalence ratio (calculated as rate ratio (RR) with a 95% confidence interval (CI)) for the two periods (1989-2002 vs 2003) is 3.1 (1.9-5.2, p<0.0001), indicating a threefold higher risk (Table 2).  

The average monthly prevalence rate (λ) is 0.6 (based on all data),  increasing to 1.5 in 2003, with a peak of five cases in July. Assuming a Poisson distribution of λ = 0.6, the statistical probability (p) for the occurrence of five or more cases in one month is 0.0004, while that of 11 cases in three months is less than 0.0001.

Discussion

The only proven risk factor for an infant with Tri21 is high maternal age (>35 years). In the entire study period, the proportion of mothers older than 34 years consistently ranged at 14%. In 2003, six out of 18 (33%) mothers of children with Tri21 were older than 34 years at the time of conception. In preceding years, the percentage was slightly higher (40%; 34/84). There was no difference in the prevalence of other possible risk factors (e.g. smoking, alcohol consumption, maternal irradiation, fertility drugs, oral contraceptives) between 2003 and  the preceding birth cohort (1989-2002).

Possible hypotheses to explain the recent 2004 cluster include the extreme climatic conditions during the conception period of the Tri21 cluster, i.e. the time between June and August 2003,  which was characterized by extremely hot weather with temperatures above 40°C in this region of Germany, very low water levels of the Rhine River, and extremely low ground-water levels.

Planned molecular studies will focus on the origin of the extra chromosome 21 in the affected infants to determine the timing of the non-disjunction event, i.e. meiosis I vs meiosis II. Case-control studies will evaluate environmental factors, including climatic stress.

Table 1

 

Mainz Model: Cases of Trisomy 21
prevalence by year and month of conception

Year/Month

1

2

3

4

5

6

7

8

9

10

11

12

Total

1989

 

 

 

0

0

1

1

1

0

1

0

0

4

1990

2

0

1

0

0

4

1

0

0

2

0

0

10

1991

0

1

1

0

0

3

1

1

0

0

0

1

8

1992

0

1

1

0

0

0

0

0

0

0

2

0

4

1993

0

1

0

1

2

3

0

0

1

0

0

0

8

1994

1

0

0

0

0

0

0

1

0

0

1

0

3

1995

0

0

2

2

1

0

0

0

0

0

0

0

5

1996

0

1

1

0

0

0

0

0

0

1

1

1

5

1997

0

1

0

2

1

0

0

1

0

0

1

2

8

1998

2

1

0

0

0

1

1

1

1

1

0

2

10

1999

2

0

0

1

2

0

0

0

0

0

0

2

7

2000

0

0

0

0

0

0

0

1

0

2

1

0

4

2001

1

1

0

0

0

0

0

0

2

2

0

0

6

2002

0

1

0

0

0

1

0

0

0

0

0

0

2

2003

0

1

2

0

0

2

5

4

1

2

0*

1*

18

* not yet complete

 

 

 

 

 

 

 

 

 

 

 

 

102

 

 

Table 2

 
Trisomy 21 in the years 1989-2002 compared to 2003