European Journal of Pediatrics

, Volume 165, Issue 8, pp 566–568 | Cite as

MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor?

  • Heiko ReutterEmail author
  • Regina C. Betz
  • Michael Ludwig
  • Thomas M. Boemers
Short Report


Apart from Husmann and Vandersteen [in: Gearhart JP, Matthews R (eds) The Epispadias-Exstrophy Complex. Kluwer, New York, pp 199–206, 1999], we report only the second case of Down syndrome (DS) associated with exstrophy of the bladder (EB). Besides the appearance of DS, the newborn exhibited a complete atrioventricular canal (CAVC) and classical EB, including diastases of the symphysis, an epispadic penis and an open bladder plate. Despite current recommendations, the mother had not supplemented her intake of folic acid during the periconceptional period. In a comparable case, Al-Gazali et al. (Am J Med Genet 103:128–132, 2001) found the homozygous 677T allele of the methylenetetrahydrofolate (MTHFR) gene 677C→T polymorphism in a mother and her child with DS and cervical meningomyelocele. They found that the mother, who also had not supplemented her folic acid intake, had a secondarily altered folate status with an increased homocysteine level, suggesting that the homozygous TT mutation in the MTHFR gene in both mother and her child had contributed to the presentation of DS and a neural tube defect. The combined clinical findings of the present case and the observations of Al-Gazali et al. led us to investigate the 677C→T polymorphism in our mother–child pair. Likewise we found that mother and child were homozygous for the mutant 677T allele. Our findings support the suggestion of Al-Gazali et al. that the MTHFR 677TT could be a mutual genetic risk factor for the co-occurrence of trisomy 21 and midline defects, the risk of which may be reduced by periconceptional folic acid supplementation.


Exstrophy of the bladder Epispadias MTHFR polymorphism Down syndrome 



R.C.B. is supported by an Emmy Noether research grant from the Deutsche Forschungsgemeinschaft (DFG) and by a grant of the BONFOR programme of the Medical Faculty of the University of Bonn.


  1. 1.
    Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M, Bakir M, Hamid ZA, Adulrazzaq Y, Dawodu A, James SJ (2001) Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect. Am J Med Genet 103:128–132CrossRefPubMedGoogle Scholar
  2. 2.
    Botto LD, Mulinare J, Erickson JD (2002) Occurrence of omphalocele in relation to maternal multivitamin use: a population-based study. Pediatrics 109:904–908CrossRefPubMedGoogle Scholar
  3. 3.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuve LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 10:111–113CrossRefPubMedGoogle Scholar
  4. 4.
    Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, Pogribna M, Rozen R, James SJ (2000) Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 67:623–630CrossRefPubMedGoogle Scholar
  5. 5.
    Husmann DA, Vandersteen DR (1999) Anatomy of the cloacal exstrophy. In: Gearhart JP, Matthews R (eds) The epispadias-exstrophy complex. Kluwer, New York, pp 199–206Google Scholar
  6. 6.
    Li D, Pickell L, Liu Y, Wu Q, Cohn JS, Rozen R (2005) Maternal methylenetetrahydrofolate reductase deficiency and low dietary folate lead to adverse reproductive outcomes and congenital heart defects in mice. Am J Clin Nutr 82:188–195PubMedGoogle Scholar
  7. 7.
    Ludwig M, Utsch B, Reutter H (2005) Genetic and molecular biological aspects of the bladder exstrophy-epispadias complex (BEEC). Urologe A 44:1037–1044CrossRefPubMedGoogle Scholar
  8. 8.
    Mastroiacovo P, Robert E, Källén B (1999) Is there an association of Down syndrome and omphalocele? Am J Med Genet 82:443CrossRefPubMedGoogle Scholar
  9. 9.
    Mills JL, Druschel CM, Pangilinan F, Pass K, Coc C, Seltzer RR, Conley MR, Brody LC (2005) Folate-related genes and omphalocele. Am J Med Genet 136A:8–11CrossRefGoogle Scholar
  10. 10.
    O’Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M, Scott JM, Mills JL (2002) MTRR and MTHFR polymorphism: link to Down syndrome? Am J Med Genet 15:151–555CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Heiko Reutter
    • 1
    • 2
    Email author
  • Regina C. Betz
    • 1
  • Michael Ludwig
    • 3
  • Thomas M. Boemers
    • 4
  1. 1.Institute of Human GeneticsUniversity of BonnBonnGermany
  2. 2.Department of PediatricsUniversity of BonnBonnGermany
  3. 3.Department of Clinical BiochemistryUniversity of BonnBonnGermany
  4. 4.Department of Pediatric Surgery and Pediatric UrologyChildren’s HospitalKölnGermany

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