Skip to main content Accessibility help
×
Home
  • Print publication year: 2007
  • Online publication date: August 2009

13 - Developmental disorders

Summary

An understanding of the complex processes that underlie the transition from zygote to newborn infant remains one of the major unsolved challenges in human biology. Failure of key steps in early embryogenesis leads to arrested development and embryonic wastage in a substantial proportion of conceptions (Wilcox et al., 1999). Interference with later developmental pathways which mediate the processes of morphogenesis and organogenesis can also lead to fetal demise but equally can produce a phenotypic effect evident at term. This chapter discusses, with selected examples, our current understanding of the influence that genetic and environmental factors have on these complex developmental processes in humans.

The medical significance of developmental disorders

Developmental disorders in humans are diverse in nature and individually relatively rare, but as a group constitute a “common disease”. Improvements in their recognition and pathogenesis, both as isolated entities and as components of syndromes, have been greatly aided by advances in the clinical speciality of dysmorphology and the construction of clinical databases which catalogue rare associations of phenotypic features (Donnai and Read, 2003).

The overall birth prevalence of disorders which are primarily considered to be due to defective morphogenesis is estimated to be between 2 and 3% (Kalter and Warnaky, 1983). If malformations associated with still births and abnormalities which do not present a requirement for significant medical intervention are included in this estimate, the figure rises to ∼ 5%.

Related content

Powered by UNSILO
References
Amiel, J. and Lyonnet, S. (2001). Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet, 38, 729–39.
Badner, J. A., Sieber, W. K., Garver, K. L. and Chakravarti, A. (1990). A genetic study of Hirschsprung disease. Am J Hum Genet, 46, 568–80.
Barbera, J. P., Rodriguez, T. A., Greene, N. D.et al. (2002). Folic acid prevents exencephaly in Cited2 deficient mice. Hum Mol Genet, 11, 283–93.
Belloni, E., Martucciello, G., Verderio, D.et al. (2000). Involvement of the HLXB9 homeobox gene in Currarino syndrome. Am J Hum Genet, 66, 312–19.
Berry, R. J., Li, Z., Erickson, J. D.et al. (1999). Prevention of neural-tube defects with folic acid in China. N Engl J Med, 341, 1485–90.
Bodian, M. and Carter, C. O. (1963). A family study of Hirschsprung's disease. Ann Hum Genet, 26, 261–77.
Bolk-Gabriel, S., Salomon, R., Pelet, A.et al. (2002). Segregation at three loci explains familial and population risk in Hirschsprung disease. Nature Genet, 31, 89–93.
Bosi, G., Garani, G., Scorrano, M., Calzolari, E. and IMER Working Party. (2003). Temporal variability in birth prevalence of congenital heart defects as recorded by a general birth defects registry. J Pediatr, 142, 690–8.
Botto, L. D., Moore, C. A., Khoury, M. J. and Erickson, J. D. (1999). Neural-tube defects. N Engl J Med, 341, 1509–19.
Botto, L. D., Mulinare, J. and Erickson, J. D. (2002). Occurrence of omphalocele in relation to maternal multivitamin use: a population-based study. Pediatrics, 109, 904–8.
Carter, C. O. and Evans, K. A. (1969). Inheritance of congenital pyloric stenosis. J Med Genet, 6, 233–54.
Carter, M., Ulrich, S., Oofuji, Y., Williams, D. A. and Ross, M. E. (1999). Crooked tail (Cd) models human folate-responsive neural tube defects. Hum Molec Genet, 8, 2199–204.
Carrasquillo, M. M., McCallion, A. S., Puffenberger, E. G.et al. (2002). Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet, 32, 237–44.
Castilla, E. E., Lopez-Camelo, J. S., Campana, H. and Rittler, M. (2001). Epidemiological methods to assess the correlation between industrial contaminants and rates of congenital anomalies. Mutat Res, 489, 123–45.
Chambers, C. D. and Jones, K. L. (2002). Is genotype important in predicting the fetal alcohol syndrome?J Pediatr, 141, 751–2.
Cohen, M. M. (1997). The child with multiple birth defects. 2nd edn. Oxford, New York: Oxford University Press.
Correa, A., Botto, L., Liu, Y., Mulinare, J. and Erickson, J. D. (2003). Do multivitamin supplements attenuate the risk for diabetes-associated birth defects?Pediatrics, 111, 1146–51.
Czeizel, A. E. and Dudás, I. (1992). Prevention of the first occurrence of neural tube defects by periconceptual vitamin supplementation. N Engl J Med, 327, 1832–5.
Donnai, D. and Read, A. P. (2003). How clinicians add to knowledge of development. Lancet, 362, 477–84.
Duncan, S., Mercho, S., Lopes-Cendes, I.et al. (2001). Repeated neural tube defects and valproate monotherapy suggest a pharmacogenetic abnormality. Epilepsia, 42, 750–3.
Edwards, J. H. (1960). The simulation of Mendelism. Acta Genet, 10, 63–70.
Edwards, M. J., Saunders, R. D., Shiota, K. (2003). Effects of heat on embryos and foetuses. Int J Hyperthermia, 19, 295–324.
Falconer, D. S. (1965). The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann Hum Genet, 29, 51–71.
Fleming, A. and Copp, A. J. (1998). Embryonic folate metabolism and mouse neural tube defects. Science, 280, 2107–8.
Fraser, F.C. and Gwyn, A. (1998). Seasonal variation in birth date of children with cleft lip. Teratology, 57, 93–5.
Frey, L. and Hauser, W. A. (2003). Epidemiology of neural tube defects. Epilepsia, 44, Suppl 3, 4–13.
Garver, K.L., Law, J. C. and Garver, B. (1985). Hirschsprung disease: a genetic study. Clin Genet, 28, 503–8.
Graham, J. M. Jr. and Edwards, M. J. (1998). Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology, 58, 209–21.
Greene, N. D. and Copp, A. J. (1997). Inositol prevents folate resistant neural tube defects in the mouse. Nature Med, 3, 60–6.
Hall, J. G. (1996). Twinning: mechanisms and genetic implications. Curr Opin Genet Dev, 6, 343–7.
Hoffman, J. I. and Kaplan, S. (2002). The incidence of congenital heart disease. J Am Coll Cardiol, 39, 1890–900.
Holmes, L. B. (2002). Teratogen-induced limb defects. Am J Med Genet, 112, 297–303.
Inoue, K. and Lupski, J. R. (2002). Molecular mechanisms for genomic disorders. Annu Rev Genomics Hum Genet, 3, 199–242.
Jurlioff, D. M. and Harris, M. J. (2000). Mouse models for neural tube defects. Hum Molec Genet, 9, 993–1000.
Kalter, H. and Warnaky, J. (1983). Medical progress. Congenital malformations: etiologic factors and their role in prevention. N Engl J Med, 308, 424–31.
Kalter, H.The non-teratogenicity of gestational diabetes (1998). Paediatr Perinat Epidemiol, 12, 456–8.
Katsanis, N., Ansley, S. J., Badano, J. L.et al. (2001). Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science, 293, 2256–9.
Khoury, M. J., Beaty, T. H. and Cohen, B. H. (1991). Applications of the concept of attributable fraction in medical genetics. Am J Med Genet, 40, 177–82.
Kouseff, B. (1999). Gestational diabetes mellitus (class A): a human teratogen?Am J Med Genet, 83, 402–8.
Kurnit, D. M., Layton, W. M. and Matthysse, S. (1987). Genetics, chance and morphogenesis. Am J Hum Genet, 41, 979–95.
Li, E. (2002). Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet, 3, 662–73.
Little, J. (1993). The Chernobyl accident, congenital anomalies and other reproductive outcomesPaediatr Perinat Epidemiol, 7, 121–51.
Martinez-Frias, M. L. (1994). Epidemiological analysis of outcomes of pregnancy in diabetic mothers: identification of the most characteristic and most frequent congenital anomalies. Am J Med Genet, 51, 108–13.
May, P. A. and Gossage, J. P. (2001). Estimating the prevalence of fetal alcohol syndrome. A summary. Alcohol Res Health, 25, 159–67.
Miller, E., Hare, J. W., Cloherty, J. P.et al. (1981). Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med, 304, 1331–4.
Ming, J. E. and Muenke, M. (2002). Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet, 71, 1017–32.
MRC Vitamin Study Research Group. (1991). Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet, 338, 131–7.
Nadeau, J. H. (2003). Modifier genes and protective alleles in humans and mice. Curr Opin Genet Dev, 13, 290–5.
Pani, L., Horal, M. and Loeken, M. R. (2002). Polymorphic susceptibility to the molecular causes of neural tube defects during diabetic embryopathy. Diabetes, 51, 2871–4.
Paulsen, M. and Ferguson-Smith, A. C. (2001). DNA methylation in genomic imprinting, development and disease. J Pathol, 195, 97–110.
Polizzi, A., Huson, S. M. and Vincent, A. (2000). Teratogen update: maternal myasthenia gravis as a cause of congenital arthrogryposis. Teratology, 62, 332–41.
Prentice, A. and Goldberg, G. (1996). Maternal obesity increases congenital malformations. Nutr Rev, 54, 146–50.
Qu, S., Tucker, S. C., Ehrlich, J. S.et al. (1998). Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly. Development, 125, 2711–21.
Ray, J. G., Meier, C., Vermeulen, M. J.et al. (2002). Association of neural tube defects and folic acid food fortification in Canada. Lancet, 360, 2047–8.
Ray, J. G., O'Brien, T. E. and Chan, W. S. (2001). Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM, 94, 435–44.
Reece, E. A., Homko, C. J. and Wu, Y. K. (1996). Multifactorial basis of the syndrome of diabetic embryopathy. Teratology, 54, 171–82.
Roessler, E. and Muenke, M. (2003). How a hedgehog might see holoprosencephaly. Hum Mol Genet. 12, R15–R25.
Schinzel, A. A., Smith, D. W. and Miller, J. R. (1979). Monozygotic twinning and structural defects. J Pediatr, 95, 921–30.
Schwartz, R. and Teramo, K. A. (2000). Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol, 24, 120–35.
Sells, C. J., Robinson, N. M., Brown, Z. and Knopp, R. H. (1994). Long-term developmental follow-up of infants of diabetic mothers. J Pediatr, 125, S9–S17.
Shaw, G. M., Lammer, E. J., Wasserman, C. R., O'Malley, C. D. and Tolarova, M. M. (1995). Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet, 346, 393–6.
Sheffield, J. S., Butler-Koster, E. L., Casey, B. M., McIntire, D. D. and Leveno, K. J. (2002). Maternal diabetes mellitus and infant malformations. Obstet Gynecol, 100, 925–30.
Shields, D. C., Kirke, P. N., Mills, J. L.et al. (1999). The “thermolabile” variant of methylenetetrahydrofolate reductase and neural tube defects: an evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet, 64, 1045–55.
Sibilia, M. and Wagner, E. F. (1995). Strain-dependent epithelial defects in mice lacking the EGF receptor. Science, 269, 234–8.
Slavotinek, A. and Biesecker, L. G. (2003). Genetic modifiers in human development and malformation syndromes, including chaperone proteins. Hum Mol Genet, 12, R45–R50.
Smithells, R. W. (1973). Defects and disabilities of thalidomide children. Br Med J, 1(5848), 269–72.
Sorensen, H. T., Norgard, B., Pedersen, L., Larsen, H. and Johnsen, S. P. (2002). Maternal smoking and risk of hypertrophic infantile pyloric stenosis: 10 year population based cohort study. BMJ, 325, 1011–12.
Southard-Smith, E. M., Angrist, M., Ellison, J. S.et al. (1999). The Sox10 (Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res, 3, 215–25.
Spranger, J., Benirschke, K. and Hall, J. G.et al. (1982). Errors of morphogenesis: concepts and terms. J Pediatr, 100, 160–5.
Stearns, S. C. (2002). Progress on canalization. Proc Natl Acad Sci USA, 99, 10229–30.
Stevenson, R. E. (1993 a). The genetic basis of human anomalies. In Stevenson, R. E., Hall, J. G. and Goodman, R. M. eds., Human malformations and related anomalies, vol 1. New York: Oxford University Press, pp. 115–35.
Stevenson, R. E. (1993 b). The Environmental Basis of Human Anomalies. In Stevenson, R. E., Hall, J. G. and Goodman, R. M. eds., Human malformations and related anomalies, vol 1. New York: Oxford University Press, pp. 137–68.
Stoler, J. M., Ryan, L. M. and Holmes, L. B. (2002). Alcohol dehydrogenase 2 genotypes, maternal alcohol use, and infant outcome. J Pediatr, 141, 780–5.
Thilly, W. G. (2003). Have environmental mutagens caused oncomutations in people?Nat Genet, 34, 255–9.
Threadgill, D. W., Dlugosz, A. A., Hansen, L. A.et al. (1995). Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science, 269, 230–4.
Essien, F. B. and Wannberg, S. L. (1993). Methionine but not folinic acid or vitamin B-12 alters the frequency of neural tube defects in Axd mutant mice. J Nutrition, 123, 27–34.
Watkins, M. L., Rasmussen, S. A., Honein, M. A., Botto, L. D. and Moore, C. A. (2003). Maternal obesity and risk for birth defects. Pediatrics, 111, 1152–8.
Whitehead, A. S., Gallagher, P., Mills, J. L.et al. (1995). A genetic defect in 5,10 methylene tetrahydrofolate reductase in neural tube defects. Q J Med, 88, 763–6.
Wilcox, A. J., Baird, D. D. and Weinberg, C. R. (1999). Time of implantation of the conceptus and loss of pregnancy. N Engl J Med, 340, 1796–9.
Yang, Q., Khoury, M. J. and Mannino, D. (1997). Trends and patterns of mortality associated with birth defects and genetic diseases in the United States, 1979–1992: an analysis of multiple-cause mortality data. Genet Epidemiol, 14, 493–505.
Zhao, Q., Behringer, R. R. and Crombrugghe, B. (1996). Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. Nature Genet, 13, 275–83.