How to determine the causes and recurrence risks of congenital anomalies - a clinical approach
Professor PA Farndon2 Do the nature and pattern of anomalies suggest the underlying cause?
Determining the embryonic origin of the tissue or organ involved in a specific anomaly can be helpful in determining its cause or timing, particularly with multiple abnormalities when a common embryological origin may become apparent.
The nature of an anomaly is related to the stage of embryogenesis at which genetic and environmental factors acted during organogenesis or during maturation. During human development there are critical times during which organ systems are susceptible (table 2).
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Table 2 Embryological timing of some anomalies |
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Malformation |
Defect in |
Cause prior to |
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Holoprosencephaly |
Prechordal mesoderm |
23 days |
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Sirenomelia |
Caudal axis |
23 days |
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Anencephaly |
Anterior neuropore |
26 days |
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Meningomyelocele |
Poster neuropore |
28 days |
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Transposition of the great vessels |
Direction of development of bulbous cordis septum |
36 days |
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Radial aplasia |
Development of radius |
38 days |
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Cleft lip |
Development of primary palate |
6 weeks |
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Ventricular septal defect |
Closure of ventricular septum |
6 weeks |
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Diaphragmatic hernia |
Closure of pleuropotential canal |
6 weeks |
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Syndactyly |
Programmed cell death between digits |
6 weeks |
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Duodenal atresia |
Recanalisation of duodenum |
7-8 weeks |
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Omphalocoele |
Intestinal loop return to abdominal cavity |
10 weeks |
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Bicornuate uterus |
Fusion of lower portion of Mullerian ducts |
10 weeks |
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Cleft palate |
Development of secondary palate |
10 weeks |
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Hypospadias |
Fusion of urethral folds |
12 weeks |
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Cryptochidism |
Descent of testes |
7-9 months |
Teratogenic influences - genetic or environmental - acting during the first two weeks of development are likely to result in the death of the embryo rather than cause malformations. The third to the eighth week postconception is the embryonic period during which organogenesis occurs, and so most major malformations arise during this critical period. The final stage of development is from the third month to birth. As this is the period of somatic growth and maturation of tissues, few malformations may be expected to arise, but the fetus may be at risk from extrinsic factors such as fetal constraint.
Malformations initiated during early organogenesis tend to have more complex outcomes; a single malformation occurring then can result in a cascade of secondary and tertiary events resulting in what appear to be multiple anomalies (see malformation sequence below).
Later in pregnancy, compression, constriction or immobility can result in defects in organs already normally developed.