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Appendix C: Causes of congenital anomalies and classification according to developmental mechanism and clinical presentation

Causes of congenital anomalies

It has been estimated that about one quarter of all congenital anomalies may have a genetic cause (44). However, more recent estimates suggest the proportion could be higher, as advances in cytogenetic and molecular techniques in the last two decades are allowing the identification of previously undetected chromosomal abnormalities, gene mutations and genetic polymorphisms. The two most common genetic causes of congenital anomalies are single-gene defects and chromosomal abnormalities.

Single-gene defects are caused by changes (mutations) in the structure of genes. These are responsible for slightly over 17% of congenital anomalies (44). Single-gene defects may be inherited from either one or both parents, or be caused by a sporadic (new) mutation. Single- gene mutations seem to be associated more often with multiple congenital anomalies that are syndromic, rather than with isolated malformations, though new research is increasingly uncovering single-gene defects that cause isolated anomalies such as cleft lip with or without cleft palate and some types of congenital heart defects.

Abnormalities caused by chromosomal changes are identified in about 10% of children with congenital anomalies (44), and may involve the autosomes or the sex chromosomes. Changes include numerical abnormalities such as having an extra chromosome – e.g. trisomies (Down syndrome or trisomy 21, trisomy 13 and trisomy 18); missing a chromosome – e.g. monosomies (monosomy X or Turner syndrome); and chromosomal structural abnormalities – deletions (e.g. deletion of the proximal region in the long arm of chromosome 22 associated with the DiGeorge and velocardiofacial syndromes) and duplications (e.g. duplication of the short arm of chromosome 9). Chromosomal abnormalities are almost always associated with patterns of multiple congenital anomalies.

Identified environmental and maternal causes are responsible for an estimated 4% to 10% of congenital anomalies (45).

Examples include:

  • maternal nutritional status
  • exposure to chemicals, and possibly illicit drugs
  • maternal infections (e.g. rubella)
  • physical factors, such as ionizing radiation and hyperthermia (45)
  • chronic maternal diseases (e.g. diabetes)
  • exposure to known teratogenic prescription medicines (e.g. retinoic acid, valproic acid) – for more information on medications see reference (46).

For approximately 66% of congenital anomalies, the cause remains unknown (45).

This group includes those congenital anomalies that are believed to have environmental causes or to be multifactorial. Multifactorial means that multiple undefined gene variants interact with environmental factors to cause a specific anomaly.

Many potential gene–environment interactions have been tested in relation to differentcongenital anomalies. For example, mutations and polymorphisms of numerous genes, including TGFA, TGFB3, CYP1A1, NAT1, NAT2 and GSTT1, have been studied to determine their level of association with an increased risk for oral clefts in the offspring of women who smoke cigarettes (47). Another example of a gene–environment interaction involves prenatal exposure to phenytoin, a widely used anticonvulsant drug. Phenytoin is associated with structural congenital anomalies in 3% to 10% of infants exposed to this medication in utero. It has been shown that the presence of congenital anomalies in these infants correlates with reduced activity of epoxide hydrolase, a microsomal enzyme that normally detoxifies phenytoin metabolites (48). When the enzyme epoxide hydrolase is not working properly, some intermediate teratogenic metabolites do not get eliminated. This can result in a congenital anomaly in the developing fetus.

Congenital anomalies according to developmental mechanisms


Malformation is a structural defect of an organ, part of an organ, or larger region of the body that arises during organogenesis, that is, during the initial formation of a structure, as a result of an intrinsically abnormal developmental process. For most organs, organogenesis takes place during the first 8 weeks after fertilization. The resulting structure may be abnormally formed or incompletely formed, or may fail to form altogether. Although the term malformation is occasionally used to refer to congenital anomalies, it is important to realize that congenital anomalies include more than malformations.


Disruption is a structural defect of an organ, part of an organ, or larger region of the body, resulting from the extrinsic breakdown of, or an interference with, an originally normal developmental process. Examples of disruption defects include the amniotic band complex, some transverse limb deficiencies, and Moebius sequence (cranial nerve paralyses and limb and other abnormalities).


Dysplasias refer to abnormalities of histogenesis or formation of tissues and most commonly affect skin, brain, cartilage or bone. Dysplasias may be localized (e.g. naevus) or generalized (e.g. achondroplasia and other chondrodysplasias, neurofibromatosis).


Deformation is an abnormal form, shape or position of a part of the body, caused by mechanical forces. These forces affect structures after their initial development. Examples include intrauterine crowding as a result of twin pregnancies or uterine abnormalities, and oligohydramnios (diminished amniotic fluid) in bilateral renal agenesis leading to Potter sequence (i.e. distinctive facial findings, lung hypoplasia and some cases of clubfoot).

Congenital anomalies according to clinical presentation in a child


Most major congenital anomalies (about 75%) occur in isolation, meaning that there are no other unrelated major congenital anomalies present. Frequently, isolated major anomalies are associated with one or more minor anomalies.


A sequence is a pattern of related anomalies that are known, or presumed, to derive from a single primary anomaly or mechanical factor. A sequence represents a cascade of events (anomalies) that are consequences of a single primary malformation, disruption or deformation. Examples include the Robin sequence (in which, because of micrognathia, there is posterior displacement of the tongue, which interferes with closure of the palatal shelves, leading to cleft palate) and clubfoot associated with spina bifida. A sequence is considered as an isolated anomaly, except when it is part of a syndrome.

Multiple congenital anomaly

Multiple congenital anomaly is the occurrence of two or more major anomalies that are unrelated. This means that the major anomalies are presumed to be a random association, and do not constitute a sequence or a previously recognized syndrome. Most cases of multiple congenital anomalies fall into this category.


Association is a pattern of multiple anomalies that occur with a higher than random frequency and that is not a sequence or a syndrome. Examples include the VACTERL association (Vertebral, Anal, Cardiac, Tracheo–oEsophageal fistula, Renal, and Limb defects) and the MURCS association (MUllerian duct aplasia–Renal aplasia– Cervicothoracic Somite dysplasia). As knowledge and techniques advance, some of these entities may be recognized as syndromes. This was the case with the CHARGE association (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness) that was found in recent years to be caused by a mutation of the CHD7 gene and is now considered to be a genetically determined syndrome (49).


A syndrome is a pattern of multiple anomalies thought to be pathogenetically related, but not representing a sequence. They are due to a single cause – genetic or environmental – or to gene–environment interactions. Examples include Down syndrome (trisomy 21, a chromosomal abnormality), deletion of the proximal region in the long arm of chromosome 22 (a genomic disorder due to microdeletion), achondroplasia (single gene disorder), and congenital rubella syndrome (infectious cause). Despite advances in genetics, there are still clinically recognized syndromes for which the cause has not been identified.

For further information on case classification, please refer to reference 50.

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