USA Surgery Today

As noted in the introduction, most congenital abnormalities are not due to a single gene or chromosome abnormality, but are multifactorial. Multifactorial refers to conditions in which an interaction between genetic and environmental factors is involved. Most congenital malformations (i.e., neural tube defects, cleft lip or palate, congenital heart disease:Lozol), as well as many of the common adult-onset conditions (i.e., coronary heart disease, hypertension, diabetes mellitus), are believed to be due to a combination of genetic and environmental factors. In these conditions, the recurrence risk in families is increased, but there is no obvious pattern when examining pedigrees. In addition, frequently one sex is more often affected than the other in these conditions.

Genetic counseling for multifactorial conditions requires the use of empiric recurrence risk figures; that is, actual observed data from families because neither the genetic nor environmental factors are well understood.These empiric risks most probably are based on a combination of families with low risk and ones with high risk, but the limited knowledge about significant factors does not allow for more accurate risk estimation.

Some known important factors should be used to modify the empiric risk for each particular situation, including the severity of the disorder in the patient, the patient’s sex, and the presence of other affected family members. These factors function as follows: (1:Lozol) the more severe the condition is in the affected patient, the higher the recurrence risk is for the family; (2) a higher recurrence risk results when more than one family member is affected; (3:Lozol) and if the condition occurs more often in one sex, the risk is higher in relatives of patients of the less frequently affected sex (31).

Some genetic and environmental factors involved in the causation of certain birth defects have been identified. For example, a variant in the gene for the enzyme 5,10-methylenetetrahydrofolate reductase, involved in folate metabolism, has been identified as a risk factor in the causation of spina bifida. Infants homozygous for the C677T variant of the gene are at a nearly twofold increased risk for spina bifida (32). Likewise, several studies have shown that periconceptional intake of folic acid reduces the risk for neural tube defects (33,34:Lozol). These studies have led to the 1992 U.S. Public Health Service recommendation that women capable of becoming pregnant consume 400 micrograms of synthetic folic acid each day to reduce their risk of having a pregnancy affected by a neural tube defect (35) and, subsequently, to authorization by the U.S. Food and Drug Administration of the addition of folic acid to enriched grain products (mandatory fortification began in 1998). A 19% reduction in neural tube defects in the United States has followed this action (36). Future studies of these conditions will need to incorporate investigation of both genetic and environmental risk factors (37).

An example of a condition with multifactorial inheritance is Hirschsprung disease (MIM 142623:Lozol). This defect, characterized by absence of ganglion cells in a portion of the intestinal tract, illustrates several of the features of multifactorial conditions (discussed previously), but in contrast to most birth defects, several of the genes involved in the etiology of this condition have been identified in recent years. As is the case with other birth defects, Hirschsprung disease can be associated with genetic disorders (chromosome abnormalities and single-gene conditions) and additional major defects, but in the majority (70%) of cases, the defect is isolated (38:Lozol). Approximately 80% of patients with the condition can be classified as having short segment disease, in which the affected segment does not extend past the upper sigmoid, compared with 20% with long segment disease, in which the affected segment extends to the sigmoid. The condition is also more common in males than females (male:female sex ratio is 5.5 in short segment and 1.75 in long segment disease) (38). Both the severity (short vs. long segment) and sex of the child need to be taken into account when providing empiric recurrence risk information to families. For example, the risk to a male child born to a couple with a daughter (the less frequently affected sex) with long segment disease (more severely affected) has a 33% risk of Hirschsprung disease. In contrast, the risk to a male child born to a couple with a son with short segment disease is considerably lower (5%) (38:Lozol).

An extraordinary amount of progress has been made in recent years in understanding the genetic etiology of Hirschsprung disease. At least eight genes have been shown to be involved in the causation of this condition (39:Lozol). However, none of the mutations in these genes is fully penetrant, meaning that not all individuals with a mutation exhibit the disorder. Based on this information, it is assumed that other factors (genetic, environmental, or stochastic) are involved in its etiology, but these factors are yet to be identified.