Because our knowledge of the pathogenetic basis of birth defects
is limited, all classification schemes of birth defects and malformations
are somewhat arbitrary and tentative. Most medical textbooks classify
birth defects according to the organ system or body part that is
affected (eg, cardiovascular system, limbs). Such classifications
can help develop intervention strategies (eg, for surgical palliation)
and identification of the general causes of these defects. However, the
utility of anatomical classifications becomes limited once specific
information on the etiology, natural history, and recurrence is
Birth defects can also be classified depending on whether they
occur as isolated findings or as a component of multiple congenital
anomalies. This particular distinction is probably the most valuable
in the evaluation of any infant and child with a birth defect. Compared
with children with isolated birth defects, children with multiple birth
defects have greater morbidity and mortality and are more likely
to have a chromosomal abnormality and/or syndrome diagnosis.
Birth defects can also be classified by etiologic categories such
as chromosome, single gene, multifactorial, and teratogenic.
Categorization of defects by the developmental process that is
perturbed is useful for generating hypotheses about causative pathogenetic mechanisms,
although many birth defects can result from the perturbation of
more than one pathway, making it difficult to identify the primary disturbance.
Although no specific classification is appropriate for all cases,
birth defects will be presented according to the developmental process
that is disturbed to facilitate understanding of pathogenesis and
provide a background for understanding future observations. Accordingly, a
brief review of the genetic controls of development, and the cardinal
processes that, when disturbed, cause birth defects is provided.
Development is the process by which a fertilized ovum
becomes a mature organism capable of reproduction. Thus, a single
fertilized egg divides and grows to form different cell types, tissues, and
organs, all of which are arranged in a species-specific body plan
(ie, the arrangement and patterning of body segments). Many of the
instructions necessary for normal development are encoded by genes
that are the same in each cell of an organism. The mechanisms by which
identical genetic constitutions create a complex adult organism,
composed of many different cells and tissues, and the determinants
of the fate of each cell (that is, what governs a cell, for example,
to become a heart cell or a brain cell), are critical processes. Understanding
the pathogenesis of human malformation and genetic syndromes is
rooted in developmental biological principles.
Evolution of species requires that development of individual
organisms be replicated with high fidelity. Otherwise, it might
be difficult to recognize that a group of organisms share similar
properties that define a species. In sexually reproducing species,
the necessary tools and instructions for building an organism that
closely resembles its parents are located in the fertilized ovum
(zygote). Much of this information is transmitted from parent to
offspring via genes that encode signaling molecules and their receptors,
DNA transcription factors, components of the extracellular matrix,
enzymes, transport systems, and many other proteins. Each of these genetic
mediators is expressed in combinations of spatially and temporally
overlapping patterns that are used repeatedly to control different
developmental processes. Mutations in the genes mediating development
are a common cause of human birth defects.
Interactions between neighboring cells are often controlled by
proteins that can diffuse across small distances to induce a response
and are termed paracrine factors because they are
secreted into the space surrounding a cell, unlike hormones that
are secreted into the bloodstream. Major paracrine-signaling molecules
include (1) the fibroblast growth factor (FGF) family, (2) the hedgehog
family, (3) the wingless (Wnt) family, and (4) the transforming
growth factor β (TGF-β) family.
Mutations in genes encoding these molecules may lead to abnormal
communication between cells.
Many different mechanisms regulate the expression of a gene.
Genes encoding proteins that function to activate or repress other
genes are called transcription factors. Transcription
factors commonly do not activate/repress only a single
target, but regulate the transcription of many genes that, in turn,
regulate other genes in a cascading effect.
Extracellular matrix proteins (EMPs) are secreted macromolecules
that serve as scaffolding for all tissues and organs. These molecules
include collagens, fibrillins, proteoglycans, and large glycoproteins
such as fibronectin, laminin, and tenascin. EMPs are not simply
passive structural elements. To facilitate cell migration, EMPs must
transiently adhere to a cell’s surface, which is accomplished
by two families of receptors, integrins and glycosyltransferases.
Integrins integrate the extracellular matrix and the cytoskeleton,
allowing them to function in tandem.