Congenital malformations - Edocr

6 PART I GENERAL CONSIDERATIONS
five weeks, from the fourth to the eighth week,
all major organs and systems of the body form
from the three germ layers and assume their final
positions. By the end of this stage, the appearance
of embryo changes to a distinctly human
form. Because all essential external and
internal structures are formed during this period,
this is the most critical and vulnerable period of
development (Fig. 1-1). The majority of major
congenital malformations are a result of alteration
in normal development during this stage.
The remainder of gestation is primarily a period
of growth in size and is characterized by
rapid body growth and differentiation of tissues
and organ systems. During this period, the fetus
is less vulnerable to teratogenic effects of various
agents but these agents may still interfere
with growth and development of organs such
as brain and eyes during the fetal period.
ETIOLOGY OF BIRTH DEFECTS
The branch of medicine concerned with the
study of abnormal prenatal development is teratology
and includes the study of causes and
pathogenesis of birth defects. The causes of congenital
anomalies are divided into four broad
categories; genetic, environmental, multifactorial,
and unknown. Initially, as many as 50–60%
of all congenital anomalies were considered to
have an unknown etiology but with recent advances
in genetics, the etiology of many syndromes
is being identified. Based on earlier data,
a genetic cause was considered to be responsible
in as many as 10–30% of all birth defects,
environmental factors in 5–10%, multifactorial
inheritance in 20–35%, and unknown causes
were responsible in 30–45% of the cases. 5,19,21,22
However, more recent data indicate that the etiology
of a congenital malformation is unknown
in about 17% of the cases. 7
Genetic factors are responsible for a large
majority of congenital malformations with known
causes and play an important role in disorders
of multifactorial inheritance. A chromosomal
abnormality occurs in 1 of 170 liveborn infants.
Among chromosomally abnormal neonates, onethird
have an extra sex chromosome, one-fourth
have trisomy of an autosome, and the remaining
have an aberration of chromosomal structure
such as a deletion or translocation. 23 However,
a significant majority of these infants have no phenotypic
manifestations at birth. Earlier studies reported
that nearly 10% of infants with lethal multiple
congenital malformations have abnormal
cytogenetic studies. 23 However, this proportion
is likely to be much higher today with advances
in genetics. A chromosomal abnormality leading
to a congenital malformation can be either numerical
or structural. The examples of numerical
abnormalities of chromosomes include Down
syndrome (trisomy 21) and Turner syndrome
(45 XO monosomy). The examples of structural
chromosomal abnormalities include translocations,
deletions, microdeletions, duplications, or
inversions. With better understanding of the human
genome and improved techniques in molecular
cytogenetics, more and more structural
chromosomal abnormalities are being identified
as a cause of congenital anomalies previously
considered to be of unknown etiology.
Environmental factors also play an important
role in the etiopathogenesis of many congenital
malformations. Maternal exposure to certain
environmental agents can lead to disruption
of the normal developmental process and result
in both minor and major congenital anomalies.
These agents with a potential to induce a structural
anatomic anomaly in a developing fetus
are termed teratogens (Greek: teratos [monster]
and gen [producing]). Table 1-2 summarizes
some common examples of teratogens in different
categories and the associated congenital
malformations. The exact mechanisms by which
each teratogen induces anomalies are not clearly
known but include altered gene expression, histogenesis,
cell migration and differentiation,
apoptosis, protein or nucleic acid synthesis and
function, or supply of energy. The risk of having
a congenital anomaly after exposure to a
teratogenic agent depends on the nature and
the dose of the agent, timing and duration of
exposure, presence of concurrent exposures,