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Chapter 15
Genetics of Development
165
A
B
D
E
F
M
M
M
C
FIGURE 15-2. Birth defects associated with various developmental processes. (A) Primary ciliary dyskinesia (PCD;
immotile cilia syndrome).
Electron micrograph shows a cilium from an individual with PCD where the outer dynein arms
are absent and with three abnormal single microtubules (M) instead of the normal 9
2 arrangement. (B) Achondroplasia.
Photograph shows a boy with short stature, short limbs (particularly in the proximal portions), short fingers, dispropor-
tionate trunk, bowed legs, relatively large head, prominent forehead, and deep nasal ridge. (C) Thanatophoric dysplasia.
Photographs shows a newborn infant born at 32 weeks of gestation with a depressed nasal bridge, short extremities and
extra skinfold creases, small chest, and prominent abdomen. The infant died a few hours after this picture was taken.
(D)Crouzon syndrome (E) Osteogenesis imperfecta.
Radiograph shows multiple bone fractures of the upper and lower
limbs resulting in an accordionlike shortening of the limbs. (F) Ehlers-Danlos syndrome. Photograph shows the extremely
stretchable skin of the infant. (continued)
X. SELECTED PHOTOGRAPHS OF DEVELOPMENTAL DISORDERS
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Board Review Series Genetics
G
H
J
K
I
*
**
FIGURE 15-2.
(Continued) (G) Marfan syndrome. Photograph shows a girl with an unusually tall stature, exceptionally long
limbs, and arachnodactyly (elongated hands and feet with very slender digits). (H) Waardenburg syndrome. Photograph
shows a young boy with a white forelock of hair, partial albinism, heterochromia of the iris, and lateral displacement of the
medial canthi. (I) Nonsyndromic congenital intestinal aganglionosis (Hirschsprung disease). Radiograph after barium
enema of a patient with Hirschsprung disease. The upper segment of the normal colon (*) is distended with fecal mate-
rial. The lower segment of the colon (**) is narrow. The lower segment is the portion of the colon where the ganglionic
cells in the myenteric and submucosal plexuses are absent and peculiar contractions are observed. This case shows a
high transition zone (T) between the normal colon and aganglionic colon. The arrows indicate a long segment of agan-
glionic descending colon. (J) Unilateral cleft lip and cleft palate. (K) Treacher Collins syndrome (mandibulofacial dysos-
tosis).
Photograph shows underdevelopment of the zygomatic bones, mandibular hypoplasia, lower eyelid colobomas,
downward-slanting palpebral fissures, and malformed external ears (note the hearing aid cord).
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1.
The most common genetic cause of
human birth defects is which one of the fol-
lowing?
(A)
chromosome abnormalities
(B)
multifactorial inheritance
(C)
Mendelian single gene inheritance
(D)
teratogen exposure
2.
Which one of the following does not have
a genetic component?
(A)
cleft lip
(B)
amniotic band
(C)
spina bifida
(D)
polydactyly
3.
A single umbilical artery with heart
defects is an example of which one of the fol-
lowing?
(A)
a syndrome
(B)
a polytopic field defect
(C)
an association
(D)
a sequence
4.
Which one of the following establishes the
anterior/posterior axis in human develop-
ment?
(A)
the primitive streak
(B)
the notchord
(C)
the future left side of the embryo
(D)
the future right side of the embryo
5.
The anterior/posterior location of a num-
ber of anatomical structures is deter-
mined by which of the following?
(A)
the PAX gene family
(B)
the HOX gene family
(C)
the TGF-
gene family
(D)
the fibroblast growth factor family
6.
Increased paternal age is associated with a
risk of having a child with which one of
the following?
(A)
osteogenesis imperfecta
(B)
achondroplasia
(C)
Ehlers Danlos syndrome
(D)
Marfan syndrome
7.
Which one of the following modes of
inheritance is associated with orofacial cleft-
ing?
(A)
autosomal recessive
(B)
autosomal dominant
(C)
X-linked recessive
(D)
multifactorial
8.
Neural crest derived cell types are regu-
lated by which one of the following?
(A)
the HOX gene family
(B)
the fibroblast growth factor family
(C)
the PAX gene family
(D)
TGF-
family
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1. The answer is (B).
Multifactorial inheritance accounts for approximately 25% of all human
birth defects.
2. The answer is (B).
Amniotic band is a deformation caused by mechanical forces that inter-
fere with normal growth.
3. The answer is (D).
A single umbilical artery is often associated with heart defects but no
syndrome can be identified.
4. The answer is (A).
The establishment of the anterior/posterior axis is associated with the
appearance of the primitive streak.
5. The answer is (B).
The HOX gene family determines the anterior/posterior orientation in
the developing embryos.
6. The answer is (B).
Many of the mutations responsible for achondroplasia are de novo and
their origin is mostly paternal.
7. The answer is (D).
Orofacial clefting is multifactorial, being determined by both genetic
and environmental factors.
8. The answer is (C).
The PAX gene family codes for DNA-binding transcription factors that
regulate neural crest derived cell types.
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I. THE DEVELOPMENT OF CANCER (ONCOGENESIS)
In general, cancer is caused by mutations of genes that regulate the
cell cycle, DNA repair,
and/or
programmed cell death (i.e., apoptosis)
. A majority of cancers (so-called
“sporadic can-
cers”
) are caused by mutations of these genes in somatic cells that then divide wildly and
develop into a cancer. A minority of cancers (so-called
“hereditary cancers”
) are predisposed by
mutations of these genes in the parental germ cells that are then passed on to their children. In
addition, certain cancers are linked to
environmental factors
as prime etiological importance
(e.g., bladder cancer/aniline dyes, lung cancer/smoking or asbestos, liver angiosarcoma/
polyvinyl chloride, skin cancer/tar or UV irradiation). From a scientific point of view, the cause
of cancer is not entirely a mystery but still remains in the theoretical arena which include the
following:
A. Standard Theory (Figure 16-1).
The standard theory suggests that cancer is the result of cumu-
lative
mutations in proto-oncogenes and/or tumor suppressor genes
, eventually producing a
cancer cell. However, if cancer is caused only by mutations in these specific cell cycle genes,
it is very hard to explain the appearance of the nucleus in a cancer cell. The nucleus in a can-
cer cells looks as if something has detonated an explosion, resulting in an array of chromo-
somal aberrations (e.g., chromosome pieces, scrambled chromosomes, chromosomes fused
together, wrong number of chromosomes, chromosomes with missing arms, or chromo-
some with extra segments; so-called
“karyotype chaos”
). The question is: “Which comes first,
the mutations in cell cycle genes or the chromosomal aberrations?”
B. Modified Standard Theory.
The modified standard theory suggests that cancer is the result of
a
dramatically elevated random mutation rate
caused by environmental carcinogens or mal-
function in the DNA replication machinery or DNA repair machinery. The random muta-
tions eventually hit the proto-oncogenes and/or tumor suppressor genes, producing a can-
cer cell.
C. Early Instability Theory.
The early instability theory suggests that cancer is the result of
dis-
abling (either by mutation or epigenetically) of “master genes” that are required for cell division.
No specific master genes have been identified. Therefore, each time a cell undergoes the
complex process of cell division, some daughter cells get chromosomes fused together, the
wrong number of chromosomes, chromosomes with missing arms, or chromosome with
extra segments, which will affect gene dosage of the proto-oncogenes and tumor-suppressor
genes. The chromosomal aberrations get worse with each cell division, eventually producing
a cancer cell.
D. All-Aneuploidy Theory.
The all-aneuploidy theory suggests that cancer is the result of
aneu-
ploidy
(i.e., abnormal number of chromosomes) that occurs during cell division. Although a
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