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BRS Genetics
t a b l e
14-2
Summary Table of Bleeding Disorders
Genetic Disorder
Gene/Gene Product Chromosome
Clinical Feature
Hemophilia A
Hemophilia B
von Willebrand
Disease
F8 gene/factor VIII
Xq28
F8 intron 22-A gene inversion
(“flip” inversion) most com-
mon mutation
Reduced factor VIII clotting
activity
F9 gene/ factor IX
Xq27.1-q27.2
Wide variety of mutations
Reduced factor IX clotting
activity
VWF gene/ von Willebrand factor
12p13.3
Wide variety of mutations
Reduced synthesis or functional-
ity of vWF
Severe hemophilia A:
Usually diagnosed before 1 year of age;
prolonged oozing after injuries; renewed bleeding after initial
bleeding has stopped; delayed bleeding; large “goose eggs”
after minor head bumps; abnormal bleeding after minor
injuries; deep muscle hematomas; episodes of spontaneous
joint bleeding are frequent; and 2–5 spontaneous bleeding
episodes/month without adequate treatment.
Moderately severe hemophilia A:
Usually diagnosed before 5–6
years of age; prolonged oozing after injuries; renewed bleed-
ing after initial bleeding has stopped; delayed bleeding; abnor-
mal bleeding after minor injuries; episodes of spontaneous
joint bleeding are rare; and 1 bleeding episode/month
→
1
bleeding episode/year.
Mild hemophilia A:
Usually diagnosed later in life; prolonged
oozing after injuries; renewed bleeding after initial bleeding
has stopped; delayed bleeding; abnormal bleeding after major
injuries, episodes of spontaneous joint bleeding are absent;
and 1 bleeding episode/year
→
1 bleeding episode/10 years.
Severe hemophilia B:
Usually diagnosed before 1 year of age;
prolonged oozing after injuries; renewed bleeding after initial
bleeding has stopped; delayed bleeding; large “goose eggs”
after minor head bumps; abnormal bleeding after minor
injuries; deep muscle hematomas; episodes of spontaneous
joint bleeding are frequent; and 2 to 5 spontaneous bleeding
episodes/month without adequate treatment.
Moderately severe hemophilia B:
Usually diagnosed before 5 to
6 years of age; prolonged oozing after injuries; renewed bleed-
ing after initial bleeding has stopped; delayed bleeding; abnor-
mal bleeding after minor injuries; episodes of spontaneous
joint bleeding are rare; and 1 bleeding episode/month
→
1
bleeding episode/year.
Mild hemophilia B:
Usually diagnosed later in life; prolonged
oozing after injuries; renewed bleeding after initial bleeding
has stopped; delayed bleeding; abnormal bleeding after major
injuries; episodes of spontaneous joint bleeding are absent;
and 1 bleeding episode/year
→
1 bleeding episode/10 years.
Type 1 VWD:
Can be diagnosed at any age; lifelong easy bruising;
nose bleeding (epistaxis); skin bleeding; prolonged bleeding
from mucosal surfaces; heavy menstrual bleeding; and mild to
moderately severe bleeding symptoms while some patients
are asymptomatic.
Type 2 VWD:
can be diagnosed at any age; lifelong easy bruising;
nose bleeding (epistaxis); skin bleeding; prolonged bleeding
from mucosal surfaces; heavy menstrual bleeding; and moder-
ate to moderately severe bleeding.
Type 3 VWD:
Nose bleeding (epistaxis); severe skin bleeding;
severe bleeding from mucosal surfaces; muscle hematomas;
and severe joint bleeding.
V. SUMMARY TABLE OF BLEEDING DISORDERS (Table 14-2)
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1.
Reduced factor VIII clotting activity with
normal von Willebrand factor is a finding in
which one of the following?
(A)
von Willebrand disease
(B)
hemophilia B
(C)
Christmas disease
(D)
hemophilia A
2.
A gene inversion, called a “flip” inversion,
is the most common mutation in which one
of the following?
(A)
hemophilia A
(B)
hemophilia B
(C)
von Willebrand disease
(D)
Christmas disease
3.
Which one of the following inherited
bleeding disorders is autosomal dominant?
(A)
hemophilia A
(B)
hemophilia B
(C)
von Willebrand disease
(D)
Christmas disease
4.
The bleeding disorder that is most likely
to be asymptomatic is which one of the fol-
lowing?
(A)
hemophilia A
(B)
hemophilia B
(C)
Type 1 von Willebrand disease
(D)
Type 3 von Willebrand disease
5.
The most common bleeding disorder is
which one of the following?
(A)
hemophilia A
(B)
hemophilia B
(C)
von Willebrand disease
(D)
Christmas disease
151
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152
1. The answer is (D).
Hemophilia A is caused by a mutation in the F8 gene for coagulation fac-
tor VIII.
2. The answer is (A).
An F8 intron gene inversion, called a “flip” inversion, is responsible for
the majority cases of hemophilia A.
3. The answer is (C).
Von Willebrand disease is the most common inherited bleeding disorder.
4. The answer is (C).
The bleeding disorder most likely to be asymptomatic is Type 1 von
Willebrand disease because there is von Willebrand factor present but in reduced amounts.
5. The answer is (C).
The most common inherited bleeding disorder is von Willebrand disease,
but only a small number of patients come to medical attention because of symptoms.
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153
t a b l e
15-1
Causes of Human Birth Defects
Causes
Percentage
Unknown factors
45%
Multifactorial inheritance (environmental and genetic causes combined)
25%
Chromosome abnormalities (numerical or structural)
10%
Mendelian single gene inheritance
5%
Teratogen exposure
5%
Uterine factors (e.g., oligohydramnios, uterine fibroids)
3%
Twinning
1%
I. CAUSES OF HUMAN BIRTH DEFECTS (Table 15-1)
II. TYPES OF HUMAN BIRTH DEFECTS
A. Malformation (genetic based).
A morphological defect caused by an
intrinsically abnormal
developmental process
. Intrinsic implies that the developmental potential of the primordium
is abnormal from the beginning (e.g., a chromosome abnormality of a gamete at fertiliza-
tion). A malformation occurs during the embryonic period (weeks 3 to 8 of gestation) when
all major organ systems begin to develop (i.e., organogenesis). Malformation may also be
due to nutritional deficiencies (e.g., lack of folate in neural tube defects). Malformation
examples include: polydactyly, oligodactyly, spina bifida, cleft palate, and most kinds of con-
genital heart malformations.
B. Dysplasia (genetic based).
A morphological defect caused by an
abnormal organization of cells
into tissues.
A dysplasia occurs during the embryonic period (weeks 3 to 8 of gestation) when
all major organ systems begin to develop (i.e., organogenesis). Dysplasia examples include:
thanatophoric dwarfism and congenital ectodermal dysplasia.
C. Disruption (not genetic based).
A morphological defect caused by the breakdown of or inter-
ference with an intrinsically normal developmental process. A disruption occurs at any time
during gestation. Disruption examples include: bowel atresia due to vascular accidents,
amniotic band disruptions, and most cases of porencephaly (cystic lesions of the brain).
D. Deformation (not genetic based).
An abnormality of form or position of a body part caused by
mechanical forces that interfere with normal growth or position of the fetus in utero. A
deformation occurs usually in the second and third trimester of the pregnancy. Deformation
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154
Board Review Series Genetics
examples include: abnormal position of the feet, clubfoot, and abnormal moulding of the
head.
III. PATTERNS OF HUMAN BIRTH DEFECTS
When a patient presents with multiple birth defects, the following patterns may be
presented:
A. Sequence.
A pattern of multiple defects derived from a single known or presumed structural
defect or mechanical factor. Sequence examples include Robin sequence and oligohydram-
nios sequence.
B. Syndrome.
A pattern of multiple defects all of which are pathogenetically related. In clinical
genetics, “syndrome” implies a similar cause in all affected individuals. Syndrome examples
include Down syndrome, fetal alcohol syndrome, and Marfan syndrome.
C. Polytopic Field Defect.
A pattern of multiple defects derived from the disturbance of a single
developmental field. Developmental fields are regions of the embryo that develop in a
related fashion although the derivative structures may not be close spatially in the infant or
adult. Polytopic field defect examples include holoprosencephaly.
D. Association.
A pattern of multiple defects that occurs more often than expected by chance
alone (i.e., nonrandom) but has not yet been classified as a sequence, syndrome, or poly-
topic field defect. As development genetics advances, many associations will very likely be
reclassified as a sequence, syndrome, or polytopic defect. Association examples include
abnormal ears associated with renal defects; single umbilical artery associated with heart
defects; and, the association of vertebral, heart, and kidney defects.
IV. DETERMINATION OF THE LEFT/RIGHT (L/H) AXIS
L/R axis determination is established early in embryological development and is caused by a
cascade of paracrine signaling proteins.
A.
L/R axis determination begins with the asymmetric (future left-side) expression of the signal-
ing protein
Sonic hedgehog (Shh) protein
from the notochord, which is located in the midline.
B.
This results in the expression of the signaling protein
nodal protein
(a member of the TGF-
family) only on the left side of the embryo (left side
nodal positive; right side nodal neg-
ative) and may be the earliest event in L/R axis determination.
C.
After the L/R axis is determined in the embryo, the L/R asymmetry of a number of anatomi-
cal organs (e.g., heart, liver, stomach) can then be patterned under the influence of the tran-
scription factor
zinc-finger protein of the cerebellum (ZIC3)
.
D.
Clinical consideration:
Primary Ciliary Dyskinesia (PCD; or Immotile Cilia Syndrome)/
Kartagener Syndrome.
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