Академический Документы
Профессиональный Документы
Культура Документы
GENETICS
Question List
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Pulmonology
Endocrinology
Renal
Reproductive system
Pulmonology
Head and neck
Head and neck
Neurology
Hematology
Endocrinology
Neurology
Head and neck
Cardiology
Renal
Cardiology
Pulmonology
Head and neck
Cardiology
Head and neck
Reproductive system
Oncology
Neurology
Head and neck
Musculoskeletal
Genitourinary
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
Genetics Q No:
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
Musculoskeletal
Dermatology
Hematology
Gastrointestinal system
Pulmonology
Dermatology
Endocrinology
Neurology
Neurology
Musculoskeletal
Neurology
Neurology
Gastrointestinal system
Neurology
Neurology
Cardiology
Hepatobiliary system
Hematology
Hematology
Reproductive system
Neurology
Neurology
Head and neck
Head and neck
Hematology
161
GENETICS
A.
Explanation:
F508 is the most common CETR gene mutation in patients with cystic fibrosis (CE).
This mutation deletes the three nucleotides that code for phenylalanine at amino
acid position 508. F508 is the mutation responsible in approximately 70% of CF
cases diagnosed worldwide.
The CETR gene codes for the cystic fibrosis transmembrane regulator (CETR)
protein, an integral membrane protein. The F508 mutation causes abnormal protein
folding and failure of glycosylation. The CRTR protein is degraded before it reaches
the cell surface, causing its complete absence from the apical membrane of exocrine
ductal epithelial cells. The molecular technique described in this question could help
CF patients by restoring CFTR proteins to the membrane.
(Choice A) Phenylketonuria results from mutations in the hepatocyte intracellular
enzyme phenylalanine hydroxylase. The result is protein misfolding. This enzyme is
not normally transported to the cell surface.
(Choice B) Sickle cell anemia results from mutations in the -globin gene of
hemoglobin S. This protein is not a transmembrane protein.
(Choice C) Marfan syndrome results from an inherited defect in the extracellular
glycoprotein, fibrillin-1. Fibrillin-1 is not an integral transmembrane protein. The
abnormal fibrillin-1 monomers disruptfibrillin-1 polymerization and prevent the
normal formation of microfibrils in interstitial connective tissue.
(Choice E) In Fredericks ataxia, the frataxin gene, which codes for a mitochondrial
protein important in respiratory function and iron homeostasis, is mutated. Here, a
GAA repeat disrupts transcription, not post-translational processing.
Educational Objective:
In most cases of CF, the mutation in the CFTR gene product causes defective posttranslational folding and glycosylation. The result is degradation of the CETR integral
membrane protein before it reaches the cell surface.
162
GENETICS
A.
Short
Explanation:
The 47 XXY karyotype is diagnostic of Klinefelter syndrome. The extra sex
chromosome is acquired due to meiotic nondisjunction during gametogenesis.
Variants include 48 XXXY and 46 XY/46 XXY mosaicism. Neonates are pheno
typically normal. Signs do not become evident until puberty. The major features of
this disorder are described below:
1. Klinefelter syndrome causes primary testicular failure due to hyalinization and
fibrosis of the seminiferous tubules and the subsequent lack of testosterone
synthesis. The testes are small and firm. These abnormalities result in
oligo/azoospermia, infertility, and absence of secondary sex characteristics.
Gonadotropin (FSHI LH) levels are increased, and the testosterone concentration is
low.
2. Testosterone deficiency also leads to the characteristic eunuchoid body habitus.
Patients have tall stature and gynecomastia. Facial and body hair is absent and
muscle mass is decreased.
3. Cognitive symptoms: Mild mental retardation is seen in some patients, though the
majority has normal intelligence. The risk and severity of mental retardation
increases with each additional X chromosome.
(Choice A) Patients with Turners syndrome have short stature, broad chest, and
primary amenorrhea. Only females are affected. Most of the patients have the
karyotype 45 XO, though some are 45 X0/46 XX mosaics.
(Choice C) Macroorchidism, large jaw and mental retardation are seen in patients
with fragile X syndrome, a common cause of hereditary mental retardation, inherited
as an X-linked trait.
(Choice D) Arachnodactyly, scoliosis and aortic root dilation are signs of Marfan
syndrome, which occurs due to an inherited defect of the extracellular matrix protein
fibrillin.
(Choice E) Patients with Prader-Willi syndrome have short stature, hypotonia and
obesity. This syndrome occurs due to a micro deletion on chromosome 15 that is
inherited from the father. Patients are mentally retarded.
Educational Objective:
47 XXY is the most common karyotype producing Klinefelter syndrome. Patients
present with tall stature, small firm testes, azoospermia and gynecomastia. Mild
mental retardation may be present.
163
GENETICS
Q NO 3: Bilateral renal masses composed of fat, smooth muscle and blood vessels
are detected in a young Caucasian woman. The patient is most likely to suffer
from:
A. Brain hamartomas and ash-leaf skin patches
B. Multiple peripheral neuro fibromas and caf au lait skin spots
C. Bilateral acoustic neuromas
D. Cerebellar hemangiomas and liver cysts
E. Capillary angiomas of the face and choroid
F. Multiple telangiectasias of the skin and mucosa
Explanation:
Renal angiomyolipoma is a benign tumor composed of blood vessels, smooth
muscle, and fat (angio-myo-lipoma). These tumors can be diagnosed with an
abdominal CT scan, as the density of fat is less than that of water.
Angiomyolipomas are associated with tuberous sclerosis. In patients with bilateral
renal angiomyolipomas, the incidence of tuberous sclerosis is 80-90%. Tuberous
sclerosis is an autosomal dominant condition characterized by cortical tubers and
subependymal hamartomas in the brain, with consequent seizures and mental
retardation. Cardiac rhabdomyomas, facial angiofibromas, and leat-shaped patches
of skin lacking pigment (ash leaf patches) can occur in this condition as well.
164
GENETICS
165
GENETICS
Educational Objective:
Patients with Turner syndrome may have karyotype 45, XO (complete monosomy),
45X0/46XX (mosaicism), or 46XX (with partial deletion of one X chromosome).
Mosaicism appears to account for a majority of cases of Turner syndrome.
166
GENETICS
If the mother is a carrier, the probability, p3, that she will transmit the mutant allele
to the child is 1/2. Finally the probability that the child will inherit two mutant
alleles, i.e. the probability of inheriting a mutant allele from the father and from the
mother, is p1 x p2 x p3 = 1/3.
Educational Objective:
The probability that an autosomal recessive disease will be transmitted to a child can
be calculated from the maternal and paternal pedigrees.
167
GENETICS
168
GENETICS
(Choice F)The 47, XYY karyotype is characterized by tall stature, severe acne, and
mild delays in both motor and language development. Male newborns with this
karyotype are pheno typically normal with no obvious dysmorphism.
Educational Objective:
Trisomy 13 (Patau syndrome) most often occurs secondary to nondisjunction during
maternal meiosis I. A severe condition trisomy 13 is strongly associated with cleft lip
and palate, polydactyly, rocker-bottom feet and holoprosencephaly.
169
GENETICS
170
GENETICS
A.
Explanation:
Huntington disease manifests with the triad of movement disorder (chorea),
behavioral abnormalities (aggressiveness, apathy or depression), and dementia.
Huntington disease is transmitted as an autosomal dominant trait with 100%
penetrance, meaning that if a child inherits the abnormal gene, that child will
inevitably develop Huntington disease. Most patients develop symptoms in their4os
or5os. An earlier age of onset is associated with a larger number of trinucleotide
repeats. During spermatogenesis, CAG repeats in the abnormal HD gene rapidly
increase. Thus, patients who receive an abnormal gene from their fathers tend to
develop the disease earlier in life. (The number of trinucleotide repeats on HD gene
remains the same during maternal transmission.) The tendency for clinical
symptoms to worsen and/or occur earlier in subsequent generations is called
anticipation.
Anticipation is common in disorders associated with trinucleotide repeats, as in
Fragile X syndrome, myotonic dystrophy, and Friedreich ataxia.
(Choice A) The transmission of an abnormal gene from a parent to a child does not
always cause disease. For example women with BRCA-2 mutations do not always
develop breast cancer. The likelihood that the properties of a gene will be expressed
is called penetrance. Huntington disease is a disorder with 100% penetrance; all
individuals who have an abnormal HD gene will develop Huntington disease.
(Choice B) Sometimes, one gene mutation leads to multiple phenotypic
abnormalities, a genetic phenomenon named pleiotropy. In Huntington disease,
pleiotropy is clearly at work because the mutation of one gene (HD) causes
dysfunction of behavior, of movement, and of cognition.
(Choice D)The presence of two populations of cells with different genotypes in one
patient is called mosaicism. Examples of mosaicism include milder forms of Turner
(genotype 46XX/45X0), Klinefelter (46XY/47XXY), and Down syndromes.
(Choice E) Deletion is the loss of genetic material. Examples of deletion are
DiGeorge syndrome (22q 11 micro deletions) and cri-du-chat syndrome (5p
deletion).
(Choice F) Genomic imprinting is a selective inactivation of the genes of either
maternal or paternal origin, causing a phenomenon sometimes called parent-oforigin gene expression. Genomic imprinting occurs in Prader-Willi and Angelman
syndromes. Both conditions involve deletion of the same gene on the same
chromosome (15), but yew different clinical manifestations occur depending on the
origin of the mutation. If the deletion comes from the father, Prader-Willi syndrome
occursaffected children show insatiable hunger and thirst and emotional lability;
171
GENETICS
172
GENETICS
173
GENETICS
174
GENETICS
175
GENETICS
176
GENETICS
Q NO 13: A neonate born to 41-year-old woman in her 39th week of gestation has a
flattened face and epicanthal folds. The childs echocardiography reveals an
endocardial cushion defect. Which of the following most likely occurred prior to
conception?
A. Meiotic non-disjunction
B. Robertsonian translocation
C. Expansion of trinucleotide repeats
D. Formation of fragile site
E. Inactivation of one chromosome
F. Deletion of chromosomal part
Explanation:
The infant described in this clinical vignette has some typical features of Down
syndrome. Characteristic appearance of these patients includes flat facies, epicanthal
folds, oblique palpebral fissures and a single palmar crease. Congenital heart defects
are seen in 50% of patients with Down syndrome, and endocardial cushion defects
are most commonly observed.
The majority of patients with Down syndrome have trisomy 21 that occurs as a
result of chromosomal nondisjunction (failure of chromosomes to separate) during
the first meiotic division of the ovum. The incidence of this abnormality increases
with maternal age.
(Choice B) Robertsonian translocation occurs due to a break near the centromeres of
two chromosomes, with transfer of genetic material between the chromosomes.
Robertsonian translocation accounts for 3-4% of Down syndrome cases, and is
inherited from one of the parents, most commonly the mother, during conception.
Common translocations are t(14:21) and t(21 22).
(Choice C) Disorders associated with expansion of trinucleotide repeats on the
specific gene include Huntington disease, myotonic dystrophy and fragile X
syndrome.
(Choice D) Formation of a fragile site on X chromosome is characteristic for fragile X
syndrome.
(Choice E) Selective inactivation of maternal or paternal alleles is called imprinting.
As a result of this process, the same genetic abnormality can cause different
disorders when inherited from the mother or the father. Prader-Willi and Angelman
syndromes are the classic examples of such disorders.
(Choice F) Many inherited diseases are caused by loss of part of chromosome
(deletion). Cri-du-chat syndrome (5p deletion), DiGeorge syndrome (22q11
microdeletion) and Prader-Willi syndrome (l5q deletion) are some examples.
Educational Objective:
Down syndrome is associated with characteristic physical exam findings such as a
flattened facies, epicanthal folds, oblique palpebral fissures, single palmar crease,
shortened fifth digit, large tongue and others. Congenital heart defects, especially
endocardial cushion defects, are common in children with Downs syndrome. The
majority of cases occur due to maternal meiotic nondisjunction.
177
GENETICS
178
GENETICS
Q NO 15: A Caucasian newborn with facial dysmorphia and cleft palate is found to
have a deletion involving the long arm of chromosome 22. These findings are most
consistent with:
A. Kartageners syndrome
B. Tuberous sclerosis
C. DiGeorge syndrome
D. Friedreichs ataxia
E. Marfan syndrome
F. Down syndrome
G. Turners syndrome
Explanation:
Deletions involving the long arm of chromosome 22 can result in facial, cardiac and
immunological abnormalities. DiGeorge syndrome is one such manifestation.
DiGeorge syndrome is defined by thymic aplasia and failure of parathyroid
formation, due to defective embryonic development of the third and fourth
pharyngeal pouches. Patients typically present with hypocalcemic tetany and
recurrent viral and fungal infections due to T-cell deficiency. Cardiac defects
associated with this syndrome are Tetralogy of Fallot and interrupted aortic arch.
Chromosome 22q 11.2 deletions are found in 90% of cases of DiGeorge syndrome.
(Choice A) Kartagener syndrome produces immotile cilia due to an autosomal
recessive microtubular defect. Male infertility, recurrent sinusitis, and bronchiectasis
result. There is an association with situs inversus.
(Choice B) Tuberous sclerosis is an autosomal dominant syndrome characterized by
cutaneous angiofibromas (adenoma sebaceum), seizures, and mental retardation.
Pathological lesions include CNS hamartomas and benign neoplasms, renal and other
visceral cysts, a variety of other hamartomas, and cardiac rhabdomyomas.
(Choice D) Friedreichs ataxia is an autosomal recessive spinocerebellar degeneration
with predominantly spinal ataxia. It is not usually associated with facial or palatal
malformations, but can be associated with hypertrophic cardiomyopathy.
(Choice E) Marfan syndrome is an autosomal dominant defect in a connective tissue
glycoprotein that can cause cystic medical necrosis of the aorta. It is not often
associated with a cleft palate, but rather a high arched palate, crowded teeth and a
narrow face.
(Choice F) Down syndrome results from trisomy 21. Patients have flat facies,
prominent epicanthal folds, and occasionally a cleft palate.
(Choice G) Turners syndrome is an XC sex chromosome disorder resulting in short
stature, webbed neck, ovarian failure, and possible coarctation of the aorta.
Educational Objective:
A variety of genetic disorders can result in facial and/or palatal malformations,
including deletions of the long arm of chromosome 22. However deletions involving
the long arm of chromosome 22 are also associated with DiGeorge syndrome
(congenital thymic and parathyroid aplasia, congenital cardiovascular anomalies).
179
GENETICS
Q NO 16: In a small city with a stable Caucasian population, the carrier frequency
for cystic fibrosis is 1/30 Caucasian individuals. In a nearby community, the cystic
fibrosis carrier frequency in Asian individuals is 1/100. What is the probability that
a child born to a mother from the Caucasian community and a father from the
Asian community will suffer from the disease?
A. 1/900
B. 1/1000
C. 1/3000
D. 1/6000
E. 1/12000
Explanation:
The mother in this scenario has a 1/30 probability of carrying the mutant CFTR allele
and the father has a 1/100 probability of carrying the mutant CFTR allele. If either
parent is a carrier the probability that the child will in her it the mutant allele from
that parent is 1/2. To inherit the cystic fibrosis disease the child must independently
inherit a mutant allele from both parents. The probability that the mother is a carrier
and that she will transmit the mutant allele is 1/30x 112 and the probability that the
father is a carrier and will transmit the mutant allele is 1/30x 1/2. The probability
that both events will occur producing a child with cystic fibrosis is the product of the
probabilities of these independent
Events = (1/30x1/2) x (1/100 x 1/2) = 1/12000.
Educational Objective:
After participating in this learning exercise you should be able to calculate the
probability that a child of parents from two populations with different mutant allele
carrier frequencies will inherit an autosomal recessive disease.
180
GENETICS
Q NO 17: Virus A cannot normally infect human epithelial cells. After exposure to
virus B in non-human cells, virus A acquires the ability to infect human epithelial
cells; however, the viral particles generated as a result of this infection still cannot
infect human epithelial cells. The phenomenon described is best categorized as
which of the following?
A. Reassortment
B. Recombination
C. Transformation
D. Phenotypic mixing
E. Interference
Explanation:
The acquisition of a new viral surface protein is often all that is necessary for a virus
to infect a new type of host cell. In the illustration above, the virus A genome
obtains some of the surface components of virus B (and vice versa) while both
viruses are present simultaneously in the same human cell. This exchange is defined
as phenotypic mixing, which generally occurs when a host cell is co-infected by two
viral strains and progeny virions are produced that contain nucleocapsid or envelope
proteins from the first strain and the genome of the second strain (or vice versa).
Since virus A acquired some virus B surface proteins but no genetic exchange
occurred, the progeny are considered phenotypically mixed. The next generation will
revert to having only virus A type surface proteins (virus A phenotype) and will again
be non-infectious for human epithelium.
(Choice A) Reassortment refers to changes in genomic composition that occur when
host cells are co-infected with two segmented viruses that exchange whole genome
segments. This process can cause sudden alterations in the surface antigens of the
viral progeny, as observed with the highly mutagenic influenza virus. When
reassortment takes place in a cell co-infected by two viral strains any genomic
change in the first generation progeny that is responsible for new infectivity to
human epithelial cells will also be present in the second generation.
(Choice B) Recombination may be defined as the exchange of genes between two
chromosomes (double-stranded DNA molecules) by crossing over within homologous
regions. When recombination takes place in a cell co-infected by two viral strains any
genomic change in the first generation progeny that is responsible for new infectivity
to human epithelial cells will also be present in the second generation.
181
GENETICS
182
GENETICS
183
GENETICS
Q NO 19: A stillborn fetus delivered at the 28th week of gestation has flat facial
features and excessive skin at the posterior neck. Autopsy findings include a
ventricular septal defect and duodenal atresia. Which of the following is the most
likely karyotype abnormality in this fetus?
Trisomy 21
B. Trisomy 18
C. Trisomy 13
D. 47, XXX
E. 47, XXY
F. 47, XYY
G. 45, XO
A.
Explanation:
Flat facial features and excessive skin at the nape of the neck are two of numerous
phenotypic features associated with Down syndrome (trisomy2l). Other classic
phenotypic findings include slanted palpebral fissures and a single transverse palmar
crease. Visceral anomalies are common. Cardiac defects are found in approximately
half of all infants with Down syndrome, with the endocardial cushion defect
(atrioventricular septal defect) and ventricular septal defect most often seen.
Gastrointestinal tract abnormalities are also identified in 10-15% of this patient
population, and can include duodenal atresia, Hirschsprungs disease, and
tracheoesophageal fistula.
Down syndrome incidence increases with maternal age. The vast majority of cases
arise due to chromosomal nondisjunction during maternal meiosis I, which results in
a full trisomy 21 present at conception.
(Choice B)Trisomy 18 (Edwards syndrome) often results in fetal death. Clinical
manifestations in liveborn infants include prominent occiput micrognathia, small
mouth, low-set and malformed ears, and rocker-bottom feet. Clenched hands with
the index finger overriding the middle finger and the fifth finger overriding the fourth
finger are characteristic for this condition.
(Choice C)Trisomy 13 (Patau syndrome) often results in fetal death. Clinical
manifestations in liveborn infants include cleft lip and palate polydactyly,
microcephaly, rocker-bottom feet and umbilical hernia. Cardiac and renal defects are
usually present.
(Choices D, E, and F) Karyotypes 47, XXX, 47, XXY (Klinefelter syndrome), and 47,
XYY do not cause death in utero. Newborns with these karyotypes are phenotypically
normal with no obvious dysmorphism.
(Choice G) Stillborn fetuses with Turner syndrome (45XO) are likely to have
edematous hands and feet cystic hygroma of the neck and coarctation of the aorta.
Turner syndrome is not associated with flat facial features ventricular septal defects
or duodenal atresia
Educational Objective:
Down syndrome (trisomy 21) occurs in approximately 1 in 730 live births. The
majority of fetuses with this chromosomal defect die in utero. The triple marker test,
quadruple marker test, and integrated test allow for Down syndrome screening.
Amniocentesis and chromosomal analysis of fetal cells can be used to verify the
diagnosis.
184
GENETICS
A.
Explanation:
This patient has a hydatidiform mole. A mole is a form of gestational trophoblastic
disease that can be classified as complete or partial. A complete mole has no fetal
structures and is composed entirely of large, edematous and disordered chorionic
villi that appear grossly as clusters of vesicular structures with a bunch of grapes
appearance. Complete moles almost always have a 46 XX karyotype, and all
chromosomes are paternally derived (Choice A). A complete mole forms when a
sperm fertilizes an egg and replicates its own chromosomes while eliminating the
maternal chromosomes. Androgenesis is the term for this process of formation and
survival of tissue of completely paternal derivation.
Unlike in a complete mole, a partial hydatidiform mole shows formation of some fetal
structures grossly. Additionally, a partial mole typically results from fertilization of an
ovum (one set of haploid maternal chromosomes) by two or more sperm (two sets
of haploid paternal chromosomes) resulting in karyotypes like 69 XXY or 69 XXX.
(Choice B) In most normal pregnancies, half of the chromosomes are from the father
and half are from the mother.
(Choices C and D) Conditions caused when a disproportionate amount of
chromosomes are either paternal or maternal include: partial molar pregnancy,
diseases caused by chromosomal nondisjunction such as Down, Edwards, and Patau
syndromes, and Klinefelter (XXY) and XYY syndromes.
Educational Objective:
A complete mole results from fertilization of an ovum that is devoid of genetic
material and subsequent reduplication of the paternal genetic complement giving a
characteristic 46 XX genotype.
185
GENETICS
186
GENETICS
Q NO 22: A Caucasian male presents to your office with mild headaches of recentonset and left leg weakness. The lesions on physical exam are shown in the photo
below.
187
GENETICS
Q NO 23: A stillborn fetus delivered at the 23rd week of gestation is found to have
an edematous neck and broad chest. Autopsy reveals aortal coarctation, a bicuspid
aortic valve, and kidneys that are fused at the midline. Which of the following is the
most likely karyotype abnormality in this fetus?
A. Trisomy 21
B. Trisomy 18
C. Trisomy 13
D. 47, XXX
E. 47, XXY
F. 45, XO
Explanation:
Turner syndrome (45, XO) is the likely diagnosis in a stillborn fetus with nuchal
edema broad chest, and coarctation of the aorta. Most fetuses possessing the 45 XO
karyotype abort spontaneously, with studies suggesting that 15% of all spontaneous
abortions are due to Turner syndrome. The most prominent finding in the neonate or
fetus with Turner syndrome is lymphedema of the hands and feet. Abnormal nuchal
lymphogenesis causes subcutaneous nuchal edema and cystic hygroma in utero. The
lymphedema is also responsible for other common manifestations of Turner
syndrome, including the webbed neck and low posterior hair line. Cardiac
abnormalities associated with Turner syndrome include coarctation of the aorta and
a bicuspid aortic valve. Horseshoe kidney (fusion of kidneys at the midline) is also
identified in many Turner syndrome females. In the adult, classic clinical
manifestations of Turner syndrome include short stature, broad shield-like chest,
webbed neck, and primary ovarian failure. The ovaries become infiltrated with
fibrous tissue (streak ovaries) and fail to produce estrogens.
(Choice A) The fetus with Down syndrome (trisomy 21) will typically have a flat face,
abnormal ears, slanted palpebral fissures, redundant skin at the nape of the neck,
hypotonia, pelvic dysplasia, and single transverse palmar crease.
(Choice B) Trisomy 18 (Edwards syndrome) is the second most common autosomal
trisomy identified in liveborn infants. Clinical manifestations include prominent
occiput, micrognathia, small mouth, low-set and malformed ears, and rocker-bottom
feet. Clenched hands with the index finger overriding the middle finger and the fifth
finger overriding the fourth finger are characteristic for this condition.
(Choice C) Trisomy 13 (Patau syndrome) is the third most common autosomal
trisomy identified in liveborn infants, and the most severe. Affected fetuses typically
have holoprosencephaly, microcephaly, polydactyly and rocker-bottom feet. Multiple
facial abnormalities (eg, hypotelorism, microphthalmia, cleft lip, cleft palate, absent
or malformed nose) frequently occur.
(Choice D) The 47 XXX karyotype is typically clinically silent. Some affected
individuals may have slightly decreased 10 scores. An increased risk of stillbirth is
not associated with this karyotype.
(Choice E) The 47, XXY (Klinefelter syndrome) may be associated with mild mental
retardation or normal intelligence. The typical patient is a tall male with
gynecomastia, small testes, and infertility. An increased risk of stillbirth is not
associated with this karyotype.
Educational Objective:
Lymphedema is a characteristic finding in a fetus afflicted with Turner syndrome (45,
XO). The lymphedema can vary in severity, ranging from edema of the hands and
feet to hydrops fetalis. Other common fetal Turner syndrome abnormalities include
coarctation of aorta and horseshoe kidney.
188
GENETICS
Q NO 24: A 5-year-old girl is brought to the physician by her mother. The mother
tells you that the girls skin becomes red and scaling with only minimal sun
exposure. She began to notice this phenomenon when the child was month old.
Now the girls skin is thin and hyperpigmented. The patient has a few nevi on her
hands that have been rapidly enlarging. The defective gene in this patient is
responsible for
A. Regulation of cell cycle
B. Signal transduction
C. DNA excision repair
D. DNA mismatch repair
E. Prevention of micro deletion
F. Regulation of apoptosis
Explanation:
This clinical vignette describes the typical presentation of xeroderma pigmentosum,
which literally means pigmented dry skin. This autosomal recessive (AR) condition
occurs due to decreased ability to repair DNA following damage by UV light. The skin
of affected individuals is normal at birth. The disease manifests during the first year
of life with erythema, scaling and subsequent hyperpigmentation and lentigo
formation on light-exposed areas (especially the face). Later, the skin of affected
areas shows atrophy telangiectasias and intermingling areas of hypo-and
hyperpigmentations. Skin malignancies, including squamous cell carcinoma, basal
cell carcinoma and malignant melanoma, develop as early as at 5-6 years of life.
Normally the regions of DNA damaged by UV radiation are excised and replaced. In
xeroderma pigmentosum, the genes that code for various DNA repair enzymes are
abnormal. Impairment of DNA repair results due to defects in excision of abnormal
nucleotides or defects in replacement of nucleotides following excision.
Other diseases associated with impaired DNA repair include Fanconi anemia (AR,
hypersensitivity to DNA cross- linking agents) and Bloom syndrome (AR,
hypersensitivity to UV damage and chemotherapeutic agents) among others.
(Choice A) The Rb (retinoblastoma) gene is responsible for regulation of the cell
cycle. The abnormal Rb protein loses its ability to arrest the cell cycle in the 01
phase. Mutation of Rb is associated with retinoblastoma and osteosarcoma.
(Choice B) Mutation of ras protein is found in many types of cancers. Ras codes for a
0-protein that regulates signal transduction. Abnormal ras stimulates signal
transduction leading to unregulated cell division, inhibited apoptosis and decreased
cell adhesion. These predispose to malignancy and metastasis.
(Choice D) Abnormalities of genes responsible for DNA mismatch repair are found in
patients with hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome).
These patients have higher incidence of colorectal carcinoma and other
malignancies.
(Choices E and F) Xeroderma pigmentosum is not associated with mutation of genes
that prevent micro deletions or regulate apoptosis though dysregulation of apoptosis
has been implicated in many forms of human cancer.
Educational Objective:
Xeroderma pigmentosum develops due to a defect in DNA excisional repair. This
disease is characterized by increased sensitivity to UV radiation and a high incidence
of all forms of cutaneous malignancy.
189
GENETICS
190
GENETICS
Q NO 26: A married couple presents to your office for routine prenatal counseling.
You notice that the husband is 120 cm (47) tall with disproportionately-short
upper and lower extremities. He cannot provide family history because he was
adopted. His spouse has normal constitutional features and her family history is
insignificant. They are concerned about their unborn childs height. Which of the
following is the best response to their concerns?
A. The risk for the child to be short is about 50%.
B. The risk depends on the mothers carrier status.
C. The risk depends on the childs gender.
D. The risk for the child to be short is about 25%.
E. The condition is not inheritable.
Explanation:
The husband in this vignette has disproportionately-short arms and legs, which
strongly suggests achondroplasia. The most common defect in achondroplasia is an
activating mutation offibrobIastgrothfactorreceptor-3. Patients with achondroplasia
have a normal spine length, but have short limbs, a large head, and sometimes a
saddle nose. Transmission of achondroplasia is autosomal dominant. If one parent
has an abnormal autosomal gene, there is a 50% chance that the parent will
transmit the gene to the child, which means a 50% risk that the child will have the
disease. Sometimes an inherited autosomal dominant trait does not result in the
disease phenotype; this phenomenon is known as incomplete penetration.
(Choices B and C) In sex-linked disorders, the responsible gene is located on a sex
chromosome (either X or Y). Most sex-linked disorders are X-linked recessive. In Xlinked recessive disorders, women with the defective gene will not have the disorder,
but will be carriers. Women with the affected X-linked, recessive gene has a 50%
chance of passing that gene on to their male or female children. The difference is
that male children only have one X chromosome and will be afflicted with the
disorder. Affected female children will be disease-free but will be carriers. The
chances bra carrier female to give birth to an diseased female is virtually 0%; the
chances of her giving birth to an affected male child is about 50%. Males carrying an
X-linked, recessive gene are affected; their daughters always become carriers but
their sons are never affected (because they do not receive an X chromosome from
the father).
In X-linked dominant disorders both males and females are affected. Of the sons and
daughters of an affected female approximately 50% will have the disorder. For an
affected male all of his daughters will be affected and none of his sons will carry or
manifest the disease.
191
GENETICS
192
GENETICS
Q NO 27: A young couple who recently immigrated from Eastern Europe brings their
3-year-old son to your office for evaluation of an eczematous rash. On exam you
observe that the child shows signs of mental retardation and has a mousy odor.
What is the likelihood that this couples next child will be affected with the same
disease?
A. Same as the general population
B. 1/32
C. 1/16
D. 118
E. 1/4
F. 1/2
Explanation:
Mental retardation, eczema, and a mousy, musty body odor are signs of
phenylketonuria (PKU). PKU is an autosomal recessive disease caused by mutation
of the gene that code for phenylalanine hydroxylase. In the United States,
phenylalanine levels are measured in all neonates to screen for PKU.
Because PKU is inherited in an autosomal recessive fashion, we know that both of
the parents described above must be heterozygous carriers of the mutation. The
probability that their next child will inherit the disease is thus:
p1 = probability that the mother transmits the mutant allele = 1/2
p2 = probability that the father transmits the mutant allele = 1/2
Because these are independent events, the probability that a child will inherit a
mutant allele from each carrier parent is equal to p1l x p2=%.
Educational Objective:
Mental retardation, eczema, and a mousy or musty body odor in a toddler are
signs of phenylketonuria (PKU). Most infants with PKU are born to two heterozygous
carrier parents. The probability that heterozygous carrier parents will transmit an
autosomal recessive disease like PRU to a child is 74.
193
GENETICS
Q NO 28: A 43-year-old male is being evaluated for persistent fever, recurrent gum
bleeding and fatigue. Findings of a peripheral blood smear are shown on the slide
below. Which of the following chromosomal abnormalities is most likely present in
the affected cells?
A. t(8;14)
B. t(9;22)
C. t(15;17)
D. t(11;14)
E. 13q-
Explanation:
This peripheral blood smear shows several myeloblasts, which are large cells with
abundant basophilic cytoplasm. Myeloblasts have a large number of coarse rodshaped intracytoplasmic granules, called Auer rods, a finding characteristic of acute
myelogenous leukemia (AML).
AML is divided into eight types:
194
GENETICS
production of the oncogene because of the frequency with which the immunoglobulin
gene is transcribed.
(Choice B) Translocation of the abl gene from chromosome 9 to chromosome 22 is
characteristic for chronic myelogenous leukemia (CML). t(9;22) forms the
Philadelphia chromosome and results in the formation of a new gene, bcr-abl,
whose product has tyrosine kinase activity.
(Choice D) Mantle cell lymphoma is a B-cell malignancy associated with t(11;14).
This translocation results in activation of the cyclin D gene.
(Choice E) Deletion of 13q is one of the molecular defects seen in chronic
lymphocytic leukemia (CLL).
Educational Objective:
The presence of rod-shaped intracytoplasmic inclusions known as Auer rods is
characteristic of many forms of acute myeloblastic leukemia (AML). The MS variant
of AMLI acute promyelocytic leukemia, is associated with the cytogenetic
abnormality (15:17).
195
GENETICS
Q NO 29: A 23-year-old male with a long history of diarrhea and crampy abdominal
pain is suspected to have ulcerative colitis. A colon biopsy reveals extensive
inflammatory cell infiltration of the mucosa. In the two weeks following the biopsy,
the patients condition improves, despite not receiving any new treatments. A repeat
biopsy reveals markedly decreased inflammation. Which of the following cytokines
most likely contributed to this change?
A. TNF-
B. IL-1
C. IL-4
D. IL-5
E. IL-10
F. IL-12
Explanation:
Essentially, this question asks us to identify which of the listed cytokines has antiinflammatory effects. TGF- and members of the IL-10 family are currently classified
as anti-inflammatory cytokines. Almost all cells express TGF- receptors. TGE-
inhibits Th2 lymphocyte differentiation, cytotoxic T-cell activities, and B-cell
immunoglobulin secretion. It may also suppress NK cells LAK cells, and the
cytotoxicity of mononuclear phagocytes.
In humans, monocytes and B-cells are the major producers of interleukin-10 (IL-10).
IL-10 inhibits IL-2 and IFN-y production by Th1 lymphocytes, IL-4 and IL-5
production by Th2 lymphocytes, and TNF- and IL-12 production by monocytes. It
also decreases NK cell IFN-y production. Moreover, IL-10 inhibits monocyte MHC
class II and B7 expression, impairing the ability of these antigen presenting cells to
activate Th cells. (B7 provides the necessary costimulatory signal.) In the presence
of IL-10, Th lymphocytes may be rendered permanently tolerant to specific antigens.
Educational Objective:
Of the cytokines released in the setting of tissue injury, TGE- and IL-10 are thought
to down regulate local cytokine production and inflammatory reactions contributing
to the systemic acute phase response. IL-1, IL-4, IL-5, and IL-12 stimulate local
immune reactions and may therefore be considered pro-inflammatory. IL-1 also acts
systemically to promote fever and other aspects of the acute phase response.
196
GENETICS
Q NO 30: A 4-year-old Caucasian male with recurrent lower lobe pulmonal infiltrates
is found to have high chloride content in his sweat. Which of the following
abnormalities is most likely in this patient?
A. Impaired synthesis of a transmembrane protein
B. Abnormal post-translational processing of a transmembrane protein
C. Decreased epithelial expression of a normal transmembrane protein
D. Poor AIP binding by a transmembrane protein
E. Decreased ion conduction by a transmembrane protein
Explanation:
High sweat chloride concentration is found in cystic fibrosis (CE). CF is characterized
by pancreatic insufficiency, sinopulmonary infections, and malabsorption. The most
common CETR gene abnormality (found in approximately 70% of cases) is a 3-base
pair deletion that removes a phenylalanine at amino acid position 508 (F 508). The
phenylalanine deletion causes abnormal folding and failure of glycosylation. The
abnormal protein is degraded before it reaches the cell surface. The F508 and most
other CETR mutations cause a complete absence of CETR from the apical membrane
of exocrine ductal epithelial cells.
Educational Objective:
Sweat chloride concentrations over 60 mmol/L are found in patients with cystic
fibrosis (CH) F5O8 is the most common CFTR mutation found in patients with CR
This mutation impairs post-translational processing of the CRTR gene transcript. The
result is degradation of the gene product before it can be transported to the cell
surface, causing complete absence of CETR protein from the apical membrane of
exocrine duct epithelial cells.
197
GENETICS
Q NO 31: A woman presents to your office complaining of hair loss. She is worried
that she will go bald because both her father and paternal grandmother suffered
from baldness. The most likely inheritance pattern of this condition is:
A. Autosomal dominant
B. Autosomal recessive
C. X-linked
D. Mitochondrial
E. Sporadic
Explanation:
This patient describes a condition with the following inheritance pattern:
The red arrow identifies the case (patient) under consideration. This pedigree could
represent autosomal dominant or X-Linked dominant transmission because the
disease is transferred to both male and female offspring from both male and female
parents, and all generations are affected.
The most common type of hair loss in males and females is androgenetic alopecia
(male pattern baldness). Androgenetic alopecia has autosomal dominant inheritance
with variable penetrance and expression.
(Choice B) The classic pedigree for autosomal recessive inheritance shows disease
development in 25% of offspring from two asymptomatic carrier parents. Typically
only one generation is affected.
(Choice D) Conditions passed by mitochondrial inheritance are transmitted only by
females. Affected males cannot pass the disorder to their offspring.
(Choice E) By definition, sporadic cases do not follow an inheritance pattern.
Sporadic cases occur haphazardly among unrelated members of a population
overtime. For example there maybe a spontaneous gene mutation that causes a
sporadic disorder in an individual with no family history of the disease.
Educational Objective:
A pedigree involving a female index case (proband), affected father, and affected
paternal grandmother most likely corresponds to autosomal dominant or X-linked
dominant inheritance. Androgenetic alopecia is the most common cause of hair loss
in both males and females and is generally inherited as an autosomal dominant or
polygenic disorder.
198
GENETICS
Q NO 32: A 14-year-old Caucasian male is brought to your office by his mother. She
is concerned because although tall her son looks much younger than his peers and
shows no signs of masculinity. On physical examination, the boy has poorlydeveloped secondary sexual characteristics. He is unable to distinguish smells, but
has good visual acuity. Which of the following pathways is most likely defective in
this patient?
A.
B.
C.
D.
E.
A
B
C
D
E
Explanation:
The male child in the vignette has delayed puberty plus anosmia, consistent with a
diagnosis of Kallmanns syndrome. Kallmanns syndrome results from a failure of
GnRH-secreting neurons to migrate from their origin in the olfactory placode
(situated outside the central nervous system) to their normal anatomic location in
the hypothalamus. Most often1 the cause is a mutation in either the KAL-1 gene or
the fibroblast growth factor receptor-i gene, which code for proteins required in this
migration.
Patients with Kallmanns syndrome classically have central hypogonadism and
anosmia, though there may be other midline defects as well (e.g. cleft lip or cleft
palate). Most often theses patients present with delayed puberty. On physical exam,
the testes are often just 1-2 ml in volume. There is usually some pubic hair because
adrenarche occurs normally.
In Caucasians delayed puberty is defined as the absence or incomplete
development of secondary sexual characteristics by age 14 in males and by age 12
in females. Testicular enlargement is the first sign of puberty in males and breast
enlargement is the first sign in females. The initiation of puberty and the
199
GENETICS
200
GENETICS
201
GENETICS
Q NO 34: A 15-year-old Caucasian male presents to your office with gait instability
and frequent falls. Physical examination reveals kyphoscoliosis, pes cavus, and
lower-extremity ataxia. Position and joint sensation are also impaired. If the
symptoms described are from an inherited disease this patient is most likely to die
of which of the following?
A. Liver failure
B. Cardiomyopathy
C. Renal disease
D. Intracranial bleeding
E. Aortic dissection
F. Brain tumor
Explanation:
Friedreich ataxia is an autosomal recessive condition. The posterior columns and the
spinocerebellar tracts of the spinal cord show degeneration; and loss of the larger
sensory cells of the dorsal root ganglia is also seen. Friedreich ataxia presents in
children 5-15 years old as gait ataxia (progressively slow and clumsy walking). A
wide-based gait with difficulty maintaining balance is characteristic.
The following symptoms are associated with Friedreich ataxia:
1. Progressive ataxia of all four limbs, caused by cerebellar dysfunction, is seen very
early. Degeneration of dorsal columns leads to loss of position and vibration
sensation.
2. Hypertrophic cardiomyopathy develops in more than 50% of patients. It leads to
cardiac arrhythmias and congestive heart failure (CHF).
3. Skeletal abnormalities include kyphoscoliosis, pes cavus, and hammertoes.
4. Diabetes mellitus develops in about 10% of the patients.
Complications from cardiomyopathy and bulbar dysfunction (unable to protect
airway) are the most common causes of death in patients with Friedreich ataxia.
The conditions mentioned in the other choices are not associated with Friedreich
ataxia.
(Choice A) Liver failure is associated with Wilson disease.
(Choice C) Kidney disease is associated with polycystic kidney disease, and presents
at later age.
(Choice D) Intracranial bleeding is associated with rupture of Berry aneurysm.
(Choice E) Aortic dissection is associated with Marfan syndrome.
(Choice F) Brain tumor (glioma) is associated with neurofibromatosis.
Educational Objective:
Friedreich ataxia is an autosomal recessive condition. The mutated gene on
chromosome 9 has an increased number of trinucleotide repeats. Friedreich ataxia is
often associated with hypertrophic cardiomyopathy, diabetes mellitus,
kyphoscoliosis, and foot deformities.
202
GENETICS
A.
Explanation:
The infant described above displays symptoms consistent with congenital
hypothyroidism. Affected neonates appear lethargic, feed poorly, exhibit prolonged
jaundice, and demonstrate constipation, muscle hypotonia, and a hoarse cry.
Physical examination of the infant with congenital hypothyroidism reveals pale dry,
cool skin; myxedema (edema of skin and subcutaneous fat); and macroglossia
(large tongue). Coarse facial features and umbilical hernia are commonly present as
well. These infants also have an increased incidence of congenital heart defects such
as ASD and VSD.
T4 is essential for normal brain development and myelination during early life1 and
undiagnosed congenital hypothyroidism produces profound and irreversible mental
retardation. This complication is prevented by screening newborns for congenital
hypothyroidism. (By law, newborns are also screened for phenylketonuria and
galactosemia.)
(Choice B) Infants with Down syndrome have upslanting palpebral fissures, bilateral
epicanthal folds, a flat nasal bridge and a large tongue. Other common features are
congenital heart defects, duodenal atresia and Hirschsprung disease. Down
syndrome is also associated with an increased risk of leukemia.
(Choice C) Infant botulism affects children 2-6 months of age who are fed honey. It
presents with constipation and poor sucking followed by muscle paralysis. Infant
botulism tends to be less severe than adult botulism.
(Choice D) Hirschsprung disease results from the abnormal migration of neural crest
cells into the rectosigmoid colon leading to an absence of ganglion cells in the
affected wall. It presents with abdominal distention bilious emesis, and failure to
pass meconium.
(Choice E) Phenylketonuria occurs due to an inborn deficiency of phenylalanine
hydroxylase that leads to an inability to metabolize phenylalanine. It manifests with
developmental delay mental retardation, mousy body odor and fair skin coloring.
Educational Objective:
Congenital hypothyroidism presents soon after birth with hypotonia, poor feeding,
jaundice, macroglossia, constipation and umbilical hernia. It should be diagnosed as
early as possible to prevent the development of mental retardation.
203
GENETICS
204
GENETICS
205
GENETICS
Q NO 38: A 5-year-old male suffers from recurrent diarrhea that does not respond
to short-term antibiotic therapy. Light microscopy of repeated duodenal aspirates
consistently reveals the following:
206
GENETICS
A. Short
Explanation:
Fragile X syndrome is the second most common cause of congenital mental
retardation after Down syndrome. It is inherited in an X-linked fashion. The defect is
an increased number of trinucleotide repeats (CGG) in the familial mental
retardation gene (FMR-1) located on the long arm of the X-chromosome. When the
cells of affected individuals are cultured in folate-deficient medium, the area of
increased repeats does not stain and appears broken hence the name fragile X.
Patients with fragile X syndrome display the following features:
1. Body habitus: Macrosomia with increased head circumference may be present at
birth. Older patients have dysmorphic facial features including large jaw, large
protruding ears, long thin face and prominent forehead. Postpubertal males
invariably have macroorchidism (enlarged testes).
2. Cognitive impairment: Becomes evident alter the 1st year of life. Patients
demonstrate mild-to-moderate mental retardation, severe language delay and
behavioral abnormalities (such as aggressiveness). Autistic features are more
common in children with fragile X syndrome than in the general population.
(Choice A) Short stature, broad (shield) chest, webbed neck and low hair line are
signs of Turners syndrome (45 XO). Affected females have primary amenorrhea due
to lack of estrogen secretion by underdeveloped (streak) ovaries.
(Choice B) Klinefelter syndrome (47 XXY) affects only males. Patients have tall
stature1 gynecomastia and small, firm testes. Decreased testosterone secretion by
fibrotic testes causes oligospermia and infertility.
(Choice D) In Marfan syndrome there is often arachnodactyly, scoliosis, and aortic
root dilation. Other associated abnormalities include lens dislocation (ectopia lentis)
and mitral valve prolapse.
(Choice E) Short broad fingers and transverse palmar crease are seen in Down
syndrome.
Educational Objective:
Fragile X syndrome is a common cause of inherited mental retardation. The disorder
is X-linked and affects males. Patients have mental retardation, dysmorphic facial
features (large jaw large protruding ears) and macroorchidism.
207
GENETICS
208
GENETICS
209
210
GENETICS
GENETICS
This patient is most likely to be suffering from which of the following conditions?
A. Hemophilia B
B. Huntingtons disease
C. Classical galactosemia
D. Lesch-Nyhan syndrome
E. Leber hereditary optic neuropathy
Explanation:
Each of the affected individuals on this pedigree has inherited the disorder from
asymptomatic parents, consistent with an autosomal recessive inheritance pattern.
Classical galactosemia is an autosomal recessive disease. Patients with galactosemia
are homozygous for a defective galactose-1-phosphate uridyltransferase gene. In
general, most enzyme deficiency conditions follow an autosomal recessive
inheritance pattern, whereas diseases due to defective non-catalytic proteins tend to
follow an autosomal dominant pattern.
(Choice A) Hemophilia B is an X-linked recessive Factor IX deficiency that affects
males.
(Choice B) Huntingtons disease is inherited in an autosomal dominant fashion.
Affected individuals generally have one affected parent. In this condition, there is
degeneration of the striatum (mainly the caudate nucleus and putamen).
(Choice D) Lesch-Nyhan syndrome is an X-linked recessive deficiency of
hypoxanthine phosphoribosyltransferase, the enzyme that promotes conversion of
hypoxanthine to IMP and guanine to GMP (purine salvage).
(Choice E) Leber hereditary optic neuropathy follows a mitochondrial inheritance
pattern.
Educational Objective:
On average autosomal recessive conditions affect 25% of offspring of asymptomatic
heterozygous carrier parents. Classical galactosemia is an autosomal recessive
disease.
211
GENETICS
Q NO 43: An infant born to a 35-year-old female has a flat nasal bridge and a small
mouth. Karyotype analysis on the infant reveals the following:
The patient is most likely to suffer from which of the following conditions?
A. Immotile cilia
B. Macroorchidism
C. Rickets
D. Red blood cell sickling
E. Acute lymphoblastic leukemia
F. Chronic myelogenous leukemia
Explanation:
This karyotype shows trisomy 21 (47XX, +21) indicating a diagnosis of Down
syndrome, the most common cause of congenital mental retardation. In most cases,
Down syndrome results from meiotic nondisjunction in the ovum; the parents are
generally genetically normal. Affected individuals may exhibit a simian crease,
abundant neck skin, prominent epicanthal folds, a flat facial profile, mental
retardation, a cleft palate, congenital heart disease, intestinal atresia, hypotonia,
and/or a gap between the first and second toes. Individuals with Down syndrome
have a 20-40 fold increased risk of developing acute lymphoblastic leukemia (ALL).
(Choice A) Immotile cilia are found in Kartagener syndrome, a condition caused in
most cases by an autosomal recessive mutation in the gene coding for the
microtubule associated protein, dynein. Male infertility, recurrent sinusitis, and
bronchiectasis result. Situs inversus may also be present.
212
GENETICS
213
GENETICS
214
GENETICS
215
GENETICS
Educational Objective:
Primary amenorrhea in a patient with fully developed secondary sexual
characteristics suggests the presence of an anatomic defect in the genital tract, such
as imperforate hymen or Mllerian duct abnormalities.
216
GENETICS
Q NO 46: A 23-year-old Caucasian male with mild mental retardation has large
ears, a long face, a prominent mandible, and large testes. His hand joints are
hyperextensible on physical examination. Which of the following is the most
likely diagnosis in this patient?
Klinefelter syndrome
B. Turner syndrome
C. 47 XYY karyotype
D. 47 XXX karyotype
E. Testicular feminization syndrome
F. Mllerian agenesis
G. Marfan syndrome
H. Fragile X syndrome
A.
Explanation:
This patient displays the clinical features of fragile X syndrome, which is the most
common cause of inherited mental retardation and the second leading overall cause
of congenital mental retardation after Down syndrome. A male that inherits one
abnormal X chromosome will always develop the disease, as he has only one X
chromosome. A female with one abnormal X chromosome generally has a milder
clinical presentation and more normal cognitive development because she inherits
two X chromosomes, with one of the two randomly inactivated in every cell. Overall
the prognosis of females with fragile X is highly variable and cannot be accurately
predicted.
Males with fragile X syndrome typically demonstrates several of the following signs:
1. Mild-to-moderate mental retardation (10 of 40-85), speech and language delay,
autistic behavior and ADHD
2. Long face, prominent jaws1 large ears, and cleft palate
3. Macroorchidism
4. Mitral valve prolapse
5. Short height, joint laxity, scoliosis, pes cavus, double-jointed thumbs, and a single
palmar crease
(Choice A) Klinefelter syndrome (41)0(Y) may be associated with mild mental
retardation or normal intelligence. The typical patient is a tall male with
gynecomastia, small testes, and infertility.
(Choice B) Females with Turner syndrome (45XO) present with primary amenorrhea
and mild mental retardation, though normal cognitive function is also possible. The
typical patient has short stature, webbed neck, shielded chest and ovarian
dysgenesis.
(Choice C) The 47XYY karyotype is characterized by tall stature, severe acne, and
mild delays in both motor and language development. Early research suggested that
these individuals were prone to heightened aggression as well, but more recent
studies suggest the increase in criminal activity among the 41 XYY populations is
actually secondary to lower mean IQs and associated poor judgment.
(Choice D) The 47XXX karyotype is typically clinically silent. Some affected
individuals may have slightly decreased IQ scores.
(Choice E) Testicular feminization syndrome (complete androgen insensitivity) is
characterized by normal external female genitalia but entirely absent wolffian and
mullerian structures. Mental retardation, facial deformities, and macroorchidism are
not seen.
(Choice F) Mllerian agenesis results in the congenital absence of the vagina and
variable uterine development. Mental retardation, facial deformities, and
macroorchidism are not seen.
217
GENETICS
218
GENETICS
219
GENETICS
220
GENETICS
A.
Explanation:
Down syndrome is the most common autosomal trisomy identified in liveborn
infants. As many as 95% of Down syndrome cases arise due to chromosomal
nondisjunction during maternal meiosis (47 XX, +21) an abnormality that positively
correlates with increasing maternal age. Two of the more prominent and consistent
lectures of Down syndrome are mental retardation and facial dysmorphism. Almost
every organ and system, however, is affected. The characteristic Down syndrome
abnormalities are categorized by system below.
221
GENETICS
222