1. A 5-year-old girl is brought to the physician by her mother. The
mother tells you that the girl's skin becomes red and scaling with only
minimal sun exposure. She began to notice this phenomenon when the
child was 7 months old. Now the girl's 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 microdeletions
F. Regulation of apoptosis
Answer: C
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 w ith 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 result 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
anaemia (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 G1 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 G-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 w ith 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 microdeletions or regulate apoptosis,
though dysregulation of apoptosis has been implicated in many forms of
human cancer.
2. A 20-year-old woman undergoes a bilateral oophorectomy. The
ovaries are small and underdeveloped. On light microscopic
examination, the ovaries are found to consist of connective tissue with
,no follicles present. This patient is at increased risk for which of the
following:
A. Mitral valve prolapse
B. Aortic coarctation
C. Lens displacement
D. Vaginal adenosis
E. Pancreatic insufficiency
Answer: B
Explanation:
The ovaries described in the vignette are the "streak ovaries" of Turner's
syndrome (karyotype 45 XO, lacking the paternal X chromosome). In
Turner's syndrome, the ovaries develop normally during foetal life.
However, lack of the paternal X chromosome causes loss of follicles by
age 2. At puberty, these patients develop normal pubic hair, but fail to
undergo breast development or menarche due to ovarian failure.
Turner's syndrome is one of the most common causes of primary
amenorrhea. Elevated levels of LH and FSH are characteristic.
Turner's syndrome is associated with a number of extragonadal
abnormalities, including:
1. Characteristic appearance: short stature, shield chest (broad, w ith w
idely spaced nipples), w ebbed neck {broad neck w ith low hairline)
2. Lymphedema may present at any age. Lymphedema in the neonate is
suggestive of Turner's syndrome.
, 3. Cardiovascular malformations, including coarctation of the aorta,
bicuspid aortic valve, and aortic dissection in adulthood.
(Choices A and C) Mitral valve prolapse and lens displacement are
seen in patients with Marfan syndrome. These patients are also at risk
for aortic root dilation and aortic dissection.
(Choice D) Vaginal adenosis is replacement of the vaginal squamous
epithelium with glandular columnar epithelium. It occurs in the female
children of women exposed to diethylstilbestrol (DES) during pregnancy.
Vaginal adenosis is a precursor of clear cell adenocarcinoma of the
vagina.
(Choice E) Pancreatic insufficiency occurs in patients with cystic
fibrosis.
3. A 14-year-old boy is brought to the physician by his mother. She is
concerned because although tall, her son looks much younger than his
peers and show s no signs of "masculinity." On physical examination,
the boy has poorly developed secondary sexual characteristics. He is
unable to distinguish smells but has good visual acuity. Which of the
following pathways is most likely defective for this patient?
mother tells you that the girl's skin becomes red and scaling with only
minimal sun exposure. She began to notice this phenomenon when the
child was 7 months old. Now the girl's 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 microdeletions
F. Regulation of apoptosis
Answer: C
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 w ith 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 result 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
anaemia (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 G1 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 G-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 w ith 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 microdeletions or regulate apoptosis,
though dysregulation of apoptosis has been implicated in many forms of
human cancer.
2. A 20-year-old woman undergoes a bilateral oophorectomy. The
ovaries are small and underdeveloped. On light microscopic
examination, the ovaries are found to consist of connective tissue with
,no follicles present. This patient is at increased risk for which of the
following:
A. Mitral valve prolapse
B. Aortic coarctation
C. Lens displacement
D. Vaginal adenosis
E. Pancreatic insufficiency
Answer: B
Explanation:
The ovaries described in the vignette are the "streak ovaries" of Turner's
syndrome (karyotype 45 XO, lacking the paternal X chromosome). In
Turner's syndrome, the ovaries develop normally during foetal life.
However, lack of the paternal X chromosome causes loss of follicles by
age 2. At puberty, these patients develop normal pubic hair, but fail to
undergo breast development or menarche due to ovarian failure.
Turner's syndrome is one of the most common causes of primary
amenorrhea. Elevated levels of LH and FSH are characteristic.
Turner's syndrome is associated with a number of extragonadal
abnormalities, including:
1. Characteristic appearance: short stature, shield chest (broad, w ith w
idely spaced nipples), w ebbed neck {broad neck w ith low hairline)
2. Lymphedema may present at any age. Lymphedema in the neonate is
suggestive of Turner's syndrome.
, 3. Cardiovascular malformations, including coarctation of the aorta,
bicuspid aortic valve, and aortic dissection in adulthood.
(Choices A and C) Mitral valve prolapse and lens displacement are
seen in patients with Marfan syndrome. These patients are also at risk
for aortic root dilation and aortic dissection.
(Choice D) Vaginal adenosis is replacement of the vaginal squamous
epithelium with glandular columnar epithelium. It occurs in the female
children of women exposed to diethylstilbestrol (DES) during pregnancy.
Vaginal adenosis is a precursor of clear cell adenocarcinoma of the
vagina.
(Choice E) Pancreatic insufficiency occurs in patients with cystic
fibrosis.
3. A 14-year-old boy is brought to the physician by his mother. She is
concerned because although tall, her son looks much younger than his
peers and show s no signs of "masculinity." On physical examination,
the boy has poorly developed secondary sexual characteristics. He is
unable to distinguish smells but has good visual acuity. Which of the
following pathways is most likely defective for this patient?
