130 - Hereditary Disorders of Genome Instability and DNA Repair

Question 1

Y/N: Although hereditary disorders of genome instability and DNA repair are rare, heterozygous carriers of affected genes, which may comprise several percent of the general population, may carry an increased cancer risk as well

Answer 1

Yes

Question 2

Spontaneous genome instability is present in

Answer 2

Bloom syndrome
Ataxia telangiectasia
Fanconi anemia

Question 3

Genome instability is present in cells from patients with _____ only after exposure to DNA-damaging agents

Answer 3

Xeroderma pigmentosum

Question 4

The nucleotide excision repair (NER) pathway, which possesses bulky DNA lesions, including UV-induced DNA photoproducts, is impaired in _____. However, only XP patients have an increased cancer risk

Answer 4

Xeroderma pigmentosum
Cockayne syndrome
Trichothiodystrophy

Question 5

Defects in the DNA mismatch repair result in

Answer 5

Hereditary nonpolyposis colon cancer (Lynch syndrome) and its subform, Muir-Torre syndrome

Question 6

RecQ family members are mutated in

Answer 6

Bloom syndrome
Werner syndrome
Rothmund-Thomson syndrome

Question 7

Accelerated telomere shortening is a hallmark of cells from patients with the cancer-prone disorder

Answer 7

Dyskeratosis congenita

Question 8

Genome instability may result from a defect in BASC, a multienzyme complex centered around the BRCA1 protein in the nucleus, and cause the genome instability disorders including

Answer 8

Ataxia-telangiectasia
Seckel syndrome
Nijmegen breakage syndrome
Hereditary breast cancer
Bloom syndrome
Fanconi anemia
Hereditary colon cancer

Question 9

CUTANEOUS
Photosensitivity (burning on sun exposure), poikiloderma, alopecia

NEOPLASIA
Osteosarcomas, cutaneous SCC, and others

OTHER
Skeletal abnormalities, growth deficiency, juvenile cataracts, osteoporosis

Answer 9

Rothmund-Thomson syndrome

Question 10

CUTANEOUS
Cafe-au-lait macules
NEOPLASIA
Myeloid leukemia, SCC of the head and neck

OTHER
Aplastic anemia, pancytopenia growth retardation, thumb and other bone abnormalities

Answer 10

Fanconi anemia

Question 11

CUTANEOUS
Lacy, reticular pigmentation of neck and upper chest, nail dystrophy, premature gray hair, hyperhidrosis, skin cancer

NEOPLASIA
Mucosal leukoplakia leading to cancer of anus or mouth, Hodgkin disease, pancreatic adenocarcinoma

OTHER
Stenosis of lacrimal duct, anemia, pancytopenia, immunodeficiency, learning difficulties, deafness, brain calcifications, cerebellar hypoplasia, testicular atrophy, short stature, intrauterine growth retardation, retinopathy

Answer 11

Dyskeratosis congenita

Question 12

CUTANEOUS
Telangiectasias

NEOPLASIA
T-cell leukemia, lymphomas

OTHER
Progressive cerebellar ataxia, immune defects, hypogonadism, increased acute toxicity of therapeutic X-ray

Answer 12

Ataxia-telangiectasia

Question 13

Similar to AT, but no ocular telangiectasias

Answer 13

AT-like disorder

Question 14

CUTANEOUS
Cafe-au-lait macule, vitiligo

NEOPLASIA
B-cell and T-cell lymphomas, rhabdomyosarcoma, neuroblastoma

OTHER
Immune defects, growth retardation, microcephaly, mental retardation, characteristic facies

Answer 14

Nijmegen breakage syndrome

Question 15

CUTANEOUS
Cafe-au-lait macules

NEOPLASIA
Leukemia

OTHER
Proportionate dwarfism, microcephaly, mental retardation, characteristic facies (receding forehead, narrow face, large beaked nose, micrognathia), immune deficiency, pancytopenia

Answer 15

Seckel syndrome

Question 16

CUTANEOUS
Photosensitivity (burning on minimal sun exposure in some patients), freckle-like (lentiginous) macules, poikiloderma, skin cancer

NEOPLASIA
BCC, SCC, melanoma, CNS tumors

OTHER
Sensorineural deafness, progressive neurologic degeneration, primary loss of neurons

Answer 16

Xeroderma pigmentosum

Question 17

Onset of freckling (lentigines) on sun-exposed skin in XP before age _____ in most patients

Answer 17

2 years

Question 18

Median age of onset of nonmelanoma skin cancer in XP

Answer 18

8 years

Question 19

_____ abnormalities are almost as common as the cutaneous abnormalities and are an important feature of XP

Answer 19

Ocular

Question 20

Y/N: posterior portion of the eye is affected in XP

Answer 20

No - The posterior portion of the eye (retina) is shielded from UV radiation by the anterior, UV-exposed structures

Question 21

Most severe from of XP which involves the cutaneous and ocular manifestations of classic XP plus additional neurologic and somatic abnormalities, including microcephaly, progressive mental deterioration, low intelligence, hyporeflexia or areflexia, choreoathetosis, ataxia, spasticity, Achilles tendon shortening leading to quadriparesis, dwarfism, and immature sexual development

Answer 21

De Sanctis-Cacchione syndrome

Question 22

Predominant neuropathologic abnormality found at autopsy in XP patients with neurologic symptoms was

Answer 22

Loss (or absence) of neurons, particularly in the cerebrum and cerebellum

Question 23

Median age of death of persons with XP with neurodegeneration

Answer 23

29 years

Question 24

Median age of death of persons with XP without neurodegeneration

Answer 24

37 years

Question 25

XP DNA excision repair-deficient complementation groups

Answer 25

XPA-A to XPA-G

Question 26

Mutated genes identified in XP

Answer 26

DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC

Question 27

Patients with clinical XP but normal NER

Answer 27

XP variants

Question 28

XP complementation group _____ contains patients with the most-severe neurologic and somatic abnormalities (the De Sanctis-Caccione syndrome), as well as patients with minimal or no neurologic abnormalities

Answer 28

A

Question 29

Most common form of XP in Japan

Answer 29

XP complementation group A

Question 30

XP with skin and ocular involvement but without neurologic abnormalities Typically do not give a history of blistering sunburns on minimal sun exposure and at times are first diagnosed with the appearance of skin cancer in a child

Answer 30

XP complementation group C

Question 31

Most common group of XP in the United States, Europe and Egypt

Answer 31

C

Question 32

XP complementation group _____ patients are found mainly in Japan Most have mild clinical symptoms without neurologic abnormalities or skin cancer

Answer 32

F

Question 33

In XP variant, there is a defect in an error-prone, translesional DNA damage bypass polymerase, _____

Answer 33

POLH

Question 34

Y/N: Both parents of XP patients are aysmptomatic carriers of mutations in of these genes

Answer 34

Yes

Question 35

There is a _____ chance that their offspring will have inherited a mutated allele form each parent and thus have symptomatic XP

Answer 35

1 in 4

Question 36

DNA-damaging agents that have been found to yield hypersensitive responses with XP cells

Answer 36

Drugs (psoralens, chlorpromazine) Cancer chemotherapeutic agents (cisplatin, carmustine) Chemical carcinogens (benozopyrene derivatives present in cigarette smoke)

Question 37

Differential diagnosis of XP that is a disorder of amino acid absorption resulting from biallelic pathogenic variants in SLC6A19, a nonpolar amino acid transporter Affected individuals may have reduced levels of niacin with resulting pellagra-like symptoms of photosensitivity with dermatitis, diarrhea, and dementia

Answer 37

Hartnup disorder

Question 38

Differential diagnosis of XP that is characterized by lentigines without evidence of the usually associated signs of skin damage, such as atrophy and telangiectasia (ie, poikiloderma), and cutaneous findings are not limited to sun-exposed sites

Answer 38

Carney complex

Question 39

CUTANEOUS Photosensitivity (burning on minimal sun exposure in some patients) NEOPLASIA No increased incidence OTHER Typical facial features (deep-set eyes, loss of subcutaneous fat), pigmentary retinal degeneration, postnatal growth failure, sensorineural deafness, progressive neurologic degeneration, primary dysmyelination, brain calcifications

Answer 39

Cockayne syndrome

Question 40

Most common causes of death in XP

Answer 40

Skin cancer Neurologic degeneration Internal cancer

Question 41

Cells from CA patients have a defect in transcription coupled DNA repair with approximately two-thirds having mutations in the _____ gene and one-third with mutations in the _____ gene

Answer 41

CSB (ERCC6) | CSA (ERCC8)

Question 42

``` Diagnostic criteria for CS: Minor criteria (3 out of 5) ```

Answer 42

``` Cutaneous photosensitivity Pigmentary retinopathy and/or cataracts Progressive sensorineural hearing loss Tooth enamel hypoplasia Bilateral calcifications of the putamen ```

Question 43

Diagnostic criteria for CS: | Brain imaging criteria

Answer 43

White matter hypomyelination Cerebellar atrophy or hypoplasia Bilateral calcifications of the putamen

Question 44

``` Diagnostic criteria for CS: Major criteria (mandatory) ```

Answer 44

Developmental delay Progressive growth failure Progressive microcephaly

Question 45

Median age of date in CS

Answer 45

8.4 years

Question 46

Single most important prognostic factor with a statistically significant association with reduced survival, earlier onset of hearing loss, and earlier onset of contractures in CS

Answer 46

Presence of cataracts before 3 years of age

Question 47

CUTANEOUS Brittle hair, photosensitivity (burning on minimal sun exposure in some patients), ichthyosis, collodion membrane, "tiger tail banding" of hair with polarized microscopy NEOPLASIA No increased incidence OTHER Congenital cataracts, short stature, developmental delay, microcephaly, brain dysmyelination (failure to develop white matter), recurrent infections

Answer 47

Trichothiodystrophy

Question 48

Characterized by sulfur-deficient brittle hair

Answer 48

Trichothiodystrophy

Question 49

TTD is caused by different mutations in some of the same genes that cause _____

Answer 49

XP

Question 50

The functional defect in XP is abnormal repair, whereas the abnormality in TTD is thought to be related to

Answer 50

Transcription

Question 51

Majority of TTD patients have a defect in

Answer 51

XPD (ERCC2)

Question 52

Disease onset of Cockayne syndrome is usually in the _____ year of life

Answer 52

Second

Question 53

Most deaths in TTD are caused by

Answer 53

Infection

Question 54

_____ patients have an unusual combination of osteosclerosis of the axial skeleton and osteopenia of the peripheral skeleton

Answer 54

TTD

Question 55

CUTANEOUS Sebaceous tumors (benign and malignant) Keratoacanthomas NEOPLASIA Low-grade cancer of the colon, endometrium, stomach, small intestine, hepatobiliary system, upper urethral tract, larynx, and ovary; sebaceous carcinoma; BCC with sebaceous differentiation

Answer 55

Hereditary nonpolyposis colon cancer/Muir-Torre syndrome

Question 56

CUTANEOUS Photosensitivty (burning on sun exposure), malar erythema, cafe-au-lait macules NEOPLASIA Most cancer types, particularly leukemias, lymphomas, carcinomas of the breast and GI tract OTHER Immune deficiency, growth retardation, unusual facies, male infertility and female subfertility, Type II diabets

Answer 56

Bloom syndrome

Question 57

BS is caused by a mutation in

Answer 57

BLM, a RecQ helicase

Question 58

BS is most frequent among

Answer 58

Ashkenazi Jews

Question 59

_____ cells are characterized by an increase in the frequency of spontaneous sister chromatid exchanges between homologous chromosomes Characterized by hyperrecombination

Answer 59

BS

Question 60

BS patients usually die before the age of 30 years from

Answer 60

Either cancer or infection

Question 61

CUTANEOUS Graying of hair, skin atrophy, leg ulcers, melanomas NEOPLASIA Sarcomas, thyroid cancer, meningiomas, melanomas (acral lentiginous and mucous membrane melanomas) ``` OTHER Premature aging (atherosclerosis, diabetes mellitus, osteoporosis, cataracts) ```

Answer 61

Werner syndrome

Question 62

Rare disorder of premature aging (progeria) with an increased cancer risj

Answer 62

Werner syndrome (adult progeria)

Question 63

WS is caused by a mutation in

Answer 63

WRN, a RecQ helicase

Question 64

Cells in ______ demonstrate impaired DNA metabolism and a reduced replicative life span

Answer 64

WS

Question 65

Most WS patients are

Answer 65

Japanese

Question 66

Y/N: Patients with WS are clinically normal until adolescence

Answer 66

Yes

Question 67

Often, _____ are the first to make a diagnosis of WS as _____ develop early

Answer 67

Ophthalmologists | Cataracts

Question 68

10:1 ratio between epithelial and mesenchymal cancer seen in a normally aging population is shifted to _____ in WS patients

Answer 68

1:1

Question 69

Death from _____ usually occurs before the age of 50 years in WS

Answer 69

Myocardial infarction or cancer

Question 70

Rare chromosomal instability syndrome with an increased cancer risk and a typical poikiloderma that starts on the face during infancy

Answer 70

Rothmund-Thomson syndrome

Question 71

In two-thirds of patients, RTS is caused by a mutation in the DNA helicase

Answer 71

RecQL4

Question 72

RTS patients have a predisposition for cancer, in particular for

Answer 72

Osteosarcomas

Question 73

Y/N: Life expectancy is limited by cancer, but is normal in RTS without cancer

Answer 73

Yes

Question 74

FA is an autosomal recessive or in the case of _____ X-linked disease

Answer 74

Fanconi anemia complementation group B

Question 75

The estimated incidence of Fanconi anemia is higher in

Answer 75

Afrikaners and Ashkenazi Jews

Question 76

If patients with FA survive aplastic anemia and/or leukemia, they often develop solid tumors by the fifth decade of life, mostly

Answer 76

Squamous cell carcinomas of the head and neck and the anogenital areas

Question 77

FA is genetically heterogeneous with _____ complementation groups

Answer 77

19

Question 78

FA proteins have been shown to act in a common DNA damage recognition and repair pathway, which also involves

Answer 78

BRCA1 and BRCA2

Question 79

Increased chromosome breakage after exposure to DNA crosslinking agents such as mitomycin C or diepoxybutane is a feature of

Answer 79

FA

Question 80

Treatment of choice for aplastic anemia/myelodysplastic syndrome and leukemia

Answer 80

Allogenic hematopoietic stem cell transplantation

Question 81

Rare telomere instability syndrome with an increased risk for pancytopenia, myelodysplasia, and acute myeloid leukemia

Answer 81

Dyskeratosis congenita

Question 82

Dyskeratosis congenita patients commonly present with a triad of

Answer 82

Reticulated hyperpigmentation Dystrophic nails Mucosal leukoplakia

Question 83

Mode of inheritance of dyskeratosis congenita

Answer 83

X-linked | Also with autosomal dominant recessive forms

Question 84

Main cause of early death in dyskeratosis congenita

Answer 84

Bone marrow failure

Question 85

Short telomere length is a typical finding in _____ and used for diagnosis

Answer 85

Dyskeratosis congenita