130 - Hereditary Disorders of Genome Instability and DNA Repair Flashcards
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
Yes
Spontaneous genome instability is present in
Bloom syndrome
Ataxia telangiectasia
Fanconi anemia
Genome instability is present in cells from patients with _____ only after exposure to DNA-damaging agents
Xeroderma pigmentosum
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
Xeroderma pigmentosum
Cockayne syndrome
Trichothiodystrophy
Defects in the DNA mismatch repair result in
Hereditary nonpolyposis colon cancer (Lynch syndrome) and its subform, Muir-Torre syndrome
RecQ family members are mutated in
Bloom syndrome
Werner syndrome
Rothmund-Thomson syndrome
Accelerated telomere shortening is a hallmark of cells from patients with the cancer-prone disorder
Dyskeratosis congenita
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
Ataxia-telangiectasia Seckel syndrome Nijmegen breakage syndrome Hereditary breast cancer Bloom syndrome Fanconi anemia Hereditary colon cancer
CUTANEOUS
Photosensitivity (burning on sun exposure), poikiloderma, alopecia
NEOPLASIA
Osteosarcomas, cutaneous SCC, and others
OTHER
Skeletal abnormalities, growth deficiency, juvenile cataracts, osteoporosis
Rothmund-Thomson syndrome
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
Fanconi anemia
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
Dyskeratosis congenita
CUTANEOUS
Telangiectasias
NEOPLASIA
T-cell leukemia, lymphomas
OTHER
Progressive cerebellar ataxia, immune defects, hypogonadism, increased acute toxicity of therapeutic X-ray
Ataxia-telangiectasia
Similar to AT, but no ocular telangiectasias
AT-like disorder
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
Nijmegen breakage syndrome
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
Seckel syndrome
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
Xeroderma pigmentosum
Onset of freckling (lentigines) on sun-exposed skin in XP before age _____ in most patients
2 years
Median age of onset of nonmelanoma skin cancer in XP
8 years
_____ abnormalities are almost as common as the cutaneous abnormalities and are an important feature of XP
Ocular
Y/N: posterior portion of the eye is affected in XP
No - The posterior portion of the eye (retina) is shielded from UV radiation by the anterior, UV-exposed structures
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
De Sanctis-Cacchione syndrome
Predominant neuropathologic abnormality found at autopsy in XP patients with neurologic symptoms was
Loss (or absence) of neurons, particularly in the cerebrum and cerebellum
Median age of death of persons with XP with neurodegeneration
29 years
Median age of death of persons with XP without neurodegeneration
37 years
XP DNA excision repair-deficient complementation groups
XPA-A to XPA-G
Mutated genes identified in XP
DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC
Patients with clinical XP but normal NER
XP variants
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
A
Most common form of XP in Japan
XP complementation group A
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
XP complementation group C
Most common group of XP in the United States, Europe and Egypt
C
XP complementation group _____ patients are found mainly in Japan
Most have mild clinical symptoms without neurologic abnormalities or skin cancer
F
In XP variant, there is a defect in an error-prone, translesional DNA damage bypass polymerase, _____
POLH
Y/N: Both parents of XP patients are aysmptomatic carriers of mutations in of these genes
Yes
There is a _____ chance that their offspring will have inherited a mutated allele form each parent and thus have symptomatic XP
1 in 4
DNA-damaging agents that have been found to yield hypersensitive responses with XP cells
Drugs (psoralens, chlorpromazine)
Cancer chemotherapeutic agents (cisplatin, carmustine)
Chemical carcinogens (benozopyrene derivatives present in cigarette smoke)
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
Hartnup disorder
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
Carney complex
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
Cockayne syndrome
Most common causes of death in XP
Skin cancer
Neurologic degeneration
Internal cancer
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
CSB (ERCC6)
CSA (ERCC8)
Diagnostic criteria for CS: Minor criteria (3 out of 5)
Cutaneous photosensitivity Pigmentary retinopathy and/or cataracts Progressive sensorineural hearing loss Tooth enamel hypoplasia Bilateral calcifications of the putamen
Diagnostic criteria for CS:
Brain imaging criteria
White matter hypomyelination
Cerebellar atrophy or hypoplasia
Bilateral calcifications of the putamen
Diagnostic criteria for CS: Major criteria (mandatory)
Developmental delay
Progressive growth failure
Progressive microcephaly
Median age of date in CS
8.4 years
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
Presence of cataracts before 3 years of age
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
Trichothiodystrophy
Characterized by sulfur-deficient brittle hair
Trichothiodystrophy
TTD is caused by different mutations in some of the same genes that cause _____
XP
The functional defect in XP is abnormal repair, whereas the abnormality in TTD is thought to be related to
Transcription
Majority of TTD patients have a defect in
XPD (ERCC2)
Disease onset of Cockayne syndrome is usually in the _____ year of life
Second
Most deaths in TTD are caused by
Infection
_____ patients have an unusual combination of osteosclerosis of the axial skeleton and osteopenia of the peripheral skeleton
TTD
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
Hereditary nonpolyposis colon cancer/Muir-Torre syndrome
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
Bloom syndrome
BS is caused by a mutation in
BLM, a RecQ helicase
BS is most frequent among
Ashkenazi Jews
_____ cells are characterized by an increase in the frequency of spontaneous sister chromatid exchanges between homologous chromosomes
Characterized by hyperrecombination
BS
BS patients usually die before the age of 30 years from
Either cancer or infection
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)
Werner syndrome
Rare disorder of premature aging (progeria) with an increased cancer risj
Werner syndrome (adult progeria)
WS is caused by a mutation in
WRN, a RecQ helicase
Cells in ______ demonstrate impaired DNA metabolism and a reduced replicative life span
WS
Most WS patients are
Japanese
Y/N: Patients with WS are clinically normal until adolescence
Yes
Often, _____ are the first to make a diagnosis of WS as _____ develop early
Ophthalmologists
Cataracts
10:1 ratio between epithelial and mesenchymal cancer seen in a normally aging population is shifted to _____ in WS patients
1:1
Death from _____ usually occurs before the age of 50 years in WS
Myocardial infarction or cancer
Rare chromosomal instability syndrome with an increased cancer risk and a typical poikiloderma that starts on the face during infancy
Rothmund-Thomson syndrome
In two-thirds of patients, RTS is caused by a mutation in the DNA helicase
RecQL4
RTS patients have a predisposition for cancer, in particular for
Osteosarcomas
Y/N: Life expectancy is limited by cancer, but is normal in RTS without cancer
Yes
FA is an autosomal recessive or in the case of _____ X-linked disease
Fanconi anemia complementation group B
The estimated incidence of Fanconi anemia is higher in
Afrikaners and Ashkenazi Jews
If patients with FA survive aplastic anemia and/or leukemia, they often develop solid tumors by the fifth decade of life, mostly
Squamous cell carcinomas of the head and neck and the anogenital areas
FA is genetically heterogeneous with _____ complementation groups
19
FA proteins have been shown to act in a common DNA damage recognition and repair pathway, which also involves
BRCA1 and BRCA2
Increased chromosome breakage after exposure to DNA crosslinking agents such as mitomycin C or diepoxybutane is a feature of
FA
Treatment of choice for aplastic anemia/myelodysplastic syndrome and leukemia
Allogenic hematopoietic stem cell transplantation
Rare telomere instability syndrome with an increased risk for pancytopenia, myelodysplasia, and acute myeloid leukemia
Dyskeratosis congenita
Dyskeratosis congenita patients commonly present with a triad of
Reticulated hyperpigmentation
Dystrophic nails
Mucosal leukoplakia
Mode of inheritance of dyskeratosis congenita
X-linked
Also with autosomal dominant recessive forms
Main cause of early death in dyskeratosis congenita
Bone marrow failure
Short telomere length is a typical finding in _____ and used for diagnosis
Dyskeratosis congenita
