130: Hereditary Disorders of Genome Instability and DNA Repair Flashcards
What are the primary damaging agents that threaten DNA integrity?
The primary damaging agents that threaten DNA integrity include oxidative stress, ultraviolet (UV) radiation, X radiation, and chemical agents.
What is the significance of a mutator phenotype in carcinogenesis?
A mutator phenotype is significant in carcinogenesis because it is often regarded as a prerequisite for the accumulation of several mutations in specific genes of a single cell, which is necessary for malignant transformation.
What is xeroderma pigmentosum (XP) and how does it relate to DNA damage?
Xeroderma pigmentosum (XP) is a genetic disorder characterized by an impaired nucleotide excision repair (NER) pathway, leading to increased sensitivity to DNA-damaging agents such as UV radiation.
What are the clinical features associated with xeroderma pigmentosum?
The clinical features associated with xeroderma pigmentosum include:
- Skin: 50% have a history of acute burning on minimal sun exposure; freckle-like hyperpigmented macules appear on sun-exposed skin.
- Eyes: Ocular abnormalities, including photophobia and keratitis.
- Neurologic System: Early onset of symptoms, potential for mental retardation, and other neurological issues.
- Cancer Risk: Greater than 10,000-fold increased risk of cutaneous BCC, SCC, or melanoma.
What role do helicases play in DNA repair?
Helicases are proteins that unwind DNA and are essential for various metabolic processes involving DNA, such as transcription, replication, and repair. They are crucial for the nucleotide excision repair (NER) pathway, which is impaired in conditions like xeroderma pigmentosum.
What is the relationship between telomere maintenance and genetic instability?
Genetic instability can result from abnormal telomere maintenance. Some telomeric repeats are lost at each cell division, and shortened telomere lengths are a feature of aged cells.
What is a prerequisite for carcinogenesis?
A mutator phenotype, which requires the accumulation of several mutations in specific genes of a single cell.
What is the nucleotide excision repair (NER) pathway’s role in xeroderma pigmentosum (XP)?
It is impaired in XP, leading to increased cell death and mutagenesis.
What is the increased cancer risk associated with xeroderma pigmentosum (XP)?
XP patients have an increased risk of skin cancers such as BCC, SCC, or melanoma.
What are the clinical features of xeroderma pigmentosum (XP) related to skin exposure?
50% have a history of acute burning on minimal sun exposure, while the other 50% tan normally without excessive burning.
What is the median age of onset for cutaneous symptoms in xeroderma pigmentosum (XP)?
1 to 2 years old.
What ocular abnormalities are associated with xeroderma pigmentosum (XP)?
Ocular abnormalities include reduced tearing, dry eyes, and increased pigmentation of the lids.
What is the most severe form of xeroderma pigmentosum (XP) known as?
De Sanctis-Cacchione syndrome.
What is a hallmark of cells from patients with dyskeratosis congenita?
Accelerated telomere shortening.
What are the laboratory tests used to diagnose Xeroderma Pigmentosum (XP)?
Laboratory tests for diagnosing XP include:
1. Cellular Hypersensitivity: Assessing the ability of XP fibroblasts to repair UV-damaged DNA.
2. Chromosome Abnormalities: Observing increases in chromosome breakage after UV exposure.
3. DNA Repair Testing: Measuring nucleotide incorporation into DNA, which is reduced in XP cells.
4. Drug and Chemical Hypersensitivity: Testing reactions to specific drugs and carcinogens.
5. DNA Sequence Analysis: Analyzing DNA from blood or cultured cells.
6. Prenatal Diagnosis: Measuring UV-induced unscheduled DNA synthesis in amniotic fluid cells.
What is the primary cause of hypersensitivity in patients with Xeroderma Pigmentosum (XP)?
UV radiation exposure.
What are the seven DNA excision repair-deficient complementation groups identified in XP?
XP-A to XP-G.
What is the defect in cells from XP-variant patients?
An error-prone DNA polymerase (POLH) that bypasses unrepaired DNA damage.
What characterizes Complementation Group A in XP patients?
Patients with the most severe neurologic and somatic abnormalities, including the De Sanctis-Cacchione syndrome.
What is the most common form of XP in Japan?
Patients with XPA mutations.
What is the clinical feature of Complementation Group C in XP?
XP with skin and ocular involvement but without neurologic abnormalities.
What is the significance of UV-irradiated XP fibroblasts in laboratory testing?
They are hypermutable compared to normal fibroblasts, indicating a defect in DNA repair.
What type of abnormalities are observed in chromosomes after UV radiation exposure in XP patients?
Abnormally large increases in chromosome breakage and sister chromatid exchanges.
What is the role of DNA sequence analysis in diagnosing XP?
To analyze DNA obtained from blood, cheek cells, or cultured cells for abnormalities.
What is a differential diagnosis consideration for patients with cutaneous photosensitivity?
Other diseases such as porphyria, RTS, and Baller-Gerold syndrome should be ruled out.
What management strategies should be employed to protect the eyes in patients with XP?
Management includes the use of UV-absorbing glasses with side shields, methylcellulose eye drops to keep the cornea moist, and surgical treatment for neoplasms of the lids, conjunctiva, and cornea.
What are the recommended treatment options for basal cell carcinoma (BCC) in XP patients?
Treatment options include surgical excision, Mohs micrographic surgery, or electrodessication and curettage. Oral vismodegib may be considered for metastatic or locally advanced BCC.
What are the treatment options for actinic keratoses in XP patients?
Treatment options include freezing with liquid nitrogen, topical 5-fluorouracil, or imiquimod. Photodynamic therapy may also be used with caution.
What are the major criteria for diagnosing Cockayne Syndrome (CS)?
The major criteria for diagnosing Cockayne Syndrome (CS) include:
1. Developmental delay
2. Progressive growth failure
3. Progressive microcephaly.
What is the clinical significance of cataracts appearing before the age of 3 in patients with Cockayne Syndrome (CS)?
The presence of cataracts before 3 years of age is the single most important prognostic factor in Cockayne Syndrome (CS), associated with reduced survival, earlier onset of hearing loss, and earlier onset of contractures.
What are the common laboratory findings in patients with Cockayne Syndrome (CS)?
Common laboratory findings in patients with Cockayne Syndrome (CS) include:
- Sensorineural deafness
- Neuropathic electromyogram abnormalities
- Slow motor nerve conduction velocity
- Abnormal electroencephalogram
- X-ray examination may show thickened skull and microcephaly
- CT may reveal normal-pressure hydrocephalus and calcification
- MRI shows atrophy and dysmyelination of the cerebrum and cerebellum.
What are the genetic mutations associated with Cockayne Syndrome (CS)?
Cockayne Syndrome (CS) is caused by mutations in the following genes:
- CSB (ERCC6) in approximately two-thirds of patients
- CSA (ERCC8) in approximately one-third of patients.
What are the imaging findings in Cockayne Syndrome (CS)?
CT may reveal normal-pressure hydrocephalus and calcification. MRI shows atrophy and dysmyelination of the cerebrum and cerebellum.
What are the genetic mutations associated with Cockayne Syndrome (CS)?
Cockayne Syndrome (CS) is caused by mutations in the following genes: CSB (ERCC6) in approximately two-thirds of patients and CSA (ERCC8) in approximately one-third of patients.
What are the differential diagnoses for growth failure in patients with Cockayne Syndrome (CS)?
Differential diagnoses for growth failure in patients with Cockayne Syndrome (CS) include chromosomal disorders, endocrine disorders, GI disorders, congenital infections (e.g., rubella, toxoplasmosis), mitochondrial dystrophies, and other syndromes such as Cornelia de Lange syndrome, Dubowitz syndrome, Hallermann-Streiff syndrome, Russell-Silver syndrome, and Seckel syndrome.
What is the most severe form of Cockayne Syndrome (CS)?
COFS syndrome is the most severe form of CS.
What are the major diagnostic criteria for Cockayne Syndrome?
Developmental delay, progressive growth failure, and progressive microcephaly are major criteria for diagnosis.
What is the inheritance pattern of Cockayne Syndrome?
Cockayne Syndrome is an autosomal recessive disorder.
What is the significance of cataracts appearing before 3 years of age in Cockayne Syndrome?
The presence of cataracts before 3 years of age is the single most important prognostic factor associated with reduced survival.
What laboratory findings are common in patients with Cockayne Syndrome?
Clinical laboratory testing often shows sensorineural deafness and slow motor nerve conduction velocity.
What is the role of molecular testing in the management of Cockayne Syndrome?
Molecular testing is used to identify mutations in CSA, CSB, and other related genes for proper management.
What are some features of Xeroderma Pigmentosum - Cockayne Syndrome complex?
Features include freckle-like pigmentation on sun-exposed skin and reduced DNA excision repair.
What is Trichothiodystrophy characterized by?
Trichothiodystrophy is characterized by sulfur-deficient brittle hair and a broad spectrum of clinical abnormalities.
What diagnostic imaging findings are expected in a patient with Cockayne Syndrome presenting with progressive microcephaly and pigmentary retinal degeneration?
Brain MRI may show atrophy and dysmyelination of the cerebrum and cerebellum, while CT may reveal calcifications.
What is the most important prognostic factor for survival in a patient with Cockayne Syndrome presenting with progressive neurologic degeneration and cataracts?
The presence of cataracts before 3 years of age is the most important prognostic factor, associated with reduced survival.
How does photosensitivity in Cockayne Syndrome differ from Xeroderma Pigmentosum (XP)?
Unlike XP, CS patients have photosensitivity without the excessive pigmentary abnormalities seen in XP.
What are the mandatory major diagnostic criteria for Cockayne Syndrome?
The mandatory major diagnostic criteria for CS are developmental delay, progressive growth failure, and progressive microcephaly.
What laboratory findings are expected in cultured cells from a patient with Cockayne Syndrome?
Cultured cells from CS patients are hypersensitive to UV-induced inhibition of growth and colony-forming ability.
What are the clinical features associated with Trichothiodystrophy (TTD) in newborns?
Clinical features of TTD in newborns include generalized redness or a mild collodion appearance that clears over weeks, short broken hair, episodes of hair loss, a tiger tail appearance due to dark-and-light banding, hair shaft abnormalities such as undulating surface, trichoschisis, and trichorrhexis nodosa-like defects, brittle hair shafts due to reduced levels of sulfur matrix proteins and cysteine, and approximately 50% of patients exhibit clinical photosensitivity.
What is the significance of mutations in the TTDN1 gene in TTD patients?
Mutations in the TTDN1 gene are significant because patients with these mutations are more likely to display autistic behaviors, often have delayed bone age and seizures, and are less likely to have low birth weight, collodion presentation, cataracts, and brain abnormal myelination.
How is Trichothiodystrophy diagnosed based on clinical features?
The diagnosis of TTD is made based on clinical features in association with characteristic hair shaft abnormalities, such as tiger tail banding and reduced sulfur content. Identification of mutations can confirm the diagnosis, but failure to identify mutations does not diminish the clinical diagnosis. A typical presentation includes an infant with preterm delivery, short stature, congenital cataracts, and cryptorchidism.
What are the noncutaneous findings associated with Trichothiodystrophy?
Noncutaneous findings in TTD include a broad spectrum of growth and developmental abnormalities, typical abnormalities include dysmorphic features, neurologic issues, ophthalmologic problems, and recurrent infections, decreased red blood cell mean corpuscular volume and increased hemoglobin A2 levels mimic β-thalassemia trait, and developmental delay may be associated with brain dysmyelination, but patients do not exhibit retinal changes or brain calcifications seen in other syndromes.
What is the clinical course and prognosis for children with Trichothiodystrophy?
The clinical course and prognosis for children with TTD include being prone to feeding difficulties, failure to thrive, and recurrent infections, with a high mortality rate (>20%) in children younger than 10 years, with most deaths caused by infection.
What are the clinical features of Trichothiodystrophy in newborns?
Generalized redness or a mild collodion appearance, short broken hair, episodes of hair loss, and a ‘tiger tail’ appearance in hair shafts.
