130: Hereditary Disorders of Genome Instability and DNA Repair Flashcards
1
Q
What are the primary damaging agents that threaten DNA integrity?
A
The primary damaging agents that threaten DNA integrity include oxidative stress, ultraviolet (UV) radiation, X radiation, and chemical agents.
2
Q
What is the significance of a mutator phenotype in carcinogenesis?
A
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.
3
Q
What is xeroderma pigmentosum (XP) and how does it relate to DNA damage?
A
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.
4
Q
What are the clinical features associated with xeroderma pigmentosum?
A
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.
5
Q
What role do helicases play in DNA repair?
A
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.
6
Q
What is the relationship between telomere maintenance and genetic instability?
A
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.
7
Q
What is a prerequisite for carcinogenesis?
A
A mutator phenotype, which requires the accumulation of several mutations in specific genes of a single cell.
8
Q
What is the nucleotide excision repair (NER) pathway’s role in xeroderma pigmentosum (XP)?
A
It is impaired in XP, leading to increased cell death and mutagenesis.
9
Q
What is the increased cancer risk associated with xeroderma pigmentosum (XP)?
A
XP patients have an increased risk of skin cancers such as BCC, SCC, or melanoma.
10
Q
What are the clinical features of xeroderma pigmentosum (XP) related to skin exposure?
A
50% have a history of acute burning on minimal sun exposure, while the other 50% tan normally without excessive burning.
11
Q
What is the median age of onset for cutaneous symptoms in xeroderma pigmentosum (XP)?
A
1 to 2 years old.
12
Q
What ocular abnormalities are associated with xeroderma pigmentosum (XP)?
A
Ocular abnormalities include reduced tearing, dry eyes, and increased pigmentation of the lids.
13
Q
What is the most severe form of xeroderma pigmentosum (XP) known as?
A
De Sanctis-Cacchione syndrome.
14
Q
What is a hallmark of cells from patients with dyskeratosis congenita?
A
Accelerated telomere shortening.
15
Q
What are the laboratory tests used to diagnose Xeroderma Pigmentosum (XP)?
A
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.
16
Q
What is the primary cause of hypersensitivity in patients with Xeroderma Pigmentosum (XP)?
A
UV radiation exposure.
17
Q
What are the seven DNA excision repair-deficient complementation groups identified in XP?
A
XP-A to XP-G.
18
Q
What is the defect in cells from XP-variant patients?
A
An error-prone DNA polymerase (POLH) that bypasses unrepaired DNA damage.
19
Q
What characterizes Complementation Group A in XP patients?
A
Patients with the most severe neurologic and somatic abnormalities, including the De Sanctis-Cacchione syndrome.
20
Q
What is the most common form of XP in Japan?
A
Patients with XPA mutations.
21
Q
What is the clinical feature of Complementation Group C in XP?
A
XP with skin and ocular involvement but without neurologic abnormalities.
22
Q
What is the significance of UV-irradiated XP fibroblasts in laboratory testing?
A
They are hypermutable compared to normal fibroblasts, indicating a defect in DNA repair.
23
Q
What type of abnormalities are observed in chromosomes after UV radiation exposure in XP patients?
A
Abnormally large increases in chromosome breakage and sister chromatid exchanges.
24
Q
What is the role of DNA sequence analysis in diagnosing XP?
A
To analyze DNA obtained from blood, cheek cells, or cultured cells for abnormalities.
25
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.
26
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.
27
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.
28
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.
29
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.
30
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.
31
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.
32
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.
33
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.
34
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.
35
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.
36
What is the most severe form of Cockayne Syndrome (CS)?
COFS syndrome is the most severe form of CS.
37
What are the major diagnostic criteria for Cockayne Syndrome?
Developmental delay, progressive growth failure, and progressive microcephaly are major criteria for diagnosis.
38
What is the inheritance pattern of Cockayne Syndrome?
Cockayne Syndrome is an autosomal recessive disorder.
39
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.
40
What laboratory findings are common in patients with Cockayne Syndrome?
Clinical laboratory testing often shows sensorineural deafness and slow motor nerve conduction velocity.
41
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.
42
What are some features of Xeroderma Pigmentosum - Cockayne Syndrome complex?
Features include freckle-like pigmentation on sun-exposed skin and reduced DNA excision repair.
43
What is Trichothiodystrophy characterized by?
Trichothiodystrophy is characterized by sulfur-deficient brittle hair and a broad spectrum of clinical abnormalities.
44
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.
45
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.
46
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.
47
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.
48
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.
49
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.
50
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.
51
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.
52
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.
53
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.
54
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.
55
What is the primary defect in patients with Trichothiodystrophy?
A defect in the XPD (ERCC2) gene.
56
What are some noncutaneous findings associated with Trichothiodystrophy?
Dysmorphic features, neurologic issues, recurrent infections, and developmental delays.
57
How is the diagnosis of Trichothiodystrophy confirmed?
Through examination of hair shafts for characteristic abnormalities and testing for mutations.
58
What is the prognosis for children with Trichothiodystrophy?
High mortality (>20%) in children younger than 10 years, primarily due to infections.
59
What are the hair shaft abnormalities seen in Trichothiodystrophy?
Trichoschisis, trichorrhexis nodosa-like defects, and reduced levels of cysteine and cystine.
60
What is the significance of the 'tiger tail' appearance in hair shafts?
It is a characteristic feature associated with Trichothiodystrophy.
61
What are the common mutations found in Trichothiodystrophy patients?
Mutations in the XPD (ERCC2), XPB (ERCC3), and TTDA (GTF2H5) genes.
62
What developmental issues are associated with Trichothiodystrophy?
Developmental delay and dysmyelination, similar to Cockayne Syndrome (CS).
63
What is the likely diagnosis for a newborn with brittle hair and ichthyosis, and what gene mutation is most commonly associated?
The likely diagnosis is Trichothiodystrophy (TTD). The most commonly associated gene mutation is in XPD (ERCC2).
64
What laboratory findings are expected in the hair shafts of a patient with Trichothiodystrophy?
Hair shafts in TTD show tiger tail banding, reduced sulfur content, and abnormalities such as trichoschisis and trichorrhexis nodosa-like defects.
65
What clinical features distinguish Trichothiodystrophy from Xeroderma Pigmentosum?
TTD patients do not develop poikilodermatous changes or skin cancer, which are characteristic of XP.
66
What are the clinical features of Bloom Syndrome (BS)?
Cutaneous findings include facial erythema and telangiectasia resembling lupus erythematosus, often present within the first few weeks after birth in the malar area, on the nose, and around the ears. Sun exposure accentuates these abnormalities, potentially causing bullae, bleeding, and crusting of the lips and eyelids. Café-au-lait spots are common, sometimes accompanied by adjacent depigmented areas.
67
What is the management approach for patients with Bloom Syndrome (BS)?
Management focuses on identification and support for individual clinical problems, photosensitivity management, neurologic and developmental assessment, ophthalmologic consultation, prophylactic antibiotics or intravenous immunoglobulin for recurrent infections, gastrostomy tubes (G-tubes) for nutrition, rehabilitation medicine and support, and monitoring during pregnancy due to high complication rates for affected fetuses.
68
What are the complications associated with Bloom Syndrome (BS)?
Patients with BS are predisposed to multiple infections due to immune dysfunction, decreased fertility, diabetes mellitus, and approximately 20% of patients develop malignancies, with half occurring before age 20 years.
69
What is the etiology of Bloom Syndrome (BS)?
Bloom Syndrome is caused by mutations in the BLM gene, which encodes a RecQ helicase. BS cells are characterized by an increase in the frequency of spontaneous sister chromatid exchanges and exchanges between homologous chromosomes, often visualized by quadriradial chromosomes formed by hyperrecombination.
70
What is the clinical course and prognosis for patients with Bloom Syndrome (BS)?
Patients with Bloom Syndrome usually die before the age of 30 years, primarily from either cancer or infection.
71
What is Bloom Syndrome (BS)?
A rare, autosomal recessive disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency, and predisposition to various cancers.
72
What are the cutaneous findings associated with Bloom Syndrome?
Facial erythema and telangiectasia resembling lupus erythematosus, sun exposure accentuating these abnormalities, and café-au-lait spots.
73
What is the clinical course and prognosis for patients with Bloom Syndrome?
Patients usually die before the age of 30 years from either cancer or infection.
74
What is Werner Syndrome (WS)?
A rare, autosomal recessive disorder characterized by features of premature aging and increased cancer risk.
75
What are the cutaneous findings in Werner Syndrome?
Clinically normal until adolescence, then premature development of aging features like graying hair, loss of subcutaneous fat, and wrinkling of skin.
76
What noncutaneous findings are associated with Werner Syndrome?
Signs of premature aging affecting other organs, including Type 2 diabetes, osteoporosis, and cardiovascular disease.
77
What is the management recommendation for Bloom Syndrome?
There is no specific treatment; early monitoring for the development of cancers is recommended.
78
What is the primary cause of Werner syndrome (WS)?
WS is caused by a mutation in the WRN gene, which encodes a RecQ helicase. Most mutations result in truncation of the protein with loss of the nuclear targeting sequence.
79
What are the clinical features of Rothmund-Thomson syndrome (RTS)?
The hallmark of RTS includes poikiloderma with variegated cutaneous pigmentation, atrophy, and telangiectasias. RTS patients also exhibit photosensitivity, prominent erythema, and facial swelling upon sun exposure, along with sparse scalp hair, eyebrows, and eyelashes, and abnormal nails.
80
What is the estimated incidence of Fanconi Anemia (FA)?
The estimated incidence of Fanconi Anemia is 1 in 200,000 to 1 in 400,000 persons.
81
What are the management recommendations for patients with Rothmund-Thomson syndrome (RTS)?
Management for RTS includes photoprotection and regular skin checks to screen for skin cancers, amelioration of the telangiectatic component of poikiloderma by photocoagulation with a pulsed-dye laser, and consideration of cellular and clinical hypersensitivity to ionizing radiation and chemotherapeutic agents when using radiation or chemotherapy for cancer treatment.
82
What are the noncutaneous findings associated with Fanconi Anemia (FA)?
Noncutaneous findings in FA include hematopoietic manifestations usually onset before age 10 years, leading to diagnosis, and hypocellular bone marrow with progressive decrease in hematopoietic cells.
83
What is the cause of Werner syndrome (WS)?
WS is caused by a mutation in the WRN gene, which encodes a RecQ helicase.
84
What is a common complication in patients with Rothmund-Thomson syndrome?
RTS patients have a predisposition for cancer, particularly for osteosarcomas, squamous cell carcinomas, and basal cell carcinomas.
85
What cancers are patients predisposed to with Werner syndrome?
Patients have a predisposition for cancer, particularly for osteosarcomas, squamous cell carcinomas, and basal cell carcinomas.
86
What is the management recommendation for patients with Werner syndrome?
Early monitoring for the development of cancers, management of heart disease, and avoidance of risk factors for cardiovascular disease is recommended.
87
What are the noncutaneous findings in Fanconi Anemia?
Hematopoietic manifestations usually have their onset before age 10 years and most commonly lead pediatricians to make the diagnosis of FA.
88
What is the significance of RECQL4 mutations in Rothmund-Thomson syndrome?
Mutations in the helicase RECQL4 have been identified in approximately 67% of patients with RTS, while the gene defects of the other 33% remain unknown.
89
What is a common clinical course for patients with Werner syndrome?
Death from either myocardial infarction or cancer usually occurs before the age of 50 years.
90
What is a characteristic feature of Fanconi Anemia?
FA is characterized by progressive pancytopenia, growth retardation, and various congenital abnormalities of the heart, kidney, and limbs.
91
What is the underlying genetic defect in Werner Syndrome?
Werner Syndrome is caused by mutations in the WRN gene, which encodes a RecQ helicase.
92
What genetic mutation is most commonly associated with Rothmund-Thomson Syndrome?
Rothmund-Thomson Syndrome is most commonly associated with mutations in the RecQL4 gene.
93
What is the typical cause of death in Werner Syndrome?
Death in Werner Syndrome typically occurs before the age of 50 years due to myocardial infarction or cancer.
94
What is the hallmark cutaneous finding in Rothmund-Thomson Syndrome?
The hallmark cutaneous finding in Rothmund-Thomson Syndrome is poikiloderma, characterized by variegated pigmentation, atrophy, and telangiectasias.
95
What is the underlying cellular defect in Werner Syndrome?
Werner Syndrome is characterized by genome instability, including increased nonhomologous chromosome exchanges and large chromosomal deletions.
96
What other cancers are Rothmund-Thomson Syndrome patients predisposed to?
RTS patients are predisposed to osteosarcomas and squamous cell carcinomas.
97
What is the typical age of onset for clinical features in Werner Syndrome?
Clinical features of Werner Syndrome typically begin in adolescence, with the absence of a normal growth spurt.
98
What is the genetic basis for Rothmund-Thomson Syndrome Type 1?
RTS Type 1 is associated with mutations in the RecQL4 gene, but these patients may not have an increased risk for osteosarcoma.
99
What are the common clinical features of Fanconi Anemia (FA)?
The common clinical features of Fanconi Anemia include:
- **Skeletal malformations**: Aplasia or hypoplasia of the thumb, metacarpals, or radius.
- **Short stature** and **renal deformities**.
- **Strabismus**, **microphthalmia**, and **hypogonadism**.
- **CNS abnormalities**: Including hyperreflexia and mild mental retardation.
- **Cutaneous findings**: Reticulated hyperpigmentation, dystrophic nails, and mucosal leukoplakia.
100
What is the significance of the FANCD2 protein in the diagnosis of Fanconi Anemia?
The FANCD2 protein is central to the FA/BRCA pathway. The **inability of FA cells to ubiquitinate the FANCD2 protein** after exposure to DNA crosslinking agents is currently used as a **screening tool** to confirm the diagnosis of Fanconi Anemia.
101
What are the complications associated with Dyskeratosis Congenita?
Complications of Dyskeratosis Congenita include:
- **Bone marrow failure**: Reported in 93% of patients, with 71% of early deaths attributed to this.
- **Increased incidence of solid tumors**: Particularly squamous cell carcinoma of the mouth, rectum, cervix, vagina, esophagus, and skin.
- **Other complications**: Learning difficulties, progressive pulmonary disease, and intracranial calcifications.
102
What are the noncutaneous findings associated with Dyskeratosis Congenita?
Noncutaneous findings in Dyskeratosis Congenita include:
- **Pancytopenia** before the age of 10 years.
- **Predisposition to myelodysplasia** and acute myeloid leukemia.
- **Mucosal constrictions**: In the esophagus, urethra, and lacrimal duct.
- **Multiple dental caries** and early loss of teeth.
- **Learning difficulties** or mental retardation in 20% of patients.
103
What is the estimated incidence of Dyskeratosis Congenita?
The estimated incidence of Dyskeratosis Congenita is **1 in 1 million persons**. Affected females may have either the **autosomal dominant** or **autosomal recessive** form.
104
What are the common skeletal malformations associated with Fanconi Anemia (FA)?
Aplasia or hypoplasia of the thumb, metacarpals, or radius.
105
What are the cutaneous findings in Dyskeratosis Congenita?
A triad of reticulated hyperpigmentation, dystrophic nails, and mucosal leukoplakia.
106
What is a major complication of Fanconi Anemia?
The frequency of acute myelogenous leukemia has been reported to be elevated 500-fold.
107
What is the treatment of choice for aplastic anemia/myelodysplastic syndrome in Fanconi Anemia?
Allogeneic hematopoietic stem cell transplantation.
108
What is the main cause of early death in patients with Dyskeratosis Congenita?
Bone marrow failure.
109
What is the role of the FANCD2 protein in Fanconi Anemia?
It is involved in the monoubiquitination process that is central to the FA/BRCA pathway.
110
What are the noncutaneous findings in Dyskeratosis Congenita?
Pancytopenia, predisposition to myelodysplasia and acute myeloid leukemia, and multiple dental caries.
111
What is the genetic basis of Dyskeratosis Congenita?
It is caused by germline mutations in one of several telomere biology genes, such as DKC1.
112
What diagnostic test confirms Fanconi Anemia?
FA is confirmed by increased chromosome breakage after exposure to DNA crosslinking agents such as mitomycin C or diepoxybutane.
113
What is the genetic basis of Fanconi Anemia?
Fanconi Anemia is genetically heterogeneous, involving mutations in 19 complementation groups (FANCA to FANCT) that act in a common DNA repair pathway.
114
What hematologic manifestations are expected in Fanconi Anemia?
Hematologic manifestations include pancytopenia, with progressive decreases in platelets, granulocytes, and erythrocytes.
115
What is the role of the FA/BRCA pathway in DNA repair?
The FA/BRCA pathway mediates DNA recombination to repair DNA strand breaks and crosslinks, and facilitates resolution of stalled replication forks.
116
What role does the protein dyskerin play in relation to telomeres?
Dyskerin encodes a protein that has a nucleolar function and plays a role in **telomere maintenance** and **aging**.
117
What is a typical finding used for the diagnosis of dyskeratosis congenita?
A typical finding used for the diagnosis of dyskeratosis congenita is **short telomere length**. This is often assessed through DNA sequencing in certified laboratories.
118
What are the management options for dyskeratosis congenita?
Management options for dyskeratosis congenita include:
1. **Allogeneic hematopoietic stem cell transplantation** - the treatment of choice for bone marrow failure and leukemia.
2. **Lung transplantation** - may be considered for pulmonary fibrosis.
119
What are the clinical implications of having very short telomeres in dyskeratosis congenita patients?
Patients with dyskeratosis congenita who have very short telomeres are associated with **severe variants** of the condition. Their telomere lengths decline with age, which can lead to complications such as **bone marrow failure**, **myelodysplastic syndrome**, and **malignancies**.
120
What is a typical finding used for the diagnosis of dyskeratosis congenita?
Short telomere length.
121
What percentage of dyskeratosis congenita patients have a mutation in the DKC1 or TERC gene?
Approximately 70%.
122
What is the treatment of choice for bone marrow failure in dyskeratosis congenita?
Allogeneic hematopoietic stem cell transplantation.
123
What are the clinical implications of very short telomeres in dyskeratosis congenita patients?
They are associated with severe dyskeratosis congenita variants.
124
What may be considered for pulmonary fibrosis in dyskeratosis congenita patients?
Lung transplantation.
125
What limits the life span of individuals with dyskeratosis congenita?
Bone marrow failure, myelodysplastic syndrome, and malignancies.
126
What is the primary genetic defect in Dyskeratosis Congenita?
Dyskeratosis Congenita is caused by mutations in telomere biology genes, such as DKC1, TERC, or TERT.
127
What is the typical finding in telomere length for Dyskeratosis Congenita?
Patients with Dyskeratosis Congenita typically have very short telomeres, which decline further with age.
128
What is the primary cause of early death in Dyskeratosis Congenita?
The primary cause of early death in Dyskeratosis Congenita is bone marrow failure.
129
What genetic testing is used to confirm Dyskeratosis Congenita?
Genetic testing for DC includes sequencing of telomere biology genes such as DKC1, TERC, and TERT, and measurement of telomere length.
130
What are the clinical disorders associated with DNA repair disorders?
Xeroderma pigmentosum, Cockayne syndrome, Trichothiodystrophy, Bloom syndrome, Fanconi Anemia, and others.
131
What are the most frequent clinical manifestations reported in patients with Trichothiodystrophy?
| Abnormality | % of 112 Patients |
|-------------|------------------|
| Short, brittle hair with shaft abnormalities | 108 (96%) |
| Developmental delay/intellectual impairment | 82 (73%) |
| Short stature | 74 (66%) |
| Facial dysmorphism (e.g., microcephaly) | 57 (51%) |
| Ocular abnormality (e.g., cataracts) | 51 (45%) |
| Photosensitivity | 41 (37%) |
132
What are the clinical features of a patient with Trichothiodystrophy (TTD421BE)?
| Feature | Description |
|---------|-------------|
| Hair abnormalities | Tiger tail banding; brittle hair; sparse hair; other hair shaft abnormalities |
| Skin abnormalities | Brittle nails; holonychia; soft nails; ichthyosis; photosensitivity; hypothyrosis |
| Growth characteristics | Short stature and poor weight gain (third percentile and microcephaly) |
| Neurologic abnormalities | Developmental delay; intellectual impairment; abnormal gait/ataxia; abnormal MRI results (diffuse white matter changes) |
| Personality characteristics | Atypical engaging/cheerful |
| Hematological abnormalities | Recurrent infections; particularly respiratory neutropenia; elevated hemoglobin A2; low serum immunoglobulin M |
| Maternal pregnancy and fetal abnormalities | Pregnancy-induced hypertension; spotting during pregnancy; abnormal prenatal screening; elevated maternal α-fetoprotein; premature birth; intrauterine growth restriction; birth weight low for gestational age; placental abnormalities |
133
What are some of the neurological abnormalities associated with Xeroderma pigmentosum?
Neurological abnormalities include developmental delay and intellectual impairment.
134
What is the relationship between clinical disorders and molecular defects in DNA repair disorders?
Clinical disorders are associated with specific molecular defects in DNA repair mechanisms.
135
What are the common clinical features of a patient with Trichothiodystrophy?
Hair abnormalities, skin abnormalities, growth characteristics, and hematological issues.
136
What is the median age of onset for skin cancer in patients with Xeroderma pigmentosum compared to the general population?
Patients with XP have an earlier median age of onset for skin cancer than the general population.
137
What are the reported percentages of patients with Trichothiodystrophy who experience photosensitivity?
Approximately 41% of patients report photosensitivity.
