nih brown bag lunch - 2021 (002) - read-only
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Office of Research Nursing Brown Bag Lunch – March 23, 2021
Diseases of DNA Repair: Xeroderma Pigmentosum, Trichothiodystrophy and
Cockayne Syndrome
Deborah Tamura MS, RN, APNGLaboratory of Cancer Biology and Genetics
DNA Repair Section
No Conflict of Interest
Outline
• Overview of DNA Damage• Xeroderma Pigmentosum• Trichothiodystrophy• Cockayne Syndrome• Overlap Syndromes• Summary of Findings
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Learning Objectives
At the completion of this presentation the participant will be able to:
• Name a 3 diseases caused by defective DNA repair.
• List a symptom of xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome.
• Describe strategies to reduce the risk of skin cancer in xeroderma pigmentosum patients.
DNA Damage Response
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Inherited Diseases caused by Defective DNA Repair
Xeroderma PigmentosumChildren of the Night
“Is this place UV safe?”
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Ultraviolet Radiation CAUSES
DNA Damage
Still trying to convince my daughter to protect her skin from the sun
UV PHOTOPRODUCTS
Gene Transcription Disrupted at Site of Photoproduct
UV
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UV DEFENSE MECHANISMS TO PREVENT SKIN CANCER
Skin Cancer
Pigmentation &Skin Thickening
UV-Exposure
DNA Repair Cell Cycle Arrest
Apoptosis
DNA DamageDNA photoproducts
MutationRemoval of Mutated Cells(Immune-Surveillance)
NUCLEOTIDE EXCISION REPAIR PATHWAY
DiGiovanna and Kraemer JID 2012
XPA DAMAGE RECOGNITION/VERIFICATION
BEFORE TFIIH BINDING
XP‐C & XP‐E
XP‐B & XP‐DUNWIND THE DAMAGED
AREA
BASAL TRANSCRIPTION
XP-F & XP-G MAKEINCISIONS
ON EITHER SIDE OFTHE DAMAGE
POLYMERASE AND LIGASE FILL THE
GAP
XP VARIANT BYPASSES UNREPAIRED DAMAGE
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G= Normal Gene
g= Mutated Gene
g= Mutated Gene
Function of normal gene compensates for mutant gene.
Autosomal Recessive InheritanceMales and Females Equally Affected
Recurrence risk for each child is 1 in 4 or 25%
Parents are notclinically affected and have no symptoms but are carriers for the condition
Carrier Father
Carrier Mother
Gg GgGg
Gg gg
Normal Carrier Carrier Affected
GG Gg
Carrier rate 1 in five-hundred
Disease rate in US 1 in a million
More common in Japan and Middle East
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Means ‘Dry Pigmented Skin’Caused by mutations in genes of NER (7) and Pol Eta – bypass polymerase (XP-Variant)Occurs in all ethnic groups10,000-fold increased risk of skin cancer3,000-fold increased risk for oral cancer
2 y/o diagnosed at daycare center KA on lip
Xeroderma Pigmentosum
Anterior tongue tumor23y/o male from Sudan
Signs and Symptoms
Freckling before age 2 years
Early onset of skin cancers – often before age 10
Eye – photophobia; dry eyes, 1,000-fold incidence of cancer on eye surfaces
Severe UV sensitivity (50% of patients have severe blistering sunburns)
Neurodegeneration in approximately 25% of patients. More common in XP-A, XP-B, XP-D, XP-F and XP-G.
Progressive hearing loss, loss of DTRs, ataxia, cognitive decline, recurrent aspiration
Nine-month-old in shade for 45 minutes – XPD mutations
18 month - XPC23 month - XPC
19 y/o – hearing loss diagnosed at NIH XPD mutations
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The Eye Complications in Xeroderma Pigmentosum
Severe Photosensitivity
Corneal Clouding, Pterigium
Malignancy on eye surface
XPC, XPE, XPV patients do not burn and may receive more UV damage over their lifetimes.
XPC mutations
XP12BE XP-A
death age 44
4 yr 17 yr 41 yr
20 yr 41 yr
Infantile sized brain at autopsyLai…DiGiovanna…Kraemer Acta Neuropath Comm 2013
Bradford..DiGiovanna..Kraemer. J Med Gen 2010
Progressive Neuro-degeneration in Xeroderma Pigmentosum -Patient with XP-A Mutations – 40 yr Follow-up
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The UV Safe Lifestyle
“Mr. Sun is not my friend”.
• Environmental – reduce UV exposure in surroundings – homes, schools and workplaces
• Personal protection – clothing, sunscreen, eye protection
The Well-Dressed XP Person Outside
Sun block >SPF 30 applied several times per day
Hood covering ears back of neck with UV blocking face shield
Sunglasses – UV blocking with side shields
Long sleeved shirts Long pants or tights
under skirts Gloves Shoes and long socks Sun Protective Suit
The Goal is to have as little skin exposed to UV as possible.
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Patient Care Management Cancer Detection and Treatment Frequent self skin exams – at least weeklyRegular dermatologic visitsPhotographs of lesionsPrompt biopsy and surgical removal of suspicious
lesions Pharmacologic InterventionsAldara5 FUOral Retinoids Immunotherapy for invasive tumors
Referral to Patient Support Groups
Xeroderma Pigmentosum
It isn’t just for skin any more
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InternalTumors: CNS and Lung Cancers
XP24BE - XPC
32 y/o >200 skin cancers died
35 y/o glioblastoma
XP 23 BE - XPC21 y/o >100 skin cancersspinal cord astrocytoma – died of melanoma 32yr
XP295BE XPC48 y/o
history of smokingStage 1 b lung adenocarcinoma
30-fold higher rate of internal cancers – CNS tumors, lung cancer, hematologic malignancies
Hematologic Malignancies in Xeroderma Pigmentosum Patients at NIH
Hematologic Disease Sex/Age at Diagnosis
XP Group Outcome
Mixed Phenotype Acute Leukemia
F/19 yrs. C Alive – in remission tolerated standard
chemotherapy
Myelodysplastic syndrome –progressed to acute myeloid
leukemia
M/34 yrs. C Died age 38 yrs. – treated with supportive therapy
only - secondary to multiple melanomas
Myelodysplastic syndrome M/19 yrs. C Died age 20 yrs. complications of stem cell
transplant
Acute diffuse large B cell lymphoma – stage IV
Myelodysplastic syndrome – progressed to acute
megakaryocytic leukemia
M/29 yrs.
F/30 yrs.
C
C
Died age 29 yrs.Initially responded to R –
CHOP
Tolerated stem cell transplant – Died from
leukemia
Hematologic malignancies may be more common in XPC patients. XPC patients in our cohort appear to tolerate standard doses of chemotherapy. Treatment may depend on status and types of skin cancers. Recommend yearly CBC with high index of suspicion if abnormalities or symptoms occur.
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XP Women Have a Lower Age at Menopause
Median age of XP women at menopause (31.5 years old)
than in general population of Caucasians (52.9 years old)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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Cu
mu
lati
ve P
erce
nta
ge
of
Pat
ien
ts
Age at Natural Menopause
Lower Age at Natural Menopause in XP Patients than General Population
XP patients (n=12)
20 years
Increased Incidence of Thyroid Nodules in XP Patients
62% of XP Patients had Thyroid Nodules2 Patients Were Diagnosed with Thyroid
CancerPatients had Mutations in XP-C, XP-V and XP-E
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Consequences of Late Diagnosis and Poor UV Protection
DIED AGE 33 YR
Early Diagnosis and Good Protection
Who has XP?
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Trichothiodystrophy: when transcription and repair have ‘issues’
Transcription: Copying DNA To RNA
The First Step In Gene Expression
Complete Loss Of Basal Transcription Is Incompatible With Life
Impaired Transcription With Some Residual Activity Is Found In Living Patients
Caused By Mutations In: XP-B, XP-D, TTDA, TTN1, GTF2E2, Rnf113a
Severe Sun Sensitivity in Half of Patients
Tiger Tail Banding of Hair
Ichthyosis - Dry Skin
Brittle NailsShort Hair -
Sparse Eyebrows
Collodion Membrane
TrichothiodystrophySymptoms
High Rate of Pregnancy and neonatal complications
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Trichothiodystrophy
Severe Delay
Autism Age 14TTDN1
Mutations
Age 25 Moderate
Delays
TTDA-Mutations
Normal Development Age 5
Short Stature Developmental
Delay –
XP-D Mutations
Died age 9 yr
XP-D Mutations
Brain MRI Normal vs TTDLeukodystrophy
Normal Myelin
Dysmyelination
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Complications of Trichothiodystrophy Ophthalmologic
Endocrine Abnormalities –Hypogonadism
Poor Growth – bone abnormalities – Peripheral Osteopenia and Central Osteosclerosis
Immune Dysfunction –Frequent Infections
Hematologic Abnormalities –Resembles B-Thalassemia Minor
20-fold increased risk of death before age 10
Mutations in XP-D
Symptoms Occur Because Multiple Genes are not Properly Transcribed or Repaired – Do Not Develop Cancer
Cockayne Syndrome – It’s All About the Transcription
Birth incidence 1 in 250,000
Caused by Mutations in Genes: CSA or CSB
CS/XP Overlap Mutations in XPB, XPD, XPG
CS/TTD Overlap Mutations in XPD
Defective Transcription Coupled Repair – Faulty Repair of Actively Transcribing Genes Necessary for Normal Cell Function
Significantly Reduced Life Span
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COCKAYNE SYNDROME
3 y/o – Mutations in CSA - Died 13 y/o
Calcification in Basal Ganglia
Cockayne Syndrome: Physical Features
Severe Growth Deficiency – Cachetic DwarfismDeep Set EyesSensorineural Hearing LossRetinal Pigmentation –Corneal Opacity –CataractsSlender Beak-Like NosePhotosensitive - Dry Skin, Senile Appearance
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Cockayne Syndrome:Complications
Moderate CS (Type I or Classical CS)
Severe CS (Type II or Early-onset CS)
Mild CS (Type III or Mild)
Atypical CS -Photosensitivity only/adult-onset CS
Cardiovascular Problems – arrhythmias hypertension
Hepato-splenomegaly
Skeletal Abnormalities
Neurologic – Progressive Neurodegeneration and Cerebral Atrophy
Accelerated Aging Phenotype
Patient Care Management of Trichothiodystrophy and Cockayne Syndrome
Benefit from Multidisciplinary Approach
Dermatology – follow skin and hair symptoms – SUN PRECAUTIONS
Neurology – diagnosis and monitoring of symptoms
Immunology – if frequent infections – Intravenous IgG
Ophthalmology – follow cataracts and myopia
Feeding Tube for failure to thrive
Cochlear Implants for hearing loss – Cockayne children
Rehabilitative Therapies PT, OT, speech therapy - advocate for rehabilitative and support services
Special Education Classes
Refer to Patient Support Groups
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Diagnosis of DNA Repair Diseases
Clinical FeaturesDetailed Medical History – How bad was the sunburn?Early occurrence of skin cancerLaboratory Testing
UV sensitivityHost cell reactivation assayMutation analysisWhole exome or genome squencing
Confusing Features of the Overlap Syndromes
XERODERMA PIGMENTOSUM / COCKAYNE SYNDROME
XP/CS group B - XP11BE 28 yr Mother
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Xeroderma Pigmentosum/Trichothiodystrophy Trichothiodystrophy/Cockayne Syndrome
XP/TTD384 BE XPD31 yr – Died age 33 melanoma
TTD/CS 406 BE XPD9 yr – Died age 19 Pneumonia
Support Groups
• The XP Society• The XP Family Support Group• XP Grupo Luz de Esperanza • The Trichothiodystrophy Support Group –
online chat group – founded in Australia• Cockayne Syndrome and Trichothiodystrophy
Support Group – Care and Share• Multiple International Support Groups: Great
Britain, France, Spain, South Africa
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What Have We Learned in the Last 20 years?
• Early diagnosis and stringent UV protection can prevent cutaneous and ocular damage in XP patients. UV protection does not prevent neurodegeneration.
• XP patients develop internal cancers.
• TTD and CS patients have a wide range of symptoms and require multidisciplinary care.
• There are patients with symptoms of 2 NER diseases at one time – overlap patients: XP/CS, XP/TTD, TTD/CS and possibly others.
• Age 2 months
• Outside in covered stroller for 20 minutes.
• Mutations in the XP-A gene.
When the Diagnosis is a Bad Gene – Not a Bad Parent
Mother questioned about neglect
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The Kraemer LabPrincipal Investigator:Dr. Ken Kraemer
Associate Investigator:Dr. John DiGiovanna
Senior Scientist:Dr. Sikandar Khan
Clinical Fellow:Dr. Elizabeth Heller
Jack Jeskey, MSRP Student
Elvey Fernandez, Post Bac
Research Nurse:Debby Tamura MS, RNAll the other many post docs,
medical students and post bacs who have worked in the lab for the past 45 years.
DNA Repair – The Lifeguard of the Gene Pool
Thank-You!
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