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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%

25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55

Cu

mu

lati

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erce

nta

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of

Pat

ien

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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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