Welcome to the 2020 Webinar #1
Dr. Lisa L. Wang – The History of RTS Research and Clinical Studies

Mission Statement• Promote awareness of Rothmund-Thomson Syndrome andrelated syndromes to the general public and to healthcare
professionals• Provide education and support to afected families worldwide• Provide education to healthcare professionals who may
encounter patients afected with these disorders• Promote research aimed at understanding the molecular andcellular basis of RTS and the clinical manifestations• Raise funds through events and contributions that will support
the overall eforts of the group

Ideas for Future RTS Webinars• Coping with a rare disease during the COVIDpandemic• Dermatology challenges with Dr. Moise Levy
• The diferences between Type 1 and Type 2 RTS
and genetic testing• Orthopedic issues and challenges• Cancer concerns, monitoring and treatment

RTSF Medical Advisory and Board Members• RTS Foundation Board– John Kimmel, Chair– Laurie Sperou, Vice-Chair– Shelley Sanders, Treasurer– Ta-Tara Rideau, Secretary– Emil Zakutny, D.S.W– Sheila Townsend• Medical Advisory Board– Lisa Wang, MD (Pediatric Oncology)– Moise Levy, MD (Pediatric Dermatology)– Carol Clericuzio, MD (Genetics)– Caroline Brain, MD (Pediatric Endocrinology)

The Futureof RTS
ResearchLisa L. Wang, MD
Texas Children’s Hospital
Baylor College of Medicine
Houston, TX&John Kimmel,
Founder and Chair, RothmundThomson Syndrome Foundation
Chantilly, VA

Pediatrics

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1st RTS “Sharing and Caring”
Conference
October 17-19, 2007
Houston, TX• Day 1: Educational Lectures– Genetics of RTS (Sharon E. Plon, MD, PhD)
– Dermatologic Manifestations of RTS (Mo Levy, MD)– RTS and Bone Disease (Lisa L. Wang, MD)– Radiologic Findings in RTS (Amy Mehollin-Ray, MD)– Sharing and Caring Session—Families• Day 2:
– RTS Support Group Planning1st RTS Conference 2007

Outline• History of RTS and RTS Research• Milestones in RTS Research• Current and Future Goals

History of RTS• 1868: Auguste Rothmund first described thecharacteristic rash and cataracts in inbred
Austrian families• 1923: M. Sydney Thomson described therash and skeletal anomalies in sisters;coined term “poikiloderma congenitale”

• 1957: William Taylor united the twodisorders, proposed eponym“Rothmund-Thomson Syndrome”

Taylor WB, AMA Arch Dermatol;75:236-244 (1957)

How we got startedPatient diagnosed with osteosarcoma (OS) in1999
Also carried diagnosis of Rothmund-Thomson
Syndrome (RTS)
Sister also had RTS and died of metastatic OS
QUESTION: Is there any link between these
two rare diseases?

History of Baylor College ofMedicine (BCM) RTS Study• First IRB Protocol– H-7207: “The Molecular Basis of Familial
Cancer Predisposition Syndromes”– Includes subjects with RTS and other disorders– Includes family members– First subject enrolled 01/19/1999– Yearly recontact letters• Second IRB Protocol approved 08/22/2000– H-9106: “The Molecular Basis and Clinical
Spectrum of Rothmund-Thomson Syndrome”

History of BCM RTS Study• General Clinical Research Center (GCRC)
Study approved 09/20/2000– Includes subjects with a diagnosis of RTS– First subject enrolled 07/25/2001– 36 subjects enrolled - came to Texas Children’s Hospital– Comprehensive evaluation including Genetics, Dermatology,Ophthalmology, Oncology, labs, skeletal surveys

 With these protocols approved and in place, we could
begin to collect medical informaton and biologic samples
to start generatng data.

1: Defining the syndrome

2001

Summary of Clinical Findings in 41 RTS Subjects
Baylor College of Medicine Study
Rash

41/41

100%

Small stature
Skeletal dysplasia
Radial ray defect

25/38
15/20
8/40

66%
75%
20%

Sparse scalp hairSparse brows/lashes
Cataracts
Skin cancer

15/30
19/26
2/32
1/41

50%
73%
6%
2%

Osteosarcoma

13/41

32%

Wang et al (2001) Am J Med Genet; 102:11-17

Clinical Diagnostic Criteria for RTS
DEFINITE RTS•Characteristic rash with or without other features:– Acute phase: Begins in infancy (usually 3-6months) as erythema/blisters on cheeks,
often sun-sensitive, spreads to extensor
surfaces of extremities, buttocks– Chronic phase: Poikiloderma consisting ofreticulated hypo- and hyper-pigmentation,
atrophy, telangiectases
Wang et al (2001) Am J Med Genet; 102:11-17

Clinical Diagnostic Criteria for RTS
PROBABLE RTS•Atypical rash plus two or more features of RTS• Positive family history ofRTS• Osteosarcoma• Skin malignancy• Radial ray defect• Other skeletal dysplasias• Juvenile cataract• Small stature• Sparse scalp hair
• Sparse brows and/orlashes• Dental abnormalities• Nail abnormalities

Wang et al (2001) Am J Med Genet; 102:11-17

Genetic Basis of RTS• When we started our research,
the cause of RTS was unknown.
• It was known to be an inherited
disorder and transmitted in an
autosomal recessive pattern.
• In 1999, a gene for RTS wasdiscovered.

2: Finding the cause of RTS
Kitao et al. (1999) Nature Genetics; 22: 82-84- 3 out of 7 RTS cases had mutations in RECQL4

3: Sequence RTS patients to see how
many have mutations in RECQL4• Mutation testing
done initially inthe lab as part ofresearch• Helped todevelop a clinicaltest for RTS• Now widely
available in theU.S.

Characterizing different RECQL4
mutation types in RTS• Mutation testing can be tricky• Need to examine intronic regions• Make sure proper test is performed2002

4: Determining if RECQL4 mutations
correlate with other features of RTS:
Osteosarcoma

2003

RECQL4 mutation status and OS in RTS

Type 2 RTS:
RECQL4 mutations
Increased risk of OS
compared to Type 1

Type 1 RTS:
No RECQL4 mutations

Lu, Adv Exp Med Biol 2014

4: Determining if RECQL4 mutations
correlate with other features of RTS:
Skeletal defects• Skeletal defects correlate with RECQL4 mutatons• Skeletal surveys are useful2008

5: Managing osteosarcoma in RTSpatients• Overall, OS in RTS issimilar to OS ingeneral populaton.
• In general, patents
tolerate treatment
fairly well.
• Difcult to predict apriori response totherapy• Do not decrease
doses up front.

2007

6: Are RTS patients more sensitive toDNA-damaging agents?

Implications for:• Sun protection (UV)• Radiology tests, screening for cancer• Prediction of side effects from cancer treatment

20087: RECQL4 Spectrum of Disorders

1. RTS
2. Baller-Gerold Syndrome (BGS)
3. RAPADILINO
2006, 2008

RECQL4 Spectrum of Disorders
RTS

BGS

• Cataracts• Dental abnormalities• Nail abnormalities• Hyperkeratosis• Skin cancers• Poikiloderma• Craniosynostosis• Sparse hair
• Anus anteposition• Radial ray defects• Small stature• Juvenile diarrhea• Facial dysmorphism• Patellar abnormalities• Lymphoma• Osteosarcoma• Jointdislocation• Palate abnormalities

RAPADILINO

Diagram showing overlapping and unique clinical features of the RECQL4 –associateddisorders. Osteosarcomas and lymphomas have been described in both RTS andRAPADILINO, but osteosarcomas predominate in RTS, while lymphomas are morecommon in RAPADILINO. There has been only one case of lymphoma reported in apatient with BGS.

History of BCM
RTS Study• Third IRB Protocol approved 10/11/2007– H-21708: “The Molecular Basis of RothmundThomson Syndrome and Osteosarcoma”—
current open protocol• Clinical Research Center (CRC) Study
approved 11/2010– “Evaluation of Calcium Absorption and Kinetics inPatients with Rothmund-Thomson Syndrome”– First subject enrolled in 2010– 29 subjects enrolled

8: Modeling RTS in the lab for basic
science research

These mice with Recql4 mutatons had skeletal features similar to RTS patents;
however, they did not develop osteosarcoma unless crossed with p53 defcient mice2015

9: Do RTS patients have altered bonemetabolism?

Some RTS patients have decreased bone mineral density(osteoporosis) and may need monitoring (DXA scans).

201710: Finding a cause for Type 1 RTS• Mutatons in ANAPC1 identfed in 10118 subeects (7114 families) with Type 1 RTS

2019GeneReviews®
Margaret P Adam, Editor-in-Chief; Senior Editors: Holly H Ardinger, Roberta A Pagon, and Stephanie EWallace. Molecular Genetics: Lora JH Bean and Karen Stephens. Anne Amemiya, Genetic Counseling.
Seattle (WA): University of Washington, Seattle; 1993-2020.ISSN: 2372-0697

https:11www.ncbi.nlm.nih.gov1books1NBsK11161

What is on the horizon for RTS research?

What is Needed to Continue
Research on RTS?
• Researchers• Patients and Families• Funding• sasic science research• Clinical & translatonalresearch• Infrastructure• Registry - clinicaldatabase; yearlyquestonnaires• siologic material forlaboratory studies• Maeor funding – e.g.,
NBatonal Insttutes of
Health (NBIH)• Foundaton grants

RESEARCHERS
Academic medicine -Physician scientist• 80% research effort – grants• 20% clinical effort - see patients
Grants must pay for:• Personnel – salaries including own• Supplies• Animal costs• Maintenance of lab (liquid nitrogen,CO2, glasswashing, etc.)

PATIENTS AND FAMILIESRTS Registry• Information entered into database• Yearly recontact• This will allow us to– describe the natural history of RTS– understand the full clinicalmanifestations in RTS patients andtheir relatives– Identify areas of research study

Roadblocks to Federal Funding• Limited resources – diminishing payline;
Covid-19 impact• Fierce competition – more common
diseases, larger labs, PhD scientists• The vicious cycle:
Funding
Publications

Submit grant –6-9 monthprocess

Personnel
salaries,supplies

Preliminary data

How Can We Sustain
Research on RTS?
• Contnue to submit grants
and conduct research• Researchers• Patients and Families• Funding• Play an actve role inresearch!
• Fill out questonnaires andprovide clinicalinformaton• Provide biologic samples
when possible• Local fundraisers tosupport RTSF and RTS
research• Facebook fundraisers• Workplace, company
supportChallenges• Raising money to support clinical research– Research is expensive– Research dollars are limited and competitive, especially for rare diseases– The Foundation needs to increase fundraising• Building the patient registry and increasing the number offamilies involved in clinical trials– There have been tremendous advances, but there is much more to be done

• Fresh ideas, energetic members, renewed commitment

2020 Webinar Series #1