Rothmund-Thomson Syndrome
Type 1 vs. Type 2

Webinar Series, #3
Lisa L. Wang, MD
Associate Professor
Texas Children’s Cancer Center
Texas Children’s Hospital
Baylor College of Medicine
Houston, TX

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

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

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

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

41/41

100%

Small stature

25/38

66%

Skeletal dysplasia

15/20

75%

Radial ray defect

8/40

20%

Sparse scalp hair

15/30

50%

Sparse brows/lashes

19/26

73%

GI disturbance

7/41

17%

Cataracts

2/32

6%

Skin cancer

1/41

2%

Osteosarcoma

13/41

32%

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

A.

Characteristic rash of RTS.
The acute phase of the rashstarts on the cheeks during
infancy (A) and spreads tobuttocks (B) and extremities(C). The chronic phasepersists as poikiloderma.

B.
C.
C.

RTS rash-extremities

RTS rash-extremities

Radial Ray Defects in RTS

Radial Ray Defects in RTS

Nail abnormalities in RTS

RTS Hyperkeratosis

RTS Hyperkeratosis

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• Hearing loss, gastrointestinal problems, immune deficiency…
Wang et al (2001) Am J Med Genet; 102:11-17

Enrollment of RTS Families
Type 1
Type 2
Probands Probands

Type 1Family
Members

Type 2Family
Members

TOTALFemale

21335083187

Male29453476

184

TOTAL507884159371

Baylor College of Medicine Study, November 2020

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

RECQL4• Genetic locus: RECQL4 at 8q24.3• Encodes member of RECQ DNA helicase family• RECQ helicases: DNA unwinding enzymes
involved in basic cellular functions (DNAreplication, recombination, transcription, repair)• Important for maintaining genomic stability

Cellular Roles of RECQL4• Initiation of DNA replication• DNA repair: double strand break
and base excision repair• Telomere maintenance• Maintenance of mitochondrialintegrity• Response to oxidative stress1st Question:
Does the presence of RECQL4mutations correspond to increased riskof osteosarcoma in RTS patients?

Sequence RECQL4 gene in RTS patientsto determine mutation frequency• Mutation testing
done initially inthe lab as part ofresearch• Now widely
available as aclinical test2003

Presence of RECQL4 mutations increases
risk of OS in RTS

p=0.000007

Lu et al, Adv Exp Med Biol. 2014;804:129-45

2nd Question:
Does the presence of RECQL4
mutations correspond to increased riskof skeletal defects in RTS patients?

Type 2 RTS and skeletal defects

2008

Skeletal Findings in RTS• 75% (21/28) had major skeletal abnormalities• The most common findings were:– Abnormal metaphyseal trabeculation (64%)– Brachymesophalangy (64%)– 1st metacarpal or thumb agenesis/hypoplasia(43%)– Osteopenia (25%)– Radial agenesis/hypoplasia (21%)– Radioulnar synostosis (18%)– Ulnar hypoplasia (18%).
– History of OS (11%)
Mehollin-Ray et al, Am J Roentgenol. 2008 Aug;191(2):W62-6

RTS Classification• Type II RTS– Poikiloderma– Mutations in RECQL4– Increased risk for OS– Association with skeletal defects• Type I RTS– Poikiloderma– No mutations in RECQL4– Less risk of cancer

Wang et al (2003) J Natl Cancer Inst; 95(9):669-74

Type 1 RTS• Cause unknown at the time
• Likely due to gene(s) other than RECQL4• Classic poikiloderma and skin findings• Less cancer risk
• More juvenile cataracts• Exome sequencing project with Dr.
Philippe Campeau (BCM-Montreal)A cause for Type 1 RTS• Mutations in ANAPC1 identified in 10/18 subjects (7/14 families) with Type 1 RTS
2019

Causative genes in RTS

RTS

Type 1

Type 2

Gene defect

ANAPC1Unknown

RECQL4# ofindividuals

104078

Type 1 and Type 2 RTS
Clinical Features
Type 1

Type 2

Poikiloderma++

Sparse hair/brows/lashes++

Bone defects+++

Osteopenia/osteoporosis++

Gastrointestinal problems+++++(juvenile)+

Squamous or basal cell skin cancer++

Osteosarcoma++

Hearing problems+++

Cataracts

Thank you