1. Skin Manifestations of Tuberous Sclerosis Complex
Julie Prendiville
BC Children’s Hospital

2. Skin Manifestations of TSC
Hypomelanotic macules
Angiofibromas
Fibrous cephalic plaques
Ungual fibromas
Collagenomas (shagreen patch)

3. Skin Manifestations of TSC
Minor diagnostic criteria
Confetti skin lesions
Oral/dental
Dental pits
Gingival and other oral fibromas
Other

4. Hypomelanotic Macules
Sometimes referred to as “ash-leaf” spots
Classic lesion has similar “lanceovate” shape to mountain ash tree leaf
Mountain Ash (Rowan) tree

5. Other Skin Findings Nuchal Skin Tags Neonatal White Plaques
Associated with cardiac rhabdomyomas

6. Differential Diagnosis
Vitiligo
Acquired autoimmune condition
Loss of melanocytes
Piebaldism
Present at birth
“Nevus depigmentosus”
Isolated white macules seen in general population
May be small macules or large segmental areas

7. Mosaicism/Segmental Hypopigmentation
Mosaicism in a child with TSC

8. Mosaicism
Unilateral facial angiofibromas with no other evidence of TSC

9. Differential Diagnosis
Facial angiofibromas may occur in other genetic conditions
Multiple endocrine neoplasia type 1
Birt-Hogg-Dube syndrome
Facial angiofibromas may be mistaken for acne

10. Treatment of Skin Manifestations
Facial Angiofibromas
Facial disfigurement
May affect self-esteem
May result in feelings of social isolation
Ungual fibromas
May cause discomfort
Cosmetic issue

11. Treatment of Facial Angiofibromas
Surgical
Medical

12. Treatment of Facial Angiofibromas
Surgical
Pulsed dye laser
For red vascular angiofibromas
CO2 laser
For fibrous angiofibromas
Excision
For larger or bleeding angiofibromas
Angiofibromas tend to recur regardless of surgical modality

13. Treatment of Facial Angiofibromas
Medical therapy
Inhibitors of mTOR
Rapamycin (sirolimus)
Everolimus

14. Treatment of Facial Angiofibromas with MTOR Inhibitors
2008: report of improvement in child with TSC receiving sirolimus (rapamycin) following kidney transplant
2010: case report of improvement with topical application of rapamycin
: multiple case reports, a few case series, and one controlled trial

15. Topical Rapamycin All published reports describe improvement
Large angiofibromas may respond poorly

16. One Double Blind Study Koenig et al. 2012 23 patients
Rapamycin 0.003% or 0.015% or placebo
73% of subjects in treatment arm reported improvement (27% no difference)
38% of subjects in placebo arm reported improvement (62% no difference)

17. How to Objectively Assess Improvement
Before and after photographs
Left /right comparison studies
Double-blinded randomized controlled studies
Standardized measurement tool
Facial angiofibroma severity index (FASI)

18. Topical Rapamycin What is the optimal concentration?
0.0035% to 1% reported in the literature
0.1% and 0.2% most commonly prescribed
What is the best vehicle?
Ointment
Cream
Gel
Solution – frequently causes skin irritation

19. Topical Rapamycin Safety
Systemic absorption appears to be minimal
Skin irritation is the most common adverse effect
May be treated with topical steroids

20. Obstacles to Treatment
Cost
30 grams of rapamycin 0.2% cream costs ~ CAD$500
Compounding
sirolimus (rapamycin) pills need to be crushed and compounded into cream or ointment
Special Authority requests
BC Pharmacare and many insurance companies require special authority approval

21. What about Everolimus
Two placebo controlled studies of oral everolimus (for renal tumors) reported a significant improvement in skin lesions
One study of topical everolimus showed benefit

22. Conclusions
Oral rapamycin and everolimus appear to improve facial angiofibromas
Topical formulations have shown benefit
Double-blind randomized controlled studies using objective measurement tools are lacking
Large angiofibromas do not appear to respond so well and may do better with laser/surgery
Combination of surgical and medical treatments can be considered