0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Observation |

Successful Treatment of Subungual Fibromas of Tuberous Sclerosis With Topical Rapamycin FREE

John G. Muzic, BS1; Scott A. Kindle, MD2; Megha M. Tollefson, MD2
[+] Author Affiliations
1University of Minnesota School of Medicine, Minneapolis
2Department of Dermatology, Mayo Clinic, Rochester, Minnesota
JAMA Dermatol. 2014;150(9):1024-1025. doi:10.1001/jamadermatol.2014.87.
Text Size: A A A
Published online

Ungual tumors, a major diagnostic criterion for tuberous sclerosis complex (TSC), are often symptomatic and have posed a therapeutic challenge.1 We present a case of successful treatment of a subungual fibroma with topical rapamycin.

REPORT OF A CASE

A female toddler with known TSC presented with multiple skin lesions characteristic of TSC; these included 5 facial collagenomas, more than 20 hypopigmented macules and patches consistent with ash leaf macules, and bilateral subungual tumors of the first toenails with associated nail plate dystrophy (Figure, A). Facial angiofibromas were not present. Other manifestations of TSC included known cardiac rhabdomyoma diagnosed prenatally and multiple daily seizures since infancy. Genetic testing had revealed mutations in both TSC1 and TSC2.

Place holder to copy figure label and caption
Figure 1.
Subungual Tumor of Right Great Toenail With Associated Nail Plate Dystrophy

A, At presentation, subungual tumors involving the patient's right great toe were causing distortion of the nail. B, At the 6-month follow-up after treatment with topical rapamycin, the subungual tumors were no longer noticeable, and dystrophy of the nail plate had subsided.

Graphic Jump Location

The patient was having pain associated with the subungual fibromas and nail plate distortion. Surgical intervention had previously been offered for treating the facial collagenomas and the subungual fibromas, but the parents had declined. After presentation to our clinic, topical rapamycin in a 1-mg/mL solution was prescribed to be applied twice daily to the collagenomas and under occlusion to the periungual and subungual areas of the first toenails. While there was minimal to no improvement in the facial collagenomas, improvement in the subungual tumors was observed at the 2-month follow-up. At the 6-month follow-up, the subungual tumors were no longer noticeable, and dystrophy of the nail plate had subsided (Figure, B). Treatment was then discontinued. There were no signs of recurrence of the fibromas 6 months later, at most recent follow-up. The topical rapamycin was well tolerated without complications.

DISCUSSION

Cutaneous stigmata of TSC can be very difficult to treat successfully, and, historically, primarily surgical interventions were considered to be the only options. Recently, several reports and small studies have demonstrated the safety and efficacy of topical rapamycin for facial angiofibromas in patients with TSC.2,3 A recent left vs right side of the face comparative study also demonstrated efficacy and good tolerability of topical rapamycin for the treatment of facial angiofibromas.4 Successful treatment of nonangiofibroma cutaneous manifestations of TSC has been sparse. To our knowledge, topical rapamycin has not been used successfully to treat the ungual fibromas of TSC. In our case, the use of topical rapamycin was well tolerated and resulted in the resolution of subungual tumors and rapid normalization of the overlying nail distortion.

The pathogenesis of TSC is characterized by an autosomal dominant mutation in TSC1 or TSC2 resulting in aberrant functioning of hamartin or tuberin, respectively. Tuberin, a GTPase-activating protein for Rheb, functions in a complex formed with hamartin. Rheb, which in turn activates mTOR, is inhibited in the presence of a normal tuberin-hamartin complex.5 In TSC, the hamartin-tuberin complex is unable to form, resulting in the constitutive activation of the mitogenic mTOR pathway. Rapamycin suppresses this pathway through the direct inhibition of mTOR.

While not entirely understood, an unrestrained mTOR pathway leads to upregulation of vascular endothelial growth factor (VEGF). It is suggested that rapamycin may exert its therapeutic effect on TSC lesions by directly killing tumor cells in addition to inhibiting VEGF production.6 Therefore, the same mechanism by which rapamycin reduces facial angiofibromas may also apply to nonangiofibroma cutaneous manifestations such as ungual tumors.

Patients with periungual and subungual fibromas associated with TSC are often quite symptomatic and often have significant distortion of the nail plate. Their treatment options have been quite limited to date. While further study is necessary, the experience with our patient suggests that topical rapamycin is a safe, well-tolerated, and potentially efficacious treatment for patients with ungual tumors associated with TSC.

ARTICLE INFORMATION

Corresponding Author: Megha M. Tollefson, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (tollefson.megha@mayo.edu).

Published Online: June 11, 2014. doi:10.1001/jamadermatol.2014.87.

Conflict of Interest Disclosures: None reported.

REFERENCES

Borkowska  J, Schwartz  RA, Kotulska  K, Jozwiak  S.  Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011;50(1):13-20.
PubMed   |  Link to Article
Haemel  AK, O’Brian  AL, Teng  JM.  Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010;146(7):715-718.
PubMed   |  Link to Article
Koenig  MK, Hebert  AA, Roberson  J,  et al.  Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D. 2012;12(3):121-126.
PubMed   |  Link to Article
Tanaka  M, Wataya-Kaneda  M, Nakamura  A, Matsumoto  S, Katayama  I.  First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br J Dermatol. 2013;169(6):1314-1318.
PubMed   |  Link to Article
Dobashi  Y, Watanabe  Y, Miwa  C, Suzuki  S, Koyama  S.  Mammalian target of rapamycin: a central node of complex signaling cascades. Int J Clin Exp Pathol. 2011;4(5):476-495.
PubMed
El-Hashemite  N, Walker  V, Zhang  H, Kwiatkowski  DJ.  Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 2003;63(17):5173-5177.
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.
Subungual Tumor of Right Great Toenail With Associated Nail Plate Dystrophy

A, At presentation, subungual tumors involving the patient's right great toe were causing distortion of the nail. B, At the 6-month follow-up after treatment with topical rapamycin, the subungual tumors were no longer noticeable, and dystrophy of the nail plate had subsided.

Graphic Jump Location

Tables

References

Borkowska  J, Schwartz  RA, Kotulska  K, Jozwiak  S.  Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011;50(1):13-20.
PubMed   |  Link to Article
Haemel  AK, O’Brian  AL, Teng  JM.  Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010;146(7):715-718.
PubMed   |  Link to Article
Koenig  MK, Hebert  AA, Roberson  J,  et al.  Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D. 2012;12(3):121-126.
PubMed   |  Link to Article
Tanaka  M, Wataya-Kaneda  M, Nakamura  A, Matsumoto  S, Katayama  I.  First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br J Dermatol. 2013;169(6):1314-1318.
PubMed   |  Link to Article
Dobashi  Y, Watanabe  Y, Miwa  C, Suzuki  S, Koyama  S.  Mammalian target of rapamycin: a central node of complex signaling cascades. Int J Clin Exp Pathol. 2011;4(5):476-495.
PubMed
El-Hashemite  N, Walker  V, Zhang  H, Kwiatkowski  DJ.  Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 2003;63(17):5173-5177.
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

1,505 Views
3 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
×