Individuals & Families

TSC Research Article Summaries: Skin

A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex

Author(s): N. Nathan, K. Burke, J. Moss and T.N. Darling
British Journal of Dermatology
DOI (of the article): 10.1111/bjd.14724

What is the topic?

The authors created an algorithm (guide) to help physicians decide what skin findings should lead to a full screening for TSC. This article is written primarily for dermatologists who see a patient with a skin finding that is suspicious for tuberous sclerosis complex (TSC).

What did the researchers hope to learn?

They hoped to find out which skin findings were most likely to lead to a diagnosis of TSC, so that people with TSC were not overlooked but people who did not have TSC were not put through unnecessary testing.

Who was studied?

The authors reviewed over 100 medical records primarily of people who were diagnosed with TSC as adults, and studied 13 more adults who were referred to dermatology because of skin findings suspicious for TSC.

How was the study conducted?

For the records review, the scientists looked for individuals diagnosed with TSC who had skin symptoms at a young age but did not get their TSC diagnosis until later. They searched for the age the first skin symptoms appeared, the specific symptoms, and details of later TSC manifestations. For the clinic patients, they examined the individuals for any other skin problems, and performed biopsies to confirm the diagnosis. They referred patients for further TSC testing when TSC skin findings were confirmed.

What did the researchers find?

The researchers found that many individuals who had only one skin feature of TSC at a young age went on to develop more symptoms of TSC, and were eventually diagnosed with TSC in adulthood. These early skin features included: hypomelanotic macules (ash leaf spots), angiofibromas, fibrous cephalic (forehead) plaques, shagreen patches (rough skin), and ungual (around the finger/toenail) fibromas. However, they found that many people referred to dermatology for skin findings suspicious for TSC were actually diagnosed with something else. Therefore, they deemed it very important for the dermatologists to do very thorough examinations and family histories, including biopsies of suspicious lesions, before diagnosing possible TSC. The algorithm they created is designed to help decide who should get full TSC screenings based on skin findings.

What were the limitations of the study?

This is published as a research letter rather than as a full scientific research article. The authors were not trying to study enough patients to make statistically significant predictions. They were gathering enough data to help produce an accurate and helpful guide for other physicians to use in diagnosing TSC.

What do the results mean for you?

These results should demonstrate the importance of a very thorough and accurate dermatology exam for anyone suspected of having TSC. Many skin findings suspicious for TSC actually have other explanations, but those proven to be TSC features are usually predictive of the disease. The authors stress that even when no other symptom of TSC is found, younger individuals with a TSC skin feature should always be monitored because there is a high likelihood of other symptoms developing later in life. Those with TSC skin findings should have thorough screenings even if they “feel fine or look healthy” because they could have internal involvement that has not yet shown symptoms.

This summary was written by Cristy Wade, MS, parent of child with TSC, clinical research coordinator, and peer reviewer for the Tuberous Sclerosis Complex Research Program (June 2016).


First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex

Author(s): Tanaka M, Wataya-Kaneda M, Nakamura A, Matsumoto S, Katayama I.
British Journal of Dermatology, 169 (6):1314–1318, December 2013
DOI 10.1111/bjd.12567

What is the topic?

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by a mutation in genes called TSC1 and TSC2. One of the manifestations of TSC is the presence of facial angiofibromas – tiny, benign tumors that appear as reddish spots on the skin.

Abnormalities in TSC1 and TSC2 genes as seen in TSC lead to over-activation of a protein complex known as mammalian target of rapamycin complex 1 (mTORC1). Hence, inhibiting the activity of mTORC1 may have beneficial effects. Rapamycin (also called sirolimus) is an inhibitor of the mTORC1 complex, and has been shown to be beneficial in the skin conditions of TSC in some studies. Additionally, rapamycin has been shown to be beneficial in other manifestations of TSC such as learning and memory deficits and tumors.

What did the researchers hope to learn?

Previous studies have shown the usefulness of rapamycin in skin conditions in TSC, but since these studies were not done with proper controls, it was difficult to study the effects of rapamycin objectively. In the present study, researchers compared a rapamycin-containing formulation and compared it with vehicle (no rapamycin) in the same individual. This design is known as the ‘left-right comparative study’ Since the severity of manifestations of TSC vary between individuals, this experimental design was better, since they were comparing treatment vs. control in the same individual.

Who was studied?

Eleven individuals with TSC were recruited, and they were administered rapamycin ointment or gel, and vehicle (without rapamycin). Since the comparison was done in the same person, the researchers chose individuals with a similar level of angiofibromas on both cheeks.

How was the study conducted?

First, tests were done in vitro (or ‘outside the body’) to ensure that rapamycin in the form of a gel or ointment actually permeated into the skin. Hence, individuals with TSC were not used for this part of the study. In the second part of the study, rapamycin-containing formation was applied on one cheek, and vehicle (no rapamycin) was applied on another cheek for a total of 12 weeks.

What did the researchers find?

In the in vitro system, researchers found that absorption of rapamycin through the skin was much greater when it was formulated in a gel, as compared to ointment.  Also, the researchers made sure that there was no irritation or adverse effect on the skin of the individuals.

After this, it was discovered that rapamycin did indeed cause a reduction of symptoms such as redness, and papule size, and enhanced the general appearance of the cheek; as compared to vehicle-treatment. These beneficial effects of rapamycin were greater in children as compared to adults. Hence, topical (i.e. something that can be applied to the skin surface) application of rapamycin gel may be useful in individuals with TSC.

What were the limitations of the study?

The one limitation of the study was the small number of individuals. That being said, the left-right comparison method made the study much more powerful.

What do the results mean for you?

The results show that rapamycin may be of potential use in angiofibromas in people with TSC. Although the study needs to be repeated in a larger number of individuals, these preliminary studies give hope to individuals with TSC.

This summary was written by Sloka Iyengar, PhD, research scientist at the Nathan Kline Institute (New York); July 2014.


Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex

Lay Title:  Sun exposure causes TSC angiofibroma development
Authors: Magdalena E. Tyburczy, Ji-an Wang, Shaowei Li, Rajesh Thangapazham, Yvonne Chekaluk, Joel Moss, David J. Kwiatkowski, and Thomas N. Darling.
Human Molecular Genetics, Advance Access published December 18, 2013.
DOI: 10.1093/hmg/ddt597

Summary

Ultraviolet (UV) radiation in sunlight has many harmful effects for all of us.  It causes sunburn acutely, aging skin when we are older, and leads to formation of skin tumors including basal cell carcinomas and melanoma.  This has led to widespread adoption of sun protective measures, including use of hats and other measures to reduce sunlight exposure, and application of sunblock to the skin.

Now, a team of researchers at the Uniformed Services University of the Health Sciences, the National Heart, Lung, and Blood Institute in Maryland, and the Brigham and Women’s Hospital in Boston, have shown that the UV radiation in sunlight contributes to the development of facial angiofibromas in TSC.  Using cultured cells from angiofibromas from TSC individuals and next generation sequencing, hallmark signature mutations indicative of UV damage to DNA were identified in the TSC2 gene in the proliferating cells that make up these tumors.  This is the first time that UV-induced mutations have been identified in cells located below the surface of the skin (subepidermal) in any human condition, so the findings were unexpected.

The findings have important implications for all TSC individuals and families.  They suggest that avoidance of sunlight and its inherent UV radiation on the face of TSC individuals could significantly reduce the frequency and severity of facial angiofibromas.  TSC facial angiofibromas typically begin to appear in early childhood, and grow worse during the teenage years and later.  Facial angiofibromas are often a significant cosmetic issue requiring repeated dermatological procedures for control.  The observation of UV mutations in angiofibromas suggest that measures recommended to the general public to minimize UV exposure may be even more important for those with TSC.  These measures include: 1) seeking shade, particularly between 10 am and 2 pm, 2) wearing clothing that blocks sunlight including a broad-rim hat, 3) applying generous amounts of a broad-spectrum, water resistant sunscreen with SPF 30 or greater to sun-exposed areas, and 4) not using tanning beds. These simple actions may help to reduce the frequency and severity of facial angiofibromas, which would be a very welcome outcome for TSC individuals.


Nipple Angiofibromas with Loss of TSC2 Are Associated with Tuberous Sclerosis Complex

Author(s): Neera Nathan, BA, Magdalena E. Tyburczy, PhD, Lana Hamieh, MD, Ji-an Wang, AS, G. Thomas Brown, MD, PhD, Chyi-Chia Richard Lee, MD, PhD, David J. Kwiatkowski, MD, PhD, Joel Moss, MD, PhD, and Thomas N. Darling, MD, PhD
Journal name:  Journal of Investigative Dermatology. 2016; 136, 535-538.
DOI:10.1016/j.jid.2015.11.015

What is the topic?

A previously unreported skin finding in tuberous sclerosis complex (TSC), nipple angiofibromas.

What did the researchers hope to learn?

The researchers hoped to learn about the frequency, presentation and genetic basis of nipple and areolar angiofibromas.

Who was studied?

Adults with TSC

How was the study conducted?

53 adults with TSC were examined for presence of angiofibromas on the nipple. Skin biopsies of angiofibromas in this region were performed to confirm the diagnosis under the microscope and genetic testing was performed on biopsied samples to help determine their cause.

What did the researchers find?

Eleven out of 53 TSC patients (approximately 20%) had 1-25 angiofibromas on their nipple and/or areola. The median age of onset was 33 years. They resembled angiofibromas of the face based on their appearance, microscopic features, and genetic changes.  Some women reported that they first noticed development of angiofibromas on their nipples after starting to breastfeed.

What were the limitations of the study?

The study subjects were primarily women with TSC and lymphangioleiomyomatosis (LAM) and therefore may not be representative of all individuals with TSC.

What do the results mean for you?   

Angiofibromas of the nipple and areola are associated with TSC. They appear much later than angiofibromas on the face, are usually painless and may bleed with trauma. Like facial angiofibromas, they are not harmful and do not require treatment. However, other types of skin growths involving the nipple are more serious, so a physician should evaluate any new or growing lesion on the nipple.

This summary was written by Neera Nathan, fourth year medical student at the George Washington University, Washington DC and former TSC research fellow with the laboratory of Thomas Darling, MD, PhD (March, 2016).  


Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus

Author(s): Neera Nathan, BA, Ji-an Wang, AS, Shaowei Li, MD, PhD, Edward W. Cowen, MD, MHSc, Mary Haughey, RN, Joel Moss, MD, PhD, and Thomas N. Darling, MD, PhD
Journal name:  J Am Acad Dermatol. 2015 Nov;73(5):802-8.
DOI: 10.1016/j.jaad.2015.07.018.

What is the topic?

Treatment of tuberous sclerosis complex (TSC) skin tumors

What did the researchers hope to learn?

The researchers hoped to learn if oral sirolimus could reduce the size and/or redness of angiofibromas, shagreen patches and ungual fibromas in patients who were already taking the drug for their lymphangioleiomyomatosis (LAM).

Who was studied?

Adult women with TSC and LAM

How was the study conducted?

A retrospective review of serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before and during treatment was performed. Each photo was scored on a 7-point scale, then photos were compared to determine if there was improvement with treatment.

What did the researchers find?

Angiofibromas and shagreen patches significantly improved after a median treatment duration of 12 and 10 months, respectively. Patients treated for up to 64 months with oral sirolimus sustained improvement in their skin tumors. Adverse events included oral ulcers, acne-like lesions and some systemic symptoms.

What were the limitations of the study?

The study was limited to adult women with LAM and was retrospective in nature.

What do the results mean for you?

The decision to treat TSC skin tumors should include consideration of whether the patient is a candidate for oral sirolimus or everolimus to treat subependymal giant cell astrocytomas, LAM or renal angiomyolipomas associated with TSC. For patients without internal disease requiring treatment, topical sirolimus may be effective.

This summary was written by Neera Nathan, fourth year medical student at the George Washington University, Washington DC and former TSC research fellow with the laboratory of Thomas Darling, MD, PhD (March, 2016).