Racial differences in the dermatological manifestations of tuberous sclerosis complex and the potential effects on diagnosis and care

Abstract

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder of non-malignant tumor growths throughout major organ systems and neurological, neuropsychiatric, renal, and pulmonary co-morbidities. Skin manifestations are readily visible, often develop early in life, and are major features that contribute to TSC diagnosis. Medical photographs of such manifestations are commonly shown as examples from White individuals creating a potential barrier to accurately identifying these features in darker skinned individuals.

Objectives: The aim of this report is to raise awareness of dermatological manifestations associated with TSC, compare their appearance by race, and consider how recognition of these features could impact diagnosis and treatment of TSC.

Design and methods: We conducted a retrospective chart review at the TSC Center of Excellence (TSCOE) at the Kennedy Krieger Institute, which included all patients in the center from 2009 (inception) through the end of the calendar year 2015 and analyzed data from the TSC Alliance Natural History Database (NHD).

Results: Among TSCOE patients, 50% of Black patients were diagnosed before the age of 1 year, compared with 70% of White patients. NHD data corroborated this trend showing a significant difference with only 38% of Blacks as compared with 50% of Whites were diagnosed at age ⩽1 year. A significant difference was observed where White participants had higher odds of having received genetic testing in both data sets. While no differences in the total number of TSC features was observed in either data set, shagreen patches and cephalic fibrous plaques were more frequently recorded in the NHD for Black individuals.

Conclusion: We highlight a disparity in the representation of Black participants within the NHD, TSCOE, and TSC trials, in addition to differences in utilization of molecular testing and topical mechanistic target of rapamycin (mTOR) inhibitor therapy between Black and White individuals. We show a trend toward later diagnosis age in Black individuals. These differences between races warrant further study across additional clinical sites and other minority groups.

Keywords: TSC; angiofibroma; diagnosis; genetic testing; neurocutaneous; race; racial disparity; tuberous sclerosis complex.

Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AJP and GVR are employees of the TSC Alliance, a non-profit organization, which reports revenue from individual donors and corporations including BridgeBio, Chemistry Rx, DiRx, Jazz Pharmaceuticals, LivaNova, Marinus, MassMutual, Neurelis, Nobelpharma America, Noema, Ovid, TotalCare Rx, UCB, and Upsher-Smith. The views expressed in this article are those of the authors and do not necessarily reflect the opinion of the TSC Alliance. TTG served as a principal site investigator for a Novartis study (EXIST-3); funding was provided to her institution only.

© The Author(s), 2022.

Figures

Figure 1.

Hypomelanotic macules in Black and White individuals with TSC. (a–d) Black individuals with hypomelanotic macules. (a) Age 11 male, on forehead. (b) Age 11 male, on back. (c) Age 14 male, on cheek. (d) Age 14 male, on leg. (e–h) White individuals with hypomelanotic macules. (e) Age 8 male, on neck. (f) Age 7 female, on arm. (g) Age 4 female, on arm. (h) Age 15 male, on leg.

Figure 2.

Facial angiofibromas in Black and White individuals with TSC. (a–d) Black individuals with facial angiofibromas, ages 11, 14, 16, and 28, respectively. (e–h) White individuals with facial angiofibromas, ages 13, 37, 39, and 28, respectively.

Figure 3.

Cephalic fibrous plaques (CFPs) in Black and White individuals with TSC. (a) A 28-year-old Black female and (b) a 7-year-old White female with cephalic fibrous plaques (CFPs) on the forehead and eyelid, respectively. White arrows indicate location of CFPs.

Figure 4.

Shagreen patches in a Black and White individual with TSC. (a) An 11-year-old Black male with a shagreen patch on the back and (b) a 37-year-old White female with a shagreen patch on the back.

Figure 5.

TSC participant selection from the NHD. We restricted our analyses to records of Black and White individuals in the NHD. Analyses not requiring an age at TSC diagnosis utilized Box 2 (n = 1966) as the data source, whereas analyses focused on age at diagnosis utilized Box 3 (n = 1487) as the data source. Total counts for each analysis are located in the respective figure legends.

Figure 6.

Age at TSC diagnosis for Black and White participants in the TSC natural history database. Scatterplot showing a total of 107 Black and 1380 White participants that had an age of diagnosis recorded in the NHD. An unpairedt-test with Welch’s correction was conducted determining a non-significant difference in the variances of age at TSC diagnosis (p = 0.7264) between Black (average age 5.4) and White (average age 5.7) individuals.

Figure 7.

Comparison of age at TSC diagnosis for Black and White participants in the TSC natural history database. A total of 107 Black and 1380 White participants had an age of diagnosis recorded in the NHD. A Fisher’s exact test was used to compare how many participants were diagnosed at age ⩽1 year as compared with age ⩾2 years. A significant difference (p = 0.027) was observed with 38% of Black participants diagnosed at age 1 or under, while 50% of White participants were diagnosed at age 1 or under.

Figure 8.

Count of major and minor TSC features in Black and White participants in the TSC natural history database. This analysis was completed on the 150 Black and 1816 White participants in the NHD regardless of a recorded age at diagnosis. Box and whiskers plots (line at median) illustrating the variation in the presence of major and minor features in Black and White participants. An unpairedt-test with Welch’s correction was conducted showing a non-significant difference (p = 0.28) in the number of major TSC features between Black (mean 5.2) and White participants (mean 5.0). The same analysis was conducted for minor TSC features illustrating a non-significant difference (p = 0.29) in the number of minor TSC features between Black (mean 0.7) and White participants (mean 0.7).

Figure 9.

Facial angiofibromas in Black and White participants in the TSC natural history database. (a) Count of Black and White individuals with or without facial angiofibromas. Out of 144 Black individuals with a recorded response, a total of 92 (64%) were reported to have facial angiofibromas. Out of a total of 1682 White individuals with a recorded response, a total of 1166 (66%) were reported to have facial angiofibromas. A Fisher’s exact text showed a non-significant difference (p = 0.189) in the percentages of Black and White individuals with facial angiofibroma. (b) A total of 67 Black participants and 791 White participants had a date recorded for the age at angiofibroma diagnosis. An unpaired t-test with Welch’s correction was conducted determining a non-significant difference in the age at facial angiofibroma diagnosis (p = 0.6198) between Black (average age 11.25 years) and White (average age 10.72 years) participants. Mean illustrated by red lines in (b).

Figure 10.

Presence of dermatological features in Black and White Participants in the TSC Natural History Database. (a) A total of 141 Black participants and 1639 White participants had a recorded answer for the presence or absence of shagreen patch. A Fisher’s exact test showed a significant difference (p < 0.0001) in the presence of shagreen patch between Black and White Participants, with 55.3% of Black and 37.6% of White individuals noted to have a shagreen patch. Odds ratio of 2.051 (95% CI: 1.457–2.919) indicates that Black individuals have an increased probability of having a shagreen patch. (b) A total of 142 Black participants and 1626 White participants had a recorded answer for the presence or absence of cephalic fibrous plaque. A Fisher’s exact test showed a significant difference (p = 0.0139) in the presence of cephalic fibrous plaque between Black and White participants, with 29.6% of Black and 20.5% of White individuals noted to have a shagreen patch. Odds ratio of 1.625 (95% CI: 1.105–2.358) indicates that Black individuals have an increased probability of having a shagreen patch.

Figure 11.

Use of topical rapamycin for facial angiofibroma in Black and White participants in the TSC natural history database. A total of 92 Black participants and 1166 White participants had a recorded answer for the use of the topical mTORi rapamycin. A Fisher’s exact test yielded a significant (p = 0.006) difference in the frequency of topical rapamycin use to treat facial angiofibroma in Black and White participants in the NHD cohort.

Figure 12.

Molecular testing in Black and White participants in the TSC natural history database. A total of 145 Black participants and 1692 White participants had a recorded answer for molecular testing. A Fisher’s exact test yielded a significant difference (p = 0.009) in the frequency of molecular testing between Black and White participants, with 54.5% of Black participants and 65.5% of White participants receiving molecular testing, respectively. Odds ratio 1.589 (95% CI: 1.129–2.251).

Figure 13.

Molecular testing in Black and White participants in the TSCOE. Out of the 41 participants in the TSCOE cohort, only 8 Black participants had molecular testing noted in the medical record (44%) versus18 White participants (78%). A Fisher’s exact test yielded a significant difference (p = 0.049) in the frequency of molecular testing between Black and White participants. Odds ratio 4.5 (95% CI: 1.188–17.83).