Distribution of shagreen patches and fibrous cephalic plaques in patients with tuberous sclerosis complex: A retrospective cohort study
Authors: Aya Takahashi, Satoshi Hattori, Ena Sakai, Lingli Yang, Ichiro Katayama, Manabu Fujimoto, Mari Wataya-Kaneda
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Shagreen patches (SPs) and fibrous cephalic plaques (FCPs) in tuberous sclerosis complex (TSC) are major skin features of the clinical diagnostic criteria. SPs are most commonly found on the back or thigh. FCPs are distributed not only on the forehead but also throughout the face, head, and neck.1Oyerinde O. Buccine D. Treichel A. et al.Fibrous cephalic plaques in tuberous sclerosis complex.J Am Acad Dermatol. 2018; 78: 717-724Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar This study examined their distribution by age, sex, and laterality without sex- or age-related bias. It is difficult to distinguish collagenomas (<1 cm) from the lesions that will evolve into SPs in the future as they are histopathologically similar.2Cascarino M. Leclerc-Mercier S. Histological patterns of skin lesions in tuberous sclerosis complex: a panorama.Dermatopathology. 2021; 8: 236-252Crossref PubMed Google Scholar Therefore, we combined collagenomas with SPs in this study. All Japanese patients with TSC examined at Osaka University Hospital from 1992 to 2020 (n = 213) were enrolled in this retrospective study (Table I). Ten of the 213 patients did not have SPs and FCPs, 7 of which were 0-9 years old. The body surface was divided into 8 approximately equal sections (Fig 1, left).3Takahashi A. Hattori S. Sakai E. et al.Distribution of hypomelanotic macules in tuberous sclerosis complex: a retrospective cohort study.J Am Acad Dermatol. 2022; 87: 237-240Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Based on clinical photographs, we measured the percentage of the total skin area involved by lesions in every section. We compared the average values to estimate the distribution (Fig 1), laterality, and differences between sexes (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/b65jyjzd6k.1, Table I).Table IPatient characteristics and the average area (%) of SPs and FCPs relative to the area of each sectionBody sitesn (%), Mean age ±SD, yAverage area (P value)FCPSPHead, face, and neckTotalChestAbdomen and groinUpper back and scapular regionLower back and buttocksThighLower leg and footUpper limbAge category (y) 0-940 (18.8), 5.7 ± 2.40.27 (ref.)0.7 (ref.)0.44 (ref.)0.21 (ref.)1.85 (ref.)1.94 (ref.)0.38 (ref.)0.01 (ref.)0.11 (ref.) 10-1949 (23), 14.4 ± 2.90.6 (0.074)1.39 (0.013)0.53 (0.76)0.87 (0.074)2.91 (0.30)3.93 (0.036)1.22 (0.16)0.17 (0.038)0.10 (0.94) 20-2935 (16.4), 24.4 ± 2.71.1 (0.037)1.99 (0.0043)0.94 (0.34)2.15 (0.037)3.32 (0.25)6.04 (0.017)1.16 (0.17)0.25 (0.045)0.06 (0.53) 30-3934 (16), 34.7 ± 2.81.71 (0.050)1.43 (0.0081)0.45 (0.97)1.4 (0.049)3.16 (0.20)3.46 (0.12)0.90 (0.43)0.32 (0.12)0.35 (0.27) 40-4926 (12.2), 43.2 ± 2.90.87 (0.66)1.88 (0.0028)0.53 (0.81)0.13 (0.66)3.08 (0.29)7.37 (0.0032)1.73 (0.06)0.25 (0.088)0.04 (0.37) >5029 (13.6), 57.5 ± 7.00.71 (0.37)2.49 (0.0016)0.26 (0.56)0.43 (0.37)3.92 (0.21)10.85 (0.0017)1.31 (0.14)0.38 (0.06)0.24 (0.49)Sex F126 (59), 29.58 ± 18.60.64 (0.065)1.6 (0.81)0.67 (0.092)0.80 (0.57)2.88 (0.75)5.17 (0.97)1.31 (0.14)0.27 (0.15)0.12 (0.42) M87 (41), 23.38 ± 14.91.14 (ref.)1.54 (ref.)0.34 (ref.)1.03 (ref.)3.11 (ref.)5.22 (ref.)0.74 (ref.)0.13 (ref.)0.20 (ref.)All213 (100), 27.1 ± 17.5Left/Right Left0.33 (0.039)0.73 (0.10)0.31 (0.24)0.51 (0.22)1.24 (0.065)2.33 (0.12)0.51 (0.63)0.11 (0.86)0.09 (0.33) Right0.51 (ref.)0.85 (ref.)0.22 (ref.)0.38 (ref.)1.74 (ref.)2.86 (ref.)0.57 (ref.)0.1 (ref.)0.05 (ref.)The associations with age, laterality, and sex were examined by GEE linear regression. Subgroup analysis by part was also conducted. A two-sided significance level of P < .05 was determined to be statistically significant. All analyses were performed using SAS 9.4 (SAS Institute Inc). Age was grouped by decade for the categorization of patients by age. Very few patients were aged 50 years or more; hence, they were grouped together. Ratios of the average percentage of area in each age group were compared to that in the lowest age group (0-9 years)FCP, Fibrous cephalic plaque; GEE, generalized estimating equation; ref., reference; SD, standard deviation; SP, shagreen patch. Open table in a new tab The associations with age, laterality, and sex were examined by GEE linear regression. Subgroup analysis by part was also conducted. A two-sided significance level of P < .05 was determined to be statistically significant. All analyses were performed using SAS 9.4 (SAS Institute Inc). Age was grouped by decade for the categorization of patients by age. Very few patients were aged 50 years or more; hence, they were grouped together. Ratios of the average percentage of area in each age group were compared to that in the lowest age group (0-9 years) FCP, Fibrous cephalic plaque; GEE, generalized estimating equation; ref., reference; SD, standard deviation; SP, shagreen patch. The largest distribution area of SPs was the "lower back and buttocks" (5.19%), and the second-largest area was the "upper back and scapula" (2.98%) (Fig 1, right). These results were the same for all ages, sexes, and laterality (Table I). Histologically, the skin of these affected sites had a thick dermis, abundant collagen fibers, and fibroblasts, which may contribute to the induction of the SPs of TSC. The average area of SPs was lowest in the 0-9-year-old group. It was second highest in the 20-29-year-old group and highest in individuals older than 50 years at most sites. (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/b65jyjzd6k.1, Table I). Our data confirmed that SPs in patients with TSCs increase with age. Active cell division in fibroblast-rich areas during one's twenties and repeated external stimuli beyond the age of 50 may indeed play a role.4Saxton R.A. Sabatini D.M. mTOR Signaling in growth, metabolism, and disease.Cell. 2017; 168: 960-976Abstract Full Text Full Text PDF PubMed Scopus (3818) Google Scholar There was no difference based on the sex of the patients in either SPs or FCPs (Table I). Regarding laterality, unlike the result of published papers,1Oyerinde O. Buccine D. Treichel A. et al.Fibrous cephalic plaques in tuberous sclerosis complex.J Am Acad Dermatol. 2018; 78: 717-724Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar,5Bongiorno M.A. Nathan N. Oyerinde O. et al.Clinical characteristics of connective tissue nevi in tuberous sclerosis complex with special emphasis on shagreen patches.JAMA Dermatol. 2017; 153: 660-665Crossref PubMed Scopus (18) Google Scholar the area of FCPs was more distributed on the right side than on the left one (P = .039). Although there was no significant difference, the areas of the right side of the "upper back" (P = .065), "lower back and buttocks" (P = .12), "thigh" (P = .63), and "total" (P = .10) were larger than that of the left side in SP (Table I). Previous studies showed more left-sided FCPs in patients with TSC,1Oyerinde O. Buccine D. Treichel A. et al.Fibrous cephalic plaques in tuberous sclerosis complex.J Am Acad Dermatol. 2018; 78: 717-724Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar or no laterality for SPs.5Bongiorno M.A. Nathan N. Oyerinde O. et al.Clinical characteristics of connective tissue nevi in tuberous sclerosis complex with special emphasis on shagreen patches.JAMA Dermatol. 2017; 153: 660-665Crossref PubMed Scopus (18) Google Scholar The reason for the discrepancy in the distribution may be the differences in measurement methods, race, or environment. In this cohort study, the distributions of SPs and FCPs were compared in many TSC patients of a broad age range, with almost the same number of men and women. The results of this study may provide clues to the specificity of each part of the skin and its effect on lesion distribution, such as laterality and providing a niche environment. None disclosed. This study was supported by the Clinical Investigator's Research Project at Osaka University Graduate School of Medicine.