Accepted Manuscript

Fibrous Cephalic Plaques in Tuberous Sclerosis Complex

Oyetewa Oyerinde, B.S., Danielle Buccine, M.D., Alison Treichel, B.S., Claire Hong,
B.S., Chyi-Chia Richard Lee, M.D. Ph.D., Joel Moss, M.D. Ph.D., Thomas N. Darling,
M.D. Ph.D.

PII: S0190-9622(17)32858-X
DOI: 10.1016/j.jaad.2017.12.027
Reference: YMJD 12192

To appear in: Journal of the American Academy of Dermatology

Received Date: 14 September 2017

Revised Date: 1 December 2017
Accepted Date: 10 December 2017

Please cite this article as: Oyerinde O, Buccine D, Treichel A, Hong C, Lee C-CR, Moss J, Darling
TN, Fibrous Cephalic Plaques in Tuberous Sclerosis Complex, Journal of the American Academy of
Dermatology (2018), doi: 10.1016/j.jaad.2017.12.027.

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1 Fibrous Cephalic Plaques in Tuberous Sclerosis Complex

2 Oyetewa Oyerinde, B.S.1, 2, Danielle Buccine, M.D.2, Alison Treichel, B.S.1, 2, Claire Hong,

3 B.S.2, Chyi-Chia Richard Lee, M.D. Ph.D.3, Joel Moss, M.D. Ph.D.1 Thomas N. Darling, M.D.

4 Ph.D.2

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5 Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National

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6 Institutes of Health, Bethesda, MD, USA
2
7 Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda,

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8 MD, USA
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9 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National

10 Institutes of Health, Bethesda, MD, USA

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11

12 Corresponding Author:
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13 Dr. Thomas Darling

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14 Uniformed Services University of the Health Sciences

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15 4301 Jones Bridge Road

16 Bethesda, Maryland 20814

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17 301-295-3528

18 Thomas.Darling@usuhs.edu
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19 Funding Sources: This work was supported by NIH R01AR062080 and the Intramural Research
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20 Program of the National Institutes of Health, National Heart, Lung, and Blood Institute.

21 This research was also made possible through the NIH Medical Research Scholars Program, a

22 public-private partnership supported jointly by the NIH and generous contributions to the

23 Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association

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24 for Dental Research, the Colgate-Palmolive Company, Genentech, and other private donors.

25 IRB Approval status: Patients were consented to protocols 00-H-0051, 95-H-0186 and/or 82-H-

26 0032 approved by the National Heart, Lung, and Blood Institute Institutional Review Board

27

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28 Conflicts of Interest: No conflict of interest reported

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29 Reprint request: Dr. Thomas Darling

30

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31 Manuscript Word Count (excluding references, figures, tables): 2,378

32 Abstract Word Count: 199

33 Capsule Summary word Count: 44

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34 References: 34

35 Figure Count: 3
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36 Table Count: 2
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37
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38 Statement on any prior presentation:

39 Presented at the National Medical Association Annual Convention and Scientific Assembly,
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40 Dermatology Symposium. Philadelphia, Pennsylvania, July 31, 2017.

41
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42 Keywords: Tuberous sclerosis complex, Fibrous cephalic plaques, Cutaneous Manifestations of

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43 Tuberous Sclerosis, Histology of Fibrous Cephalic Plaque, Diagnosis of Tuberous Sclerosis,

44 Forehead Plaque, Scalp Fibroma

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45 ABSTRACT

46 Background: Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of

47 tuberous sclerosis complex (TSC) patients. They constitute a major feature for TSC diagnosis,

48 and may present before other TSC-related cutaneous hamartomas.

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49 Objective: To describe the clinical characteristics of FCPs in TSC.

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50 Methods: 113 patients with TSC were enrolled in an observational cohort study. Retrospective

51 analysis of medical records and skin photography was performed. FCPs were categorized per

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52 anatomic location and size.

53 Results: FCPs were observed in 36% (41/113) of patients. Of 62 total lesions, 58% were 1 to <5

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cm, 13% ≥5 cm, and 29% unknown size mostly due to prior excision. The distribution of lesions
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55 was 39% forehead, 27% face (non-forehead), 3% neck, and 31% scalp. Fourteen patients had

56 similar lesions less than 1cm in diameter. Histopathologically, FCPs displayed dermal
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57 collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas.

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58 Limitations: Men were underrepresented since the cohort was enriched for TSC patients with
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59 lymphangioleiomyomatosis, which occurs in adult women.

60 Conclusion: Two-fifths of FCPs presented on the forehead, with most of the remainder in other
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61 locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis

62 of TSC.
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64 INTRODUCTION

65 Tuberous sclerosis complex (TSC) has wide phenotypic variability characterized by the

66 formation of benign tumors in multiple organs [1, 2]. TSC results from an inactivating mutation

67 in either TSC1 or TSC2 leading to aberrant activation of the mechanistic target of rapamycin

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68 (mTOR) signaling cascade in tumors [3]. The two most commonly affected organs are the brain

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69 and skin. Brain involvement is usually discovered when a child presents with seizures [1]. Nearly

70 all TSC patients develop dermatologic lesions such as facial angiofibromas, hypomelanotic

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71 macules, shagreen patches, ungual fibromas, and fibrous cephalic plaques (FCPs) [4]. These

72 lesions are included in the major diagnostic criteria from the 2012 International Tuberous

73 Sclerosis Complex Consensus Conference [5].

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74 The use of clinical diagnostic criteria and genetic testing promotes timely and accurate
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75 diagnosis. However, diagnostic delay is not uncommon, with TSC diagnosed in some individuals

76 decades after the appearance of characteristic skin lesions [6]. Nearly 12% of TSC patients are
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77 not diagnosed until adulthood, usually after an affected child receives the diagnosis [7]. One
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78 contributing factor for delayed diagnosis may be failure to consider TSC in those lacking

79 seizures; up to 15% of patients do not report history of seizures [8]. Another factor may be poor
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80 recognition of characteristic skin lesions, including FCPs.

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81 FCPs may present at birth and commonly become noticeable in early childhood [9].
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82 Seminal reports documented these plaques on the scalp or face of patients with TSC, and

83 described histopathologic similarities to angiofibromas [10, 11]. Concepts and terminologies

84 have varied, with some authors grouping lesions on the face or scalp, some discussing them

85 separately as forehead plaques and scalp fibromas, and others using the term forehead plaque to

86 include all lesions on the face and scalp. This makes it challenging to assess the literature with

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87 regards to frequencies of these lesions, reported as 19-36% for forehead plaques [9, 12], 13-30%

88 for scalp fibromas [13, 14], and 46% overall [15]. A potential source of variability is that

89 forehead plaques are more common in patients with mutations in TSC2 than TSC1 (40% vs.

90 10%) [12] It is also likely that small lesions, especially if covered by hair on the scalp, are easily

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91 missed.

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92 Our goal was to describe the clinical and histopathologic characteristics of FCPs in TSC.

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93 Herein we report the full scope and less classic presentations of FCPs to improve recognition of

94 this diagnostic feature.

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95 PATIENTS AND METHODS

96 A total of 113 adult TSC patients were examined at the National Institutes of Health

97 (NIH) in Bethesda, Maryland from 1998 to 2016. Each provided written informed consent per

98 protocols 00-H-0051, 95-H-0186 and/or 82-H-0032, which were approved by the National Heart,

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99 Lung, and Blood Institute Institutional Review Board. All patients met the revised diagnostic

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100 criteria of the 2012 International Tuberous Sclerosis Complex Consensus. The cohort was

101 enriched for those with pulmonary lymphangioleiomyomatosis (LAM) and therefore consisted

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102 mostly of women [16]. Patients were evaluated for the presence or absence of FCPs and queried

103 regarding the age of onset of lesion(s). Paired samples of FCP and normal skin were obtained

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from 11 patients and sections stained with routine haematoxylin and eosin.
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105 Pictures were taken. Lesions were classified according to size based on the length of the
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106 major axis: 1 to <5 cm, and ≥5 cm (large FCPs). These categories were arbitrarily selected to

107 provide information on size distribution in this population. Anatomic location was mapped onto
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108 a 3D mannequin head, and subsequently outlined on a representative head using Adobe
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109 Illustrator. Similar appearing lesions less than 1 cm in diameter, and clinically distinct from

110 classic angiofibromas, were also mapped. Lesions were classified as left, right, or midline.
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111 Statistical analysis of lesion lateralization was conducted using Wilcoxon signed rank test.
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112 RESULTS

113 Fibrous Cephalic Plaques

114 Frequency

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115 The 113 adult patients with TSC were comprised of 108 women and 5 men ranging in

116 age from 30 to 72 (median age 46) (Table I). Forty one patients (36%) had a FCP, one of whom

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117 was male. A total of 62 lesions were categorized by size into 36 “typical” FCPs (1 to <5 cm), 8

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118 large FCPs (>5cm), 16 of unknown size that were excised, and 2 FCPs whose size could not be

119 accurately determined from photos or medical records (Table II). Twenty-nine patients (71%)

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120 had a solitary lesion and 12 patients (29%) had multiple.
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121 Clinical Features
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122 FCPs appeared as rubbery to firm, smooth to bumpy, skin-colored, pink, red, or brown

123 plaques (Fig 1A). Patients with more darkly pigmented skin tended to have much darker lesions
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124 relative to surrounding skin than did patients with lightly pigmented skin (Fig 1B). FCPs on the
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125 scalp were associated with decreased hair density in the location of the lesion (Fig 1C). Twenty

126 patients (49%) reported onset of FCP at birth or during the first year of life (Table I). Many
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127 patients were unable to recall an age of onset, often because the lesions were unnoticed and

128 asymptomatic. Fourteen patients had excisions of 16 lesions, primarily for cosmetic reasons and
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129 rarely for bleeding or pain in the scalp. Lesions did not recur except for one patient who reported
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130 thickening and pain near the scar. TSC diagnosis was frequently delayed even in those having

131 their lesions excised. The median delay in years from onset of FCP to TSC diagnosis was 16

132 years (range -12 to 52, n=28).

133 Location

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134 The distribution of lesions was 24 (39%) on the forehead, 17 (27%) face (non-forehead),

135 2 (3%) neck, and 19 (31%) scalp. The outlines of these lesions are shown in Figure 2, excluding

136 the 18 that could not be accurately mapped due to excision (7 forehead, 6 non-forehead face, and

137 3 scalp) or inadequate documentation (1 forehead and 1 scalp). FCPs were more common on the

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138 left side, with 38 left-sided lesions (67%) and 19 right-sided (33%), (significantly different from

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139 50% expected, p=0.024, excluding 3 midline FCPs previously excised and 1 lesion with

140 unknown laterality).

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141 Histopathology

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142 Of the 11 FCPs that were biopsied and histopathologically analyzed, all had thickened,
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143 disorganized bundles of reticular collagen in the dermis with decreased elastic fibers compared

144 to unaffected skin (Fig 3A). Many lesions exhibited increased dilated vessels as observed in
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145 angiofibromas (Fig 3B). Others showed involvement of hair follicles ranging from distorted hair
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146 follicles with extensive perifollicular fibroplasia to bundles of collagen surrounding cords of
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147 abnormal epithelium emanating from the infundibular portions of the hair follicles, similar to

148 fibrofolliculomas (Fig 3C). In addition, some samples exhibited fibrosis around eccrine glands.
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149 Lesions <1cm

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150 Fourteen patients (12%) had lesions similar to FCPs that were less than 1cm in diameter
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151 (Fig 1D). Five of these 14 patients did not have an accompanying FCP. There were a total of 23

152 lesions <1cm and the median number of lesions per patient was 1 (range 1-5). Five patients

153 (36%) had multiple lesions while nine patients (64%) had solitary lesions. These lesions were

154 skin-colored, pink, red or brown papules. The majority of lesions <1cm had an unknown age of

155 onset. They were outside typical locations for angiofibromas, often in the scalp or lateral face,

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156 and did not arise from a confluence of angiofibromas. Of the twenty-three smaller lesions, 11

157 were located on the scalp (48%), 7 on the forehead (30%), and 5 on the face (22%) (Fig 2). There

158 were 13 (57%) left-sided, 9 (39%) right-sided, and 1 (4%) previously excised midline lesion; a

159 trend toward lesions on the left was not statistical significant (p=0.54). Eight of the lesions <1cm

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160 in size were histopathologically analyzed and showed features similar to FCPs, including

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161 thickened dermal collagen bundles and decreased elastic fibers. Some of the lesions additionally

162 showed vascular changes similar to angiofibromas, as well as perifollicular fibroplasia.

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163

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164 DISCUSSION

165 Fibrous cephalic plaques were present in 36% of our cohort with TSC, within the range

166 of 19-46% reported in previous studies [9, 12, 15]. Onset was commonly in infancy or early

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167 childhood. Lesions were significant enough to be excised in 34%. Despite this, TSC diagnosis

168 was often delayed until late teens or adulthood, highlighting the need for improved recognition

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169 of this cutaneous manifestation of TSC.

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170 The stereotypical location for FCP is the forehead, but only two-fifths were located on

171 the forehead in our study. They occurred just as commonly on the non-forehead face and scalp,

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172 and more rarely on the neck. Most FCPs occurred as a solitary plaque, generally measuring 1 to
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173 5 cm along the longest axis. In our experience, FCPs have a characteristic appearance,

174 particularly when large, with few lesions displaying similar features. The differential diagnosis
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175 may include melanocytic nevi, keloids, cutaneous lymphomas, neurocristic cutaneous
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176 hamartomas, and granuloma faciale. These entities can be excluded based on history and
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177 appearance, or biopsy if required. The differential diagnosis may also include the folliculocystic

178 and collagen hamartoma associated with TSC. Two TSC patients have been described with
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179 folliculocystic and collagen hamartomas on the scalp. In contrast to FCPs these hamartomas

180 show comedo-like openings that may drain a purulent material, and may also occur on the trunk
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181 [17], [18]. The presence of a FCP or multiple facial angiofibromas is a major feature for
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182 diagnosis of TSC; one additional major feature is sufficient for a clinical diagnosis [5]. A child

183 with a FCP has possible TSC and should have a thorough diagnostic evaluation regardless of

184 documented seizures [19].

185 FCPs may present before other manifestations of TSC, as an isolated skin finding or with

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186 hypomelanotic macules, the most common cutaneous manifestation of TSC in infancy [9], [20].

187 FCPs can be disfiguring, leading to stigmatization and low self-esteem. In our study, fourteen

188 patients had lesions excised primarily for cosmetic reasons. Alternatives to surgical excision

189 include vascular laser therapy for erythematous lesions or ablation with a CO2 laser [4, 21]. A

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190 combination of pinpoint electrosurgery, pulsed dye laser, and ablative fractional resurfacing was

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191 shown to flatten and soften an FCP in one patient [22]. The potential for treating these lesions

192 using an mTOR inhibitor was suggested by studies showing that fibroblast-like cells grown from

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193 FCPs show activation of mTOR signaling due to biallelic mutations in TSC2, and treatment

194 responses observed in xenograft and conditional knockout models [23-25]. Recently, topical 1%

195
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sirolimus cream was shown to improve the appearance of FCPs in 9 of 16 patients after 3 to 9
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196 months of treatment [26].
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197 Interestingly, FCPs were more common on the left side in our cohort. It appears that large

198 shagreen patches in TSC patients also predominate on the left [27]. This may be spurious but a
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199 potential biologil explanation can be postulated based on the role of the primary cilium in
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200 lateralization. Loss of Tsc1 or Tsc2 leads to aberrations in the length of the primary cilium in

201 mouse embryonic fibroblasts [28, 29], and morpholino knockdown of tsc1a in zebrafish causes
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202 ciliary dysfunction and left-right asymmetry defects [30]. The manner in which abnormalities in
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203 the primary cilium might impact embryonic development and subsequent tumor localization is
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204 unknown. Further studies are warranted to confirm possible lateralization.

205 Histopathologic examination of FCPs revealed thickened bundles of reticular collagen

206 with decreased or absent elastic fibers. In addition to these features, with similarities to the

207 shagreen patch of TSC, lesions frequently showed focal areas that were histopathologically

208 similar to angiofibroma, perifollicular fibroma, fibrofolliculoma, or combination thereof.

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209 Angiofibromatous changes have been documented previously in forehead plaques [9] and a scalp

210 fibroma [31]. Multiple fibrofolliculomas are classic for Birt-Hogg-Dubé (BHD) syndrome, but a

211 facial fibrofolliculoma was previously reported in a patient with TSC [32]. Our observations

212 indicating variable stromal and epithelial findings in FCPs, with a histopathologic spectrum

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213 varying from angiofibroma to fibrofolliculoma, support the proposition that cutaneous

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214 hamartomas in TSC and BHD syndrome share a common histogenesis [33].

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215 In addition to FCPs, 12% of our cohort presented with lesions similar in clinical and

216 histopathologic appearance to FCPs but measured <1cm in diameter. These lesions do not fulfill

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217 diagnostic criteria. Clinical diagnostic certainty is less for these small lesions than for large
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218 FCPs. In the absence of other TSC-related skin findings, confirmation with a skin biopsy is

219 necessary. Patients with histopathologically confirmed, small FCP-like lesions should be
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220 questioned for a personal or family history suggestive for TSC, closely examined for additional

221 mucocutaneous features of TSC, and considered for complete diagnostic evaluation. This
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222 presentation and work-up is analogous to small collagenomas <1cm diameter that do not meet
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223 criteria for shagreen patch [27].

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224 Limitations of this study include the retrospective design, use of patient-reported onset of

225 FCPs, and the small sample size for histopathologic analysis. Ages of onset were by patient or
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226 parent recollection and a prospective study is needed to define when these lesions appear. Our
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227 cohort was comprised mainly of adult women due to enrichment for those with pulmonary

228 lymphangioleiomyomatosis, which occurs almost exclusively in women. It is possible that our

229 results are not generalizable to men with TSC. However, one study found no significant

230 difference in frequency of fibrous forehead plaques in men compared to women [34]. We did not

231 observe the evolution of these lesions from early childhood, although FCPs in adulthood

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232 remained stable over time. FCPs in children have been observed to grow slowly and become

233 raised [9].

234 CONCLUSIONS

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235 Only about two-fifths of FCPs present on the classic location of the forehead, with the

236 remainder split between other locations on the face, neck, or scalp. In addition to thickened

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237 collagen and decreased elastic fibers, FCPs frequently show stromal and epithelial changes that

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238 fall on a spectrum between angiofibromas of TSC and fibrofolliculomas of BHD syndrome.

239 Better recognition of these lesions by clinicians may help to ensure prompt diagnosis, early

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240 treatment initiation and appropriate referral for follow-up of other TSC-related sequelae.
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242 ACKNOWLEDGEMENTS:

243 We thank Sorana Raiciulescu, M. Sc. (Uniformed Services University) for statistical analysis.

244 This work was supported by NIH R01AR062080 and the Intramural Research Program of the

245 National Institutes of Health, National Heart, Lung, and Blood Institute. This research was also

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246 made possible through the NIH Medical Research Scholars Program, a public-private partnership

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247 supported jointly by the NIH and generous contributions to the Foundation for the NIH from the

248 Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-

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249 Palmolive Company, Genentech, and other private donors. For a complete list, visit the

250 foundation website at http://www.fnih.org.

251
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252 DISCLAIMER:

253 The opinions and assertions expressed herein are those of the authors and do not necessarily
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254 reflect the official policy or position of the Uniformed Services University, the Department of

255 Defense or the National Institutes of Health.

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256 REFERENCES

257 1. Henske, E.P., et al., Tuberous sclerosis complex. Nat Rev Dis Primers, 2016. 2: p. 16035.

258 2. Roach, E.S., Applying the Lessons of Tuberous Sclerosis: The 2015 Hower Award

259 Lecture. Pediatr Neurol, 2016. 63: p. 6-22.

PT
260 3. Lam, H.C., J. Nijmeh, and E.P. Henske, New developments in the genetics and

RI
261 pathogenesis of tumours in tuberous sclerosis complex. J Pathol, 2017. 241(2): p. 219-

262 225.

SC
263 4. Teng, J.M., et al., Dermatologic and dental aspects of the 2012 International Tuberous

264 Sclerosis Complex Consensus Statements. JAMA Dermatol, 2014. 150(10): p. 1095-101.

265 5.
U
Northrup, H., D.A. Krueger, and G. International Tuberous Sclerosis Complex
AN
266 Consensus, Tuberous sclerosis complex diagnostic criteria update: recommendations of

267 the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr
M

268 Neurol, 2013. 49(4): p. 243-54.

D

269 6. Seibert, D., et al., Recognition of tuberous sclerosis in adult women: delayed presentation
TE

270 with life-threatening consequences. Ann Intern Med, 2011. 154(12): p. 806-13, W-294.

271 7. Staley, B.A., E.A. Vail, and E.A. Thiele, Tuberous sclerosis complex: diagnostic
EP

272 challenges, presenting symptoms, and commonly missed signs. Pediatrics, 2011. 127(1):

273 p. e117-25.
C

274 8. Chu-Shore, C.J., et al., The natural history of epilepsy in tuberous sclerosis complex.
AC

275 Epilepsia, 2010. 51(7): p. 1236-41.

276 9. Jozwiak, S., et al., Skin lesions in children with tuberous sclerosis complex: their

277 prevalence, natural course, and diagnostic significance. Int J Dermatol, 1998. 37(12): p.

278 911-7.

15
 16
ACCEPTED MANUSCRIPT

279 10. Butterworth T., W.M., Dermatologic Aspects of Tuberous Sclerosis. Archives of

280 Dermatology and Syphilolgy, 1941. 43(1): p. 1-41.

281 11. Nickel, W.R. and W.B. Reed, Tuberous sclerosis. Special reference to the microscopic

282 alterations in the cutaneous hamartomas. Arch Dermatol, 1962. 85: p. 209-26.

PT
283 12. Dabora, S.L., et al., Mutational analysis in a cohort of 224 tuberous sclerosis patients

RI
284 indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.

285 Am J Hum Genet, 2001. 68(1): p. 64-80.

SC
286 13. Nath, J., A. Dubey, and R. Pavan, Analysis of twenty pediatric cases of tuberous sclerosis

287 complex: are we doing enough? Indian J Dermatol Venereol Leprol, 2015. 81(1): p. 23-8.

288 14.
U
Baykal, C., et al., Fibromatous lesion of the scalp: is it an underestimated sign of
AN
289 tuberous sclerosis? J Eur Acad Dermatol Venereol, 2017. 31(2): p. e110-e112.

290 15. Wataya-Kaneda, M., Tanaka M., Hamasaki T., et al., Trends in the Prevalence of
M

291 Tuberous Sclerosis Complex Manifestations: An Epidemiological Study of 166 Japanese

D

292 Patients. PLoS One, 2013.

TE

293 16. Johnson, S.R., A.M. Taveira-DaSilva, and J. Moss, Lymphangioleiomyomatosis. Clin

294 Chest Med, 2016. 37(3): p. 389-403.

EP

295 17. Torrelo, A., et al., Folliculocystic and collagen hamartoma of tuberous sclerosis

296 complex. J Am Acad Dermatol, 2012. 66(4): p. 617-21.

C

297 18. An, J.M., et al., Folliculocystic and Collagen Hamartoma: A New Entity? Ann Dermatol,
AC

298 2015. 27(5): p. 593-6.

299 19. Krueger, D.A., H. Northrup, and G. International Tuberous Sclerosis Complex

300 Consensus, Tuberous sclerosis complex surveillance and management: recommendations

16
 17
ACCEPTED MANUSCRIPT

301 of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr

302 Neurol, 2013. 49(4): p. 255-65.

303 20. Ebrahimi-Fakhari, D., et al., Dermatological manifestations of tuberous sclerosis

304 complex (TSC). J Dtsch Dermatol Ges, 2017. 15(7): p. 695-700.

PT
305 21. Darling, T.N., Moss J., Mausner M., Dermatologic Manifestations of Tuberous Sclerosis,

RI
306 in Tuberous Sclerosis Complex Genes, Clinical Features, and Therapeutics, D.J.

307 Kwiatkowski, Whittemore V., Thiele E., Editor 2010, Wiley-Blackwell: Weinheim,

SC
308 Germany. p. 285-309.

309 22. Weiss E., G.R., New Technique Using Combined Pulsed Dye Laser and Fractional

310
U
Resurfacing for Treating Facial Angiofibromas in Tuberous Sclerosis. Lasers in Surgery
AN
311 and Medicine, 2010. 42: p. 357-360.

312 23. Li, S., et al., Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and
M

313 hamartoma morphogenesis. Nat Commun, 2011. 2: p. 235.

D

314 24. Tyburczy, M.E., et al., Sun exposure causes somatic second-hit mutations and
TE

315 angiofibroma development in tuberous sclerosis complex. Hum Mol Genet, 2014. 23(8):

316 p. 2023-9.
EP

317 25. Klover, P.J., et al., Tsc2 disruption in mesenchymal progenitors results in tumors with

318 vascular anomalies overexpressing Lgals3. Elife, 2017. 6.

C

319 26. Malissen, N., et al., Long-term treatment of cutaneous manifestations of tuberous
AC

320 sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients. J

321 Am Acad Dermatol, 2017. 77(3): p. 464-472 e3.

17
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322 27. Bongiorno, M.A., et al., Clinical Characteristics of Connective Tissue Nevi in Tuberous

323 Sclerosis Complex With Special Emphasis on Shagreen Patches. JAMA Dermatol, 2017.

324 153(7): p. 660-665.

325 28. Hartman, T.R., et al., The tuberous sclerosis proteins regulate formation of the primary

PT
326 cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum Mol

RI
327 Genet, 2009. 18(1): p. 151-63.

328 29. Armour, E.A., R.P. Carson, and K.C. Ess, Cystogenesis and elongated primary cilia in

SC
329 Tsc1-deficient distal convoluted tubules. Am J Physiol Renal Physiol, 2012. 303(4): p.

330 F584-92.

331 30.
U
DiBella, L.M., A. Park, and Z. Sun, Zebrafish Tsc1 reveals functional interactions
AN
332 between the cilium and the TOR pathway. Hum Mol Genet, 2009. 18(4): p. 595-606.

333 31. Sharma, B., et al., Scalp fibroma: a rare cutaneous manifestation of tuberous sclerosis.
M

334 BMJ Case Rep, 2014. 2014.

D

335 32. Misago, N. and Y. Narisawa, Fibrofolliculoma in a patient with tuberous sclerosis
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336 complex. Clin Exp Dermatol, 2009. 34(8): p. 892-4.

337 33. Misago, N., T. Kimura, and Y. Narisawa, Fibrofolliculoma/trichodiscoma and fibrous
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338 papule (perifollicular fibroma/angiofibroma): a revaluation of the histopathological and

339 immunohistochemical features. J Cutan Pathol, 2009. 36(9): p. 943-51.

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340 34. Au, K.S., et al., Genotype/phenotype correlation in 325 individuals referred for a
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341 diagnosis of tuberous sclerosis complex in the United States. Genet Med, 2007. 9(2): p.

342 88-100.

343

344

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345 ABBREVIATIONS AND ACRONYM LIST

346 Fibrous cephalic plaque (FCP)

347 Tuberous sclerosis complex (TSC)

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348 Mechanistic target of rapamycin (mTOR)

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349 Lymphangioleiomyomatosis (LAM)

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350 Birt Hogg Dubé (BHD)

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351 Figure Legends:

352 Figure 1. Tuberous Sclerosis Complex. Clinical Appearance of Fibrous Cephalic Plaques (FCP)

353 and FCP-like lesions <1cm in size. (A) FCP on the forehead of a lightly pigmented individual.

354 (B) Two lesions on the forehead of a darkly pigmented individual. (C) Scalp FCP exhibiting

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355 decreased hair follicle density. (D) Lesion <1cm on the forehead, with onset at birth prior to the

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356 development of multiple facial angiofibromas.

357

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358 Figure 2. Tuberous Sclerosis Complex. Locations and sizes of fibrous cephalic plaques. FCPs

359 1cm to < 5 cm in red, large FCPs ≥ 5cm in yellow. Also shown are lesions similar to FCPs <1cm

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in blue. A: Front face. B: Left face. C: Right face. D: Back of head. E: Top of head.
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361

362 Figure 3. Tuberous Sclerosis Complex. Histopathologic features of FCPs. A: FCP from
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363 scalp. Two abnormally shaped hair follicles partially surrounded by sclerotic collagen and
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364 separated by thickened bundles of reticular dermal collagen fibers (4x). B: FCP from forehead.
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365 There is increased vascularity characteristic of an angiofibroma (40x). C: FCP from

366 cheek. Cords of squamous epithelium emanate from the infundibular portion of hair
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367 follicles. The hair follicle is surrounded by sclerotic collagen that is focally arranged

368 perpendicularly to the follicular epithelium (20X).

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369 Table I: Characteristics of individuals with TSC

370
No. (%) of
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patients

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Sex
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Female 108 (96)

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Male 5 (4)
Race

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White, not Hispanic 91 (81)
Black, not Hispanic 8 (7)

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Asian or Pacific Islander 3 (3)
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Hispanic 9 (8)
Other or unknown 2 (2)
Fibrous Cephalic Plaque
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Yes 41 (36)
No 72 (64)
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Age of onset per patient report

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0-<2 year 20 (49)

2-<5 years 2 (5)
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5-<10 years 3 (7)

10-<15 years 2 (5)
15-<18 years 0 (0)
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>18 years 1 (2)

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unknown 13 (32)

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374 Table II: Size and Distribution of FCPs in TSC

No. %
All Locations 62
FCPs ≥5cm 8 13

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FCPs 1-<5cm 36 58
FCPs with prior excision 16 26

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FCPs with size not documented 2 3
Forehead 24 39

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1-<5cm on forehead 14 58
≥5cm on forehead 2 8

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Unknown size 8 33
Face (non-forehead) 17 27
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1-<5cm on face 9 53
≥5cm on face 2 12
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Unknown size 6 35
Neck: 2 3
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1-<5cm on neck 0 0
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≥5cm on neck 2 100

Unknown size 0 0
Scalp: 19 31
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1-<5cm on scalp 13 68
≥5cm on scalp 2 11
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Unknown size 4 21
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1 CAPSULE SUMMARY

2 • Fibrous cephalic plaques present early in life and are a characteristic

3 manifestation of tuberous sclerosis complex

4 • Lesions classically occur on the forehead but are frequent elsewhere on the face

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5 or scalp

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6 • Identification of fibrous cephalic plaques may promote earlier diagnosis of

7 tuberous sclerosis complex

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