SUBMITTED 24 DEC 22 1 REVISION REQ. 26 JAN 23; REVISION RECD. 26 FEB 23 2 ACCEPTED 28 MAR 23 3 ONLINE-FIRST: MAY 2023 4 DOI: https://doi.org/10.18295/squmj.5.2023.035 5 6 Trichodysplasia Spinulosa 7 *Ayida Al Khalili,1 Elsa Maciagowski,2 Khue Nguyen,2 Kevin A. 8 Watters3 9 10 1Dermatology Unit, Department of Family Medicine and Public Health, Sultan Qaboos 11 University Hospital, Sultan Qaboos University, Muscat, Oman; Departments of 12 2Dermatology and 3Pathology, McGill University Health Center, Montreal, Canada 13 *Corresponding Author’s e-mail: a.alkhalili@hotmail.com 14 15 Abstract: 16 Trichodysplasia spinulosa (TS) is a unique, rare clinical and histological dermatologic 17 entity described mainly in setting of immunosuppression. It is caused by a novel human 18 polymoavirus, trichodysplasia spinulosa-associated polyomavirus (TSPyV). We report a 19 biopsy-proven case of TS in a renal transplant patient presented to dermatology 20 outpatient clinic in Montreal, Canada in 2015. Reduction of immunosuppression and/or 21 anti-viral therapy is the main therapeutic strategies used to treat such cases. Our patient 22 was managed with valgancyclovir with no obvious response. Subsequently, a trial of 23 topical imiquimod was commenced. Awareness of TS can prompt early diagnosis and 24 management to prevent possible complications. 25 Keywords: Trichodysplasia spinulosa, immunosuppression, organ-trasplant, human 26 polyomavirus. 27 28 mailto:a.alkhalili@hotmail.com Introduction 29 Trichodysplasia spinulosa (TS) is a rare cutaneous manifestation due to viral infection 30 affecting mainly immunosuppressed hosts. The majority of the patients are solid organ 31 recipients or patients diagnosed with hematological malignancies.1 32 33 Given its rarity, in most cases there is a potential delay in diagnosis. Moreover, the 34 pathogenesis of TS is not completely understood. Few therapeutic options are suggested 35 by published case reports and no standard therapies are approved yet.2 36 37 We present a case of TS in a renal transplant recipient and review the main characteristic 38 features of this entity. 39 40 Case Report 41 A male in his 60s presented to the dermatology outpatient clinic in Montreal, Canada in 42 2015 for evaluation of facial papules. These were of two-month duration and 43 progressively increasing in number, affecting the whole face but more concentrated on 44 the nose. There was mild facial pruritus. The patient was a kidney transplant recipient 45 since July 2014 for hypertensive nephropathy. He was on therapy with mycophenolic 46 acid (Myfortic) and tacrolimus (Advagraf). Medical history was positive for, 47 osteoarthritis, gout and IgA gammopathy (Monoclonal gammopathy of undetermined 48 significance). His other medications include amlodipine, phosphate, magnesium, 49 pantoprazole and ASA. 50 51 Skin examination revealed follicular flesh-coloured to pinkish monomorphic papules 52 mainly on central face involving the forehead and nose with central white protruding 53 spines. Scalp, mucosal membranes, palms and soles were not affected (figure 1). 54 55 Considering his immunosuppressive status, our differential diagnosis includes mainly 56 infectious etiologies such as molluscum contagiosum, filiform verrucae and 57 trichodysplasia spinulosa of immunosuppression. We have also considered idiopathic 58 follicular hyperkeratotic spicules or other adnexal pathologies such as sebaceous 59 hyperplasias, trichoepitheliomas, fibrofolliculomas, trichodiscomas and facial fibrous 60 papules (angiofibromas) as possibilities. 61 62 Histopathological exam of one of the papules showed dilated follicular infundibulae with 63 keratin plugs and viral-like changes with large irregular eosinophilic/basophilic 64 trichohyalin like granules within the inner root sheath cells consistent with 65 trichodysplasia spinulosa (figure 2). Additional test such as electron microscopy or 66 polymerase chain reaction was not performed. 67 68 Based on typical clinical findings in the setting of renal transplantation and suggestive 69 histologic features, the patient was diagnosed with trichodysplasia spinulosa. He was 70 managed initially with oral valganciclovir without adequate response. Subsequently, a 71 trial of topical imiquimod was commenced. Unfortunately, he was lost to follow up in 72 dermatology clinic. 73 74 Verbal informed consent was obtained from the patient for publication. 75 76 Discussion 77 Trichodysplasia spinulosa is a rare clinicopathologic skin entity primarily described in 78 immunosuppressed individuals. It is caused by trichodysplasia spinulosa- 79 associated polyomavirus (TSPyV).2 80 81 The first case of TS was reported in 1995 by Izakovic et al., describing a new entity with 82 spiny follicular hyperkeratosis thought to be related to cyclosporine treatment.3 83 84 Four years later, possible polyomavirus association with TS was described by Haycox et 85 al. Electron microscopy findings of lesional skin were consistent with polyomavirus-86 induced changes and the condition was termed trichodysplasia spinulosa.4This was 87 confirmed only in 2010 when a novel double-stranded DNA virus was isolated from the 88 hyperkeratotic lesions using a rolling-circle amplification detection method.5 The 89 presence of 1 million viral load in lesional skin compared to non-lesional skin further 90 reinforced the causal relationship.6 91 92 TSPyV is a member of Polyomaviridae family. BKPyV and JCPyV are the first members 93 discovered in 1970s to infect human.7 These are linked to transplant-related kidney 94 disease and progressive multifocal leukoencephalopathy, respectively.8 95 96 There are four novel members from the same family linked to cutaneous conditions 97 mainly in association with immunosuppression including TSPyV. Merkel cell 98 PolyomaVirus (MCPyV) is linked to a rare neuroendocrine tumour of the skin, Merkel 99 cell carcinoma (MCC) with overall viral prevalence of 80% of the cases. Human 100 PolyomaVirus 6 (HPyV6) and 7 (HPyV7) are associated with unique pruritic dyskeratotic 101 dermatoses in immunosuppressed individuals.7 102 103 Exposure to TSPyV occurs at a very young age and usually follows an asymptomatic 104 latent course. Seroprevalence of TSPyV in immunocompetent adults is 105 High, reaching up to 80%. Moreover, seroprevalence increases even more in 106 immunocompromised individuals and more in patients with TS.1, 6 Interestingly, only a 107 minority of immunosuppressed hosts will develop TS clinically. 1 Van der Meijden et al. 108 proposed that the cause of TS is primary polyomavirus infection in immunocompromised 109 hosts rather than reactivation of a latent viral infection which can explain the rarity of this 110 condition.9 Further studies are required to uncover other variables that cause the disease 111 in specific patient populations. The only evidenced dermatologic clinical phenotype of 112 TSPyV is TS.1 113 114 Clinically, TS appears as flesh-coloured to erythematous follicular-based papules 115 concentrated on the central face with white spicules protruding from the papules. It can 116 progress to alopecia especially of the eyebrows and thickening of the skin leading to 117 leonine faces.10 TS can also affect the trunk, extremities and neck.6 118 119 The distinctive histopathological features of TS involve acanthosis of the epidermis, 120 aberrant large, distended follicles with dilated infundibulum and presence of large 121 eosinophilic, trichohyaline granules within excessive proliferating inner root sheath cells 122 of the hair bulb.10, 8 123 124 The classic clinical setting and characteristic histologic findings are usually sufficient to 125 make the diagnosis. Further testing with PCR detection of the virus from the lesions and 126 electron microscopy studies can also be used to confirm the diagnosis.10 127 128 In a recent review article, Curma et al. reported data of all published cases of TS in 129 PubMed until April 2020. A total of sixty cases were reviewed. Almost all patients were 130 immunosuppressed. The main associated conditions were hematolymphoid malignancies 131 (including multiple myeloma, acute and chronic lymphocytic leukemia, acute myelocytic 132 leukemia, Non-Hodgkin’s lymphoma, B-cell lymphoma and myelodysplastic syndrome) 133 or solid organ transplant recipients (including kidney, kidney/pancreatic, heart, lung, 134 liver, intestinal and multivisceral transplant). Other associations include systemic lupus 135 erythematosus on immunosuppressive therapy, Gorlin’s syndrome on vismodegib 136 treatment, HIV and B- cell lymphoma and myocarditis.1 137 138 Interestingly, TS was reported in the setting of remission of lymphoma with a new 139 diagnosis of colon cancer and in the setting of lymphoma relapse. 11, 12 This adds to our 140 limited understanding of the pathogenesis of the disease. 141 142 Jose et al. reviewed TS cases associated with solid organ transplant and emphasized that 143 it appears during the first year after transplant with the highest level of 144 immunosuppression.2 Our patient had developed TS within the first year following his 145 renal transplant. He was diagnosed promptly with characteristic morphology, location of 146 the eruption and histology features. 147 148 Managing TS is challenging. However, reduction of immunosuppression is the mainstay 149 of treatment. This might not be always feasible given the risk of organ rejection or flare 150 of the underlying disease. Next line of management is antiviral treatment including 151 topical cidofovir 1%-3% or oral valganciclovir.2 Particularly, 3% topical cidofovir might 152 be the most efficient.1 Topical tazarotene and manual extraction were reported useful in 153 single case reports.13, 14Oral leflunomide was reported to dramatically improve the 154 condition in two organ transplant patients.15 Spontaneous regression has also been 155 described but took longer.2 156 157 Conclusion 158 TS is an emerging folliculocentric viral infection that occurs predominantly in immune- 159 altered individuals. Since the rate of organ transplantation and relative 160 immunosuppression are increasing globally, TS may become more prevalent. We present 161 this case to increase awareness of this unique dermatosis to health care providers for early 162 diagnosis and prompt treatment to prevent facial disfigurement. Our knowledge is still 163 inadequate to explain many aspects of TS. 164 165 Authors’ Contribution 166 AAK performed the literature review and primary manuscript construction. EM reviewed 167 the case details and edited the manuscript. KN did a general review and edited the entire 168 manuscript. KAW reviewed the histopathology slides, literature review on the pathology 169 section and did a general review and grammatical editing of the manuscript. All authors 170 approved the final version of the manuscript. 171 172 References 173 1. Curman P, Näsman A, Brauner H. Trichodysplasia spinulosa: a comprehensive review 174 of the disease and its treatment. J Eur Acad Dermatol Venereol. 175 JEADV. 2021;35(5):1067-76. doi:10.1111/jdv.17081. 176 2. Jose A, Dad T, Strand A, Tse JY, Plotnikova N, Boucher HW et al. 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Pierrotti LC, Urbano PRP, Nali L, Romano CM, Bicalho CDS, Arnone M et al. 217 Viremia and viruria of trichodysplasia spinulosa-associated polyomavirus before the 218 development of clinical disease in a kidney transplant recipient. Transpl Infect Dis 219 2019;21(4):e13133. doi:10.1111/tid.13133. 220 221 222 Figure 1A: Skin-coloured monomorphic papules on central face, forehead and nose with 223 protruding central whitish spines. 224 225 226 Figure 1B: A close-up image of the papules with white central spines. 227 228 229 230 231 232 233 Figure 2A: Dilated follicular infundibulae with keratin plugs (white arrow) and viral 234 epithelial changes (black arrow) consistent with trichodysplasia spinulosa. H&E staining 235 X10 236 237 238 Figure 2B: Higher magnification of the irregular outer root sheath with TSPyV viral 239 epithelial perinuclear eosinophilic/basophilic changes (black arrow). H&E staining X20 240