CASE REPORT
Trichodysplasia Spinulosa: Rare Presentation of Polyomavirus Infection in Immunocompromised Patients Mark G. Kirchhof Kam Shojania, Mark W. Hull, Richard I. Crawford, and Sheila Au
B a c k g r o u n d : T ric h o d y s p la s ia
s p in u lo s a
(TS) is a ra re , s tr ik in g , fo llic u lo c e n tr ic
p a p u la r e r u p tio n
seen e x c lu s iv e ly in
im m u n o s u p p re s s e d p a tie n ts . T he e ru p tio n can be d is fig u rin g , a sso cia te d w ith le o n in e faces and alopecia. TS is caused b y a p o ly o m a v iru s , id e n tifie d as tric h o d y s p la s ia s p in u lo s a p o ly o m a v iru s (TSPyV). Few re p o rts e x is t in th e lite ra tu re , an d s u p p o rt fo r tre a tm e n t o p tio n s is sparse. M e t h o d a n d R e s u lts : W e re p o rt a p a tie n t w ith
TS w ith
u n d e rly in g lu p u s n e p h ro p a th y an d ren al tra n s p la n t-a s s o c ia te d
im m u n o s u p p re s s io n . D ia g n o sis w a s c o n firm e d b y b io p s y and p a th o g n o m o n ic h is to lo g ic fin d in g s in th e c o n te x t o f h e r exte n sive , s p ic u la te d m o n o m o rp h o u s p a pu les. W ith a b io p s y -c o n firm e d d ia g n o sis, o ra l v a lg a n c ic lo v ir w a s p re scrib e d , and th e p a tie n t s h o w e d m a rk e d s k in te x tu re im p ro v e m e n t an d h a ir re g ro w th . C o n c lu s io n : T he c o n tin u e d re p o rtin g o f cases o f TS w ill im p ro v e c lin ic a l id e n tific a tio n o f th is c o n d itio n an d p ro v id e b e tte r
in fo rm a tio n re g a rd in g tre a tm e n t and lo n g -te rm consequences.
C o n te x te : La tric h o d y s p la s ie s p in u lo s iq u e (TS) e st un e e ru p tio n pa p u le u se , fo llic u lo c e n triq u e , saisissan te, e t rare, q u i s'o b s e rv e
s e u le m e n t chez les p a tie n ts im m u n o d e p rim e s . L 'e ru p tio n , associee a un facie s le o n in e t a I'a lo p e cie , p e u t d e fig u re r les pe rso n n e s a tte in te s . La TS e st causee p a r le v iru s du p o ly o m e , ap pele p o ly o m a v iru s de la tric h o d y s p la s ie s p in u lo s iq u e . La d o c u m e n ta tio n ne fa it e ta t q u e de q u e lq u e s cas, e t o ffre un m a ig re c o n te n u q u a n t au x tra ite m e n ts po ssib les. M e th o d e e t r e s u lta ts : Sera exp o se ici le cas d 'u n e p a tie n te a tte in te de TS, a cco m pa gne e d 'u n e n e p h ro p a th ie lu p iq u e sous-
ja c e n te e t d 'u n e im m u n o d e p re s s io n associee a un e g re ffe renale. Le d ia g n o s tic a ete c o n firm e p a r un e b io p s ie e t p a r des sig ne s h is to lo g iq u e s p a th o g n o m o n iq u e s , da ns le c o n te x te d 'u n e va ste zon e c o u v e rte de p a p u le s m o n o m o rp h e s en fo rm e de spicule . Le d ia g n o s tic a y a n t e te c o n firm e p a r b io p sie , n o u s avo n s p re s c rit du v a lg a n c ic lo v ir p a r v o ie o ra le ; le tra ite m e n t a d o n n e lie u a une a m e lio ra tio n m a rq u e e du g ra in de la peau e t a la re p o u sse des cheveux. C o n c lu s io n : La d e s c rip tio n fre q u e n te de cas de TS fa c ilite ra ^ id e n tific a tio n c lin iq u e de la m a la d ie , t o u t en d o n n a n t un e m e ille u re
in fo rm a tio n s u r le tra ite m e n t e t les co n seq ue nces a lo n g te rm e .
richodysplasia spinulosa ( ts) is character ized by folliculocentric papules with keratotic spiny projections mainly localized to the ears and face but can involve the trunk and extremities.1,2 Alopecia is often
T
From the Department of Dermatology and Skin Science, University of British Columbia; Division of Rheumatology, Department o f Medicine, St. Paul’s Hospital, Providence Health Care; Division o f AIDS, Department of Medicine, University o f British Columbia; Department of Pathology and Laboratory Medicine, St. Paul’s Hospital, Providence Health Care; and Division o f Dermatology, Department of Medicine, St. Paul’s Hospital, Providence Health Care, Vancouver, BC. Address reprint requests to: Mark G. Kirchhof, MD, PhD, Department of Dermatology and Skin Science, University o f British Columbia, 835 West 10th Avenue, Vancouver, BC V5Z 4E8; email: [email protected].
DOI 10.2310/7750.2014.13189 © 2014 Canadian Dermatology Association
present, affecting the eyebrows, eyelashes, and scalp, with occasional generalized involvement.1,2 TS occurs predo minantly in immunosuppressed patients ranging in age from 5 to 70 years.3 Immunosuppression in patients with TS is usually related to antirejection therapies given to recipients of solid organ transplantation or chemother apeutic agents given to patients with hematologic malig nancies.3,4 Most cases are diagnosed based on the classic cutaneous features and characteristic histologic findings. These findings include proliferation of follicular inner root sheath cells with enlarged trichohyalin granules, infundibular dilatation containing keratotic debris, and an absent or fragmented hair shaft.1,5 Initial investigations failed to identify a pathogen associated with TS as fungal, bacterial, and mycobacterial cultures were repeatedly negative.1 Subsequently, it was hypothesized that TS may be viral in etiology. This was
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confirmed by electron microscopy, which showed small, regular intracellular virus particles. 1,4~6 Additional analyses have suggested that the shape and size of the viral particles are most in keeping with a polyomavirus.4-6 Molecular confirmation of the presence of a polyomavirus was reported in 2010.7 This new polyomavirus was named trichodysplasia spinulosa polyomavirus (TSPyV).7 Studies have confirmed 60 to 70% seroprevalence of virus antibodies in the general adult population, with little to no detectable virus DNA.8'9 Furthermore, a study has confirmed that active infection and high viral loads, measured by TSPyV DNA and protein in the skin, are associated with TS lesions/ '8,10 Conversely, levels of TSPyV in nonlesional skin of immunosuppressed patients were either low or absent.10 In healthy controls, TSPyV is identified in 0 to 2% of the population from blood and skin samples.7,10,11 TS is a rare but increasingly recognized sequela of immunosuppression. Prevention and treatment protocols are lacking due to the limited number of cases reported. Long-term clinical outcomes of TSPyV infection are unknown. Here we present a recent case of TS in a renal transplant patient with systemic lupus erythematosus (SLE). Treatment with valganciclovir was tried and resulted in a significant clinical improvement of symptoms. In this review, we summarize the most commonly associated immunosuppressive medications, underlying conditions, and treatment options reported for this condition.
Case Report Our patient was diagnosed with SLE in 1992 and subsequently developed renal failure requiring peritoneal dialysis and hemodialysis. On November 10, 2010, she received a living unrelated kidney transplant. Her anti rejection medications were prednisone, tacrolimus, and mycophenolate mofetil. Her past history included hyper tension, hypothyroidism, and recurrent sinusitis. In October 2011, she developed a facial eruption as well as diffuse hair loss and scalp hair thinning. She presented to our clinic in January 2012. At that time, the patient was taking the following medications: diltiazem 180 mg daily, hydroxychloroquine 200 mg daily, levothyroxine 0.13 mg daily, prednisone 5 mg daily, tacrolimus 3.5 mg twice daily, mycophenolate mofetil 1.5 g twice daily, and trimethoprim-sulfamethoxazole 1 tablet daily. Cutaneous examination revealed an extensive facial eruption consisting of thousands of tiny, acuminate, follicular, skin-colored to erythematous papules over the entire face, sparing the lips (Figure 1A). The papules were
Figure 1. A, Clinical presentation of trichodysplasia spinulosa on the face of a patient showing symmetrically distributed skin-colored to erythematous folliculocentric papules. B, Eruption is particularly prominent over the nose. Thin white projections can be noted on the papules at the ala nasi. C, Alopecia of the lateral eyebrows is a common finding.
particularly prominent on the nose, with thin white keratotic projections noted from many of the papules (Figure IB). The patient experienced discomfort and tenderness around the nares and had the sensation of swelling of the skin. The face was mildly pruritic. The ears, arms, legs, thighs, and back were also involved. Hair thinning was noted over the scalp, but discrete areas of complete hair loss were not seen, and a hair pull test was negative. The lateral aspects of the eyebrows had areas of alopecia (Figure 1C). There was decreased hair growth over her arms and legs. The initial differential diagnoses included dermatitis, keratosis pilaris, folliculitis, follicular drug eruption, and multiple filiform verrucae. Initial treatments for possible dermatitis and telogen effluvium were ineffective. The patient returned to our clinic, and two skin biopsies were taken, one from the right volar forearm and the other from the left flank. Histology from the biopsies showed distended hair follicles, infundibular keratin plugging, absence of wellformed hair shafts, proliferation of inner root sheath cells with enlarged trichohyalin granules, keratotic spines protruding from follicular ostia, and a mild lymphocytic infiltrate around the follicle and in the dermis (Figure 2). Based on these histologic findings and clinical features, a diagnosis of TS was made.1’4,12 Based on the limited information from case reports, the best treatments for TS
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Figure 2. Histopathology of the biop sies taken from this patient confirmed a diagnosis of trichodysplasia spinulosa. Biopsy from the left flank shows (A) infundibular plugging with keratotic debris, an aborted hair shaft (hematoxylin-eosin stain, X 100 original magnification), and (B) enlarged, irre gular trichohyalin granules of the inner root sheath (hematoxylin-eosin stain, X400 original magnification). Biopsy from the right volar forearm shows (C) mild lymphocytic perifolliculitis and interface dermatitis (hematoxylin-eosin stain, X200 original magnification) and (D) infundibular plugging with keratotic debris resulting in spinous projection from follicular ostium (hematoxylin-eosin stain, X 150 original magnification).
were determined to be topical cidofovir cream twice daily or oral valganciclovir. Previous literature has suggested that valganciclovir may be more effective than topical cidofovir, and considering the extent of the lesions and potential cost of compounding the topical agent, the patient was started on oral valganciclovir 900 mg orally twice daily.13,14 After 6 months, 90% resolution was observed on the face, ears, and legs; 80% improvement was noted on the forearms, arms, and back; and 50% improvement was noted on the thighs (Figure 3, A and B). There was also hair regrowth to the lateral eyebrows, arms, and legs (Figure 3C). The valganciclovir dose was reduced to 450 mg orally twice daily due to an increase in creatinine. One year later, the patient remains on valganci clovir for long-term suppression of TSPyV and continues to show marked clinical improvement. She is delighted with the resolution of her skin lesions.
the condition presents with thousands of folliculocentric, monomorphous papules with fine keratotic spicules and progressive alopecia.2 Photographs from affected patients described in the literature are strikingly similar. The TSPyV has recently been confirmed to be the etiologic agent that causes TS, which has been suspected for many years given the electron microscopic evidence of viral particles.4,5,10
Discussion and Literature Review TS was first described in 1999, subsequently, 30 case reports of affected patients have been published.1,3-6,12-30 TS had been the generally accepted name for this new condition, although several publications have identified the condition as viral/virus-associated trichodysplasia, cyclos porine-induced folliculodystrophy, or pilomatrix dysplasia of immunosuppression. The common underlying risk factor in all cases of reported TS is immunosuppression. Clinically, 432
Figure 3. Clinical improvement of trichodysplasia spinulosa on the face of our patient treated with valganciclovir. A, Qualitative improvement of clinical presentation by 80 to 90%. B, Eruption is particularly improved over the nose. C, Lateral eyebrows show significant regrowth.
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Apart from the initial evidence showing viral particles on electron microscopy, polymerase chain reaction (PCR) has now been used to confirm the presence of TSVyP within biopsy samples. The high proportion of the population carrying antibodies to TSPyV indicates that this virus is ubiquitous and exposure to the virus is very common.8,31 The diagnosis of TS can be made based on clinical features such as the clinically distinct folliculocentric papules often associated with central keratinous spicules and the pathognomonic histologic findings. The differ ential diagnosis of this condition includes paraneoplastic hyperkeratotic spicules associated with plasma cell dyscrasias, keratosis pilaris, lichen spinulosus, folliculitis, folli cular drug eruption, and multiple filiform verrucae. Histopathologically, TS presents with proliferation of inner root sheath cells with enlarged trichohyalin granules, infundibular dilation containing keratotic debris, and an absent or fragmented hair shaft. The distinct histopatho logic features combined with the clinical presentation provide a high degree of certainty in making the diagnosis of TS. Many groups have gone on to confirm the diagnosis with electron microscopy, immunofluorescence, and/or PCR.3-6 In our case, we did not feel that these ancillary tests were necessary, but they can be considered in cases for which the diagnosis is not clear. Given the high seroprevalence of antibodies to TSVyP in normal controls and the absence of clinical cases in immunocompetent patients, it follows that a normal immune system is protective against the development of TS.8,20,31 This is confirmed by patients who regain normal immune function after cessation of antineoplastic medica tions and experience concomitant improvement in TS lesions.5,19,20 Among transplant patients, modifications in immunosuppressant therapies resulted in an improvement in approximately half of the patients.6,14,15,22 Antiviral medications have also been successful in the treatment of TS. Systemic valganciclovir and valacyclovir and topical acyclovir and cidofovir have been reported to be effective in treating TS.1--14,11,27,28 Of these antiviral medications, topical cidofovir 1% or 3% cream, applied twice daily, and valganciclovir 900 mg, applied twice daily, have been most com m only used.6,12-14,19,22,26 Oral valganciclovir is reported to be the best treatment, with patients showing nearly complete resolution.6,12-14,19,22,26 Other treatments that have been used include topical steroids, topical and systemic antibacterials, topical and systemic retinoids, and topical imiquimod, all of which have either provided minimal benefit or been ineffective.1,5,6,16,20 A small proportion of patients (three of nine reported), experi enced some improvement with the use of topical retinoids
(tretinoin or tazarotene).14,16,1"’22 It is unclear if these topical vitamin A derivatives alter the state of viral infection or simply diminish the cutaneous manifestations of TS. In the case presented here, we show a significant clinical response to valganciclovir, which adds to the reported efficacy of this medication in patients with TS. Valganciclovir is a guanosine analogue that functions by inhibiting polymerase activity. Valganciclovir is traditionally used in cases of herpesvirus infections and is now mainly reserved for the treatment of cytomegalovirus infection. Valganciclovir, like ganciclovir, is phosphorylated by viral thym idine kinases in the cells infected with virus. Herpesviruses express the viral thymidine kinases that act on valganciclovir, and the resultant triphosphate guanosine analogue inhibits viral DNA polymerase. Polyomavirus infection is not predicted to result in the expression of a comparable viral thymidine kinase. For this reason, cidofovir has been the standard antiviral medication used to treat polyomavirus infection, such as BK virus infections.32 Cidofovir acts as a cytosine analogue and inhibits the human DNA polymerases, which are needed for polyomavirus replication. The mechanism by which valganciclovir inhibits polyomavirus replication remains to be elucidated, but one can hypothesize that infection with polyomavirus might lead to changes in human thymidine kinases that allow them to phosphorylate valganciclovir to its active form. The majority of cases of TS have been described in solid organ transplant recipients, particularly those who have received kidney and heart transplants.1,3-6,12-28 The other major group of patients at risk for TS are those with hematologic malignancies receiving antineoplastic che motherapy.1,3-6,1--28 The reasons for the propensity to develop TS in these very specific groups of immunosuppressed patients are unknown. The medications most commonly associated with TS development are those routinely given to transplant recipients and include systemic steroids, tacrolimus, and mycophenolate mofetil.1,3-6,12-28 Methotrexate, cyclophosphamide, and rituximab were the most common antineoplastic medications associated with TS. ’ ’ ---b The immunosuppressive medications associated with TS development are not exclusively used in solid organ transplant patients or patients with hematologic malignancy, yet TS is rare in other settings. This suggests that other factors may be involved in the development of TS apart from immunosuppressive therapies. First, there may be an under lying genetic predisposition to the development of TS, such as a polymorphism in the human leukocyte antigen genes or an interleukin deficiency that allows the TSPyV to replicate. Second, there may be repeated exposure to a reservoir or infectious vector that may precipitate the development of TS.
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For example, a recent study found that TSPyV could be detected in the urine of a renal transplant patient, which might serve as a reservoir for infectious spread.3 Finally, there may be specific combinations of medications that mediate the loss of immune function around the hair follicle. This was demonstrated in one case in which a patient was switched from tacrolimus to cyclosporine and experienced clinical improvement of TS.I:> Like most other polyomaviruses, TSPyV has a genome that encodes five putative genes.7,33 These have been designated as the VP1, VP2, and VP3 capsid antigens and the small and large T antigens.7,33 The TSPyV VP1 antigen has been used to determine the seroprevalence of TSPyV antibodies.8 It is, however, the large T antigen that is perhaps of most clinical interest as it contains binding motifs for the tum or suppressor proteins pRb and tp53.7,33 In cell lines and animals models, this large T antigen induces oncogenic transformation of the cells.7,33 In addition to the inhibition of pRb and tp53, large T antigen has been shown to inhibit apoptosis, perturb cell signaling, induce angiogenesis, and disrupt chromosomal replication fidelity.7,12,33 The small T antigen may also contribute to oncogenesis via interactions with protein phosphatase 2A.7,12,33 Although there are no reported cases of TS leading to clinically relevant tumors, the oncogenic potential of TSPyV bears continued evaluation and may justify more aggressive antiviral therapy in the future.
Conclusion We have presented a case of TS in a patient with SLE and renal transplant-associated immunosuppression. TS is a rare, virus-induced skin condition with skin lesions that can be disfiguring. Although limited anecdotal evidence exists for treatment, our experience with oral valganciclovir presented here supports this as an effective treatment for TS. Through the continued reporting of TS cases and treatment outcomes, we hope to improve clinical recogni tion of this possibly underrecognized condition and provide clinicians with important guidance for effective treatment.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
References 1. Haycox CL, Kim S, Fleckman P, et al. Trichodysplasia spinulosa— a newly described folliculocentric viral infection in an immuno compromised host. J Investig Dermatol Symp Proc 1999;4:268-71, doi: 10.1038/sj.jidsp.5640227.
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2. Tan BH, Busam KJ. Virus-associated trichodysplasia spinulosa. Adv Anat Pathol 2011;18:450-3, doi: 10.1097/PAP.0b013e318234aad2. 3. Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol 2012;148:726-33, doi:10.1001/archdcrmatol.201 1. 3298. 4. Matthews MR, Wang RC, Reddick RL, et al. Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus. J Cutan Pathol 2011;38:420-31, doi:10.1111/ I.1600-0560.2010.01664.X. 5. Wyatt AJ, Sachs DL, Shia J, et al. Virus-associated trichodysplasia spinulosa. Am J Surg Pathol 2005;29:241-6, doi:10.1097/01.pas. 0000149691.83086.dc. 6. Sperling LC, Tomaszewski MM, Thomas DA. Viral-associated trichodysplasia in patients who are immunocompromised. J Am Acad Dermatol 2004;50:318-22, doi:10.1016/S0190-9622(03)01490-7. 7. van der ME, Janssens RW, Lauber C, et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromised patient. PLoS Pathog 2010;6(7): el001024, doi: 10.1371/journal.ppat. 1001024. 8. van der ME, Kazem S, Burgers MM, et al. Seroprevalence of trichodysplasia spinulosa-associated polyomavirus. Emerg Infect Dis 2011;17:1355-63. 9. Nicol JT, Robinot R, Carpentier A, et al. Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus. Clin Vaccine Immunol 2013;20:363-8, doi:10.1128/CV1.00438-12. 10. Kazem S, van der Meijden E, Kooijman S, et al. Trichodysplasia spinulosa is characterized by active polyomavirus infection. J Clin Virol 2012;53:225-30, doi:10.1016/j.icv.2011.11.007. 11. Sadeghi M, Aronen M, Chen T, et al. Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus DNAs and antibodies in blood among the elderly. BMC Infect Dis 2012;12: 383, doi: 10.1186/1471-2334-12-383. 12. Wanat KA, Holler PD, Dentchev T, et al. Viral-associated trichodysplasia: characterization of a novel polyomavirus infection with therapeutic insights. Arch Dermatol 2012;148:219-23, doi: 10.1001/archdermatol.2011.1413. 13. Holzer AM, Hughey LC. Trichodysplasia of immunosuppression treated with oral valganciclovir. J Am Acad Dermatol 2009;60:16972, doi:10.1016/j.jaad.2008.07.051. 14. Benoit T, Bacelieri R, Morrell DS, Metcalf J. Viral-associated trichodysplasia of immunosuppression: report of a pediatric patient with response to oral valganciclovir. Arch Dermatol 2010; 146:871M, doi:10.1001/archdermatol.2010.175. 15. Chastain MA, Millikan LE. Pilomatrix dysplasia in an immunosuppressed patient. J Am Acad Dermatol 2000;43(1 Pt 1):118—22, doi: 10.1067/mjd.2000.100967. 16. Heaphy MR Jr, Shamma HN, Hickmann M, White MJ. Cyclosporine-induced folliculodystrophy. J Am Acad Dermatol 2004;50:310-5, doi:10.1016/S0190-9622(03)00774-6. 17. Campbell RM, Ney A, Gohh R, Robinson-Bostom L. Spiny hyperkeratotic projections on the face and extremities of a kidney transplant recipient. Arch Dermatol 2006;142:1643-8. 18. Khoury F, Kibbi A, Ghosn S. Virus-associated trichodysplasia spinulosa in a child with acute lymphoblastic leukemia [abstract], J Cutan Pathol 2007;34:77.
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19. Osswald SS, Kulick KB, Tomaszewski MM, Sperling LC. Viralassociated trichodysplasia in a patient with lymphoma: a case report and review. J Cutan Pathol 2007;34:721-5, doi:10.1111/ j.l600-0560.2006.00693.x. 20. Sadler GM, Halbert AR, Smith N, Rogers M. Trichodysplasia spinulosa associated with chemotherapy for acute lymphocytic leukaemia. Australas J Dermatol 2007;48:110-4, doi:10.1111/ j.l440-0960.2007.00348.x. 21. Lee JS, Frederiksen P, Kossard S. Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission. Australas J Dermatol 2008;49:57-60, doi:10.1111/j,14400960.2007.00422.x. 22. Schwieger-Briel A, Balma-Mena A, Ngan B, et al. Trichodysplasia spinulosa—a rare complication in immunosuppressed patients. Pediatr Dermatol 2010;27:509-13, doi: 10.1111/j. 1525- 1470.2010.01278.x. 23. Blake BP, Marathe KS, Mohr MR, et al. Viral-associated trichodysplasia of immunosuppression in a renal transplant patient. J Drugs Dermatol 2011;10:422-4. 24. Burns A, Arnason T, Fraser R, et al. Keratotic “spiny” papules in an immunosuppressed child. Trichodysplasia spinulosa (TS). Arch Dermatol 2011;147:1215-20, doi: 10.100 l/archdermatol.2011,286-a. 25. de Luzuriaga AR, Petronic-Rosic V, Finch T, Wasserman J. Trichodysplasia of immunosuppression [abstract]. J Cutan Pathol 2011;38:153.
26. Elaba Z, Hughey SL, Andea A. Trichodysplasia spinulosa in a lung transplant patient [abstract], J Cutan Pathol 2011;38:153. 27. Lee YY, Tucker SC, Prow NA, et al. Trichodysplasia spinulosa: a benign adnexal proliferation with follicular differentiation associated with polyomavirus. Australas J Dermatol 2013 Jan 18, doi:10.1111/ajd. 12012. 28. Brimhall CL, Malone JC. Viral-associated trichodysplasia spinulosa in a renal transplant patient. Arch Dermatol 2012;148:863^, doi:10.1001/archdermatol.2012.29. 29. Berk DR, Lu D, Bayliss SJ. Trichodysplasia spinulosa in an adolescent with cystic fibrosis and lung transplantation. Int J Dermatol 2013;52:1586-8, doi:10.1111/j.l365-4632.2011. 05391.x. 30. Moktefi A, Laude H, Brudy GL, et al. Trichodysplasia spinulosa associated with lupus. Am J Dermatopathol 2013 Aug, doi:10. 1097/DAD.06013e319293f620. 31. Chen T, Mattila PS, Jartti T, et al. Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus. J Infect Dis 2011;204:1523-6, doi:10.1093/infdis/jir614. 32. Moens U, Ludvigsen M, Van Ghelue M. Human polyomaviruses in skin diseases. Patholog Res Int 2011;2011:123491. 33. Van Ghelue M, Khan MT, Ehlers B, Moens U. Genome analysis of the new human polyomaviruses. Rev Med Virol 2012;22:354-77, doi:10.1002/rmv.l711.
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Trichodysplasia Spinulosa: Rare Presentation of Polyomavirus Infection in Immunocompromised Patients Mark G. Kirchhof Kam Shojania, Mark W. Hull, Richard I. Crawford, and Sheila Au
B a c k g r o u n d : T ric h o d y s p la s ia
s p in u lo s a
(TS) is a ra re , s tr ik in g , fo llic u lo c e n tr ic
p a p u la r e r u p tio n
seen e x c lu s iv e ly in
im m u n o s u p p re s s e d p a tie n ts . T he e ru p tio n can be d is fig u rin g , a sso cia te d w ith le o n in e faces and alopecia. TS is caused b y a p o ly o m a v iru s , id e n tifie d as tric h o d y s p la s ia s p in u lo s a p o ly o m a v iru s (TSPyV). Few re p o rts e x is t in th e lite ra tu re , an d s u p p o rt fo r tre a tm e n t o p tio n s is sparse. M e t h o d a n d R e s u lts : W e re p o rt a p a tie n t w ith
TS w ith
u n d e rly in g lu p u s n e p h ro p a th y an d ren al tra n s p la n t-a s s o c ia te d
im m u n o s u p p re s s io n . D ia g n o sis w a s c o n firm e d b y b io p s y and p a th o g n o m o n ic h is to lo g ic fin d in g s in th e c o n te x t o f h e r exte n sive , s p ic u la te d m o n o m o rp h o u s p a pu les. W ith a b io p s y -c o n firm e d d ia g n o sis, o ra l v a lg a n c ic lo v ir w a s p re scrib e d , and th e p a tie n t s h o w e d m a rk e d s k in te x tu re im p ro v e m e n t an d h a ir re g ro w th . C o n c lu s io n : T he c o n tin u e d re p o rtin g o f cases o f TS w ill im p ro v e c lin ic a l id e n tific a tio n o f th is c o n d itio n an d p ro v id e b e tte r
in fo rm a tio n re g a rd in g tre a tm e n t and lo n g -te rm consequences.
C o n te x te : La tric h o d y s p la s ie s p in u lo s iq u e (TS) e st un e e ru p tio n pa p u le u se , fo llic u lo c e n triq u e , saisissan te, e t rare, q u i s'o b s e rv e
s e u le m e n t chez les p a tie n ts im m u n o d e p rim e s . L 'e ru p tio n , associee a un facie s le o n in e t a I'a lo p e cie , p e u t d e fig u re r les pe rso n n e s a tte in te s . La TS e st causee p a r le v iru s du p o ly o m e , ap pele p o ly o m a v iru s de la tric h o d y s p la s ie s p in u lo s iq u e . La d o c u m e n ta tio n ne fa it e ta t q u e de q u e lq u e s cas, e t o ffre un m a ig re c o n te n u q u a n t au x tra ite m e n ts po ssib les. M e th o d e e t r e s u lta ts : Sera exp o se ici le cas d 'u n e p a tie n te a tte in te de TS, a cco m pa gne e d 'u n e n e p h ro p a th ie lu p iq u e sous-
ja c e n te e t d 'u n e im m u n o d e p re s s io n associee a un e g re ffe renale. Le d ia g n o s tic a ete c o n firm e p a r un e b io p s ie e t p a r des sig ne s h is to lo g iq u e s p a th o g n o m o n iq u e s , da ns le c o n te x te d 'u n e va ste zon e c o u v e rte de p a p u le s m o n o m o rp h e s en fo rm e de spicule . Le d ia g n o s tic a y a n t e te c o n firm e p a r b io p sie , n o u s avo n s p re s c rit du v a lg a n c ic lo v ir p a r v o ie o ra le ; le tra ite m e n t a d o n n e lie u a une a m e lio ra tio n m a rq u e e du g ra in de la peau e t a la re p o u sse des cheveux. C o n c lu s io n : La d e s c rip tio n fre q u e n te de cas de TS fa c ilite ra ^ id e n tific a tio n c lin iq u e de la m a la d ie , t o u t en d o n n a n t un e m e ille u re
in fo rm a tio n s u r le tra ite m e n t e t les co n seq ue nces a lo n g te rm e .
richodysplasia spinulosa ( ts) is character ized by folliculocentric papules with keratotic spiny projections mainly localized to the ears and face but can involve the trunk and extremities.1,2 Alopecia is often
T
From the Department of Dermatology and Skin Science, University of British Columbia; Division of Rheumatology, Department o f Medicine, St. Paul’s Hospital, Providence Health Care; Division o f AIDS, Department of Medicine, University o f British Columbia; Department of Pathology and Laboratory Medicine, St. Paul’s Hospital, Providence Health Care; and Division o f Dermatology, Department of Medicine, St. Paul’s Hospital, Providence Health Care, Vancouver, BC. Address reprint requests to: Mark G. Kirchhof, MD, PhD, Department of Dermatology and Skin Science, University o f British Columbia, 835 West 10th Avenue, Vancouver, BC V5Z 4E8; email: [email protected].
DOI 10.2310/7750.2014.13189 © 2014 Canadian Dermatology Association
present, affecting the eyebrows, eyelashes, and scalp, with occasional generalized involvement.1,2 TS occurs predo minantly in immunosuppressed patients ranging in age from 5 to 70 years.3 Immunosuppression in patients with TS is usually related to antirejection therapies given to recipients of solid organ transplantation or chemother apeutic agents given to patients with hematologic malig nancies.3,4 Most cases are diagnosed based on the classic cutaneous features and characteristic histologic findings. These findings include proliferation of follicular inner root sheath cells with enlarged trichohyalin granules, infundibular dilatation containing keratotic debris, and an absent or fragmented hair shaft.1,5 Initial investigations failed to identify a pathogen associated with TS as fungal, bacterial, and mycobacterial cultures were repeatedly negative.1 Subsequently, it was hypothesized that TS may be viral in etiology. This was
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confirmed by electron microscopy, which showed small, regular intracellular virus particles. 1,4~6 Additional analyses have suggested that the shape and size of the viral particles are most in keeping with a polyomavirus.4-6 Molecular confirmation of the presence of a polyomavirus was reported in 2010.7 This new polyomavirus was named trichodysplasia spinulosa polyomavirus (TSPyV).7 Studies have confirmed 60 to 70% seroprevalence of virus antibodies in the general adult population, with little to no detectable virus DNA.8'9 Furthermore, a study has confirmed that active infection and high viral loads, measured by TSPyV DNA and protein in the skin, are associated with TS lesions/ '8,10 Conversely, levels of TSPyV in nonlesional skin of immunosuppressed patients were either low or absent.10 In healthy controls, TSPyV is identified in 0 to 2% of the population from blood and skin samples.7,10,11 TS is a rare but increasingly recognized sequela of immunosuppression. Prevention and treatment protocols are lacking due to the limited number of cases reported. Long-term clinical outcomes of TSPyV infection are unknown. Here we present a recent case of TS in a renal transplant patient with systemic lupus erythematosus (SLE). Treatment with valganciclovir was tried and resulted in a significant clinical improvement of symptoms. In this review, we summarize the most commonly associated immunosuppressive medications, underlying conditions, and treatment options reported for this condition.
Case Report Our patient was diagnosed with SLE in 1992 and subsequently developed renal failure requiring peritoneal dialysis and hemodialysis. On November 10, 2010, she received a living unrelated kidney transplant. Her anti rejection medications were prednisone, tacrolimus, and mycophenolate mofetil. Her past history included hyper tension, hypothyroidism, and recurrent sinusitis. In October 2011, she developed a facial eruption as well as diffuse hair loss and scalp hair thinning. She presented to our clinic in January 2012. At that time, the patient was taking the following medications: diltiazem 180 mg daily, hydroxychloroquine 200 mg daily, levothyroxine 0.13 mg daily, prednisone 5 mg daily, tacrolimus 3.5 mg twice daily, mycophenolate mofetil 1.5 g twice daily, and trimethoprim-sulfamethoxazole 1 tablet daily. Cutaneous examination revealed an extensive facial eruption consisting of thousands of tiny, acuminate, follicular, skin-colored to erythematous papules over the entire face, sparing the lips (Figure 1A). The papules were
Figure 1. A, Clinical presentation of trichodysplasia spinulosa on the face of a patient showing symmetrically distributed skin-colored to erythematous folliculocentric papules. B, Eruption is particularly prominent over the nose. Thin white projections can be noted on the papules at the ala nasi. C, Alopecia of the lateral eyebrows is a common finding.
particularly prominent on the nose, with thin white keratotic projections noted from many of the papules (Figure IB). The patient experienced discomfort and tenderness around the nares and had the sensation of swelling of the skin. The face was mildly pruritic. The ears, arms, legs, thighs, and back were also involved. Hair thinning was noted over the scalp, but discrete areas of complete hair loss were not seen, and a hair pull test was negative. The lateral aspects of the eyebrows had areas of alopecia (Figure 1C). There was decreased hair growth over her arms and legs. The initial differential diagnoses included dermatitis, keratosis pilaris, folliculitis, follicular drug eruption, and multiple filiform verrucae. Initial treatments for possible dermatitis and telogen effluvium were ineffective. The patient returned to our clinic, and two skin biopsies were taken, one from the right volar forearm and the other from the left flank. Histology from the biopsies showed distended hair follicles, infundibular keratin plugging, absence of wellformed hair shafts, proliferation of inner root sheath cells with enlarged trichohyalin granules, keratotic spines protruding from follicular ostia, and a mild lymphocytic infiltrate around the follicle and in the dermis (Figure 2). Based on these histologic findings and clinical features, a diagnosis of TS was made.1’4,12 Based on the limited information from case reports, the best treatments for TS
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Figure 2. Histopathology of the biop sies taken from this patient confirmed a diagnosis of trichodysplasia spinulosa. Biopsy from the left flank shows (A) infundibular plugging with keratotic debris, an aborted hair shaft (hematoxylin-eosin stain, X 100 original magnification), and (B) enlarged, irre gular trichohyalin granules of the inner root sheath (hematoxylin-eosin stain, X400 original magnification). Biopsy from the right volar forearm shows (C) mild lymphocytic perifolliculitis and interface dermatitis (hematoxylin-eosin stain, X200 original magnification) and (D) infundibular plugging with keratotic debris resulting in spinous projection from follicular ostium (hematoxylin-eosin stain, X 150 original magnification).
were determined to be topical cidofovir cream twice daily or oral valganciclovir. Previous literature has suggested that valganciclovir may be more effective than topical cidofovir, and considering the extent of the lesions and potential cost of compounding the topical agent, the patient was started on oral valganciclovir 900 mg orally twice daily.13,14 After 6 months, 90% resolution was observed on the face, ears, and legs; 80% improvement was noted on the forearms, arms, and back; and 50% improvement was noted on the thighs (Figure 3, A and B). There was also hair regrowth to the lateral eyebrows, arms, and legs (Figure 3C). The valganciclovir dose was reduced to 450 mg orally twice daily due to an increase in creatinine. One year later, the patient remains on valganci clovir for long-term suppression of TSPyV and continues to show marked clinical improvement. She is delighted with the resolution of her skin lesions.
the condition presents with thousands of folliculocentric, monomorphous papules with fine keratotic spicules and progressive alopecia.2 Photographs from affected patients described in the literature are strikingly similar. The TSPyV has recently been confirmed to be the etiologic agent that causes TS, which has been suspected for many years given the electron microscopic evidence of viral particles.4,5,10
Discussion and Literature Review TS was first described in 1999, subsequently, 30 case reports of affected patients have been published.1,3-6,12-30 TS had been the generally accepted name for this new condition, although several publications have identified the condition as viral/virus-associated trichodysplasia, cyclos porine-induced folliculodystrophy, or pilomatrix dysplasia of immunosuppression. The common underlying risk factor in all cases of reported TS is immunosuppression. Clinically, 432
Figure 3. Clinical improvement of trichodysplasia spinulosa on the face of our patient treated with valganciclovir. A, Qualitative improvement of clinical presentation by 80 to 90%. B, Eruption is particularly improved over the nose. C, Lateral eyebrows show significant regrowth.
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Apart from the initial evidence showing viral particles on electron microscopy, polymerase chain reaction (PCR) has now been used to confirm the presence of TSVyP within biopsy samples. The high proportion of the population carrying antibodies to TSPyV indicates that this virus is ubiquitous and exposure to the virus is very common.8,31 The diagnosis of TS can be made based on clinical features such as the clinically distinct folliculocentric papules often associated with central keratinous spicules and the pathognomonic histologic findings. The differ ential diagnosis of this condition includes paraneoplastic hyperkeratotic spicules associated with plasma cell dyscrasias, keratosis pilaris, lichen spinulosus, folliculitis, folli cular drug eruption, and multiple filiform verrucae. Histopathologically, TS presents with proliferation of inner root sheath cells with enlarged trichohyalin granules, infundibular dilation containing keratotic debris, and an absent or fragmented hair shaft. The distinct histopatho logic features combined with the clinical presentation provide a high degree of certainty in making the diagnosis of TS. Many groups have gone on to confirm the diagnosis with electron microscopy, immunofluorescence, and/or PCR.3-6 In our case, we did not feel that these ancillary tests were necessary, but they can be considered in cases for which the diagnosis is not clear. Given the high seroprevalence of antibodies to TSVyP in normal controls and the absence of clinical cases in immunocompetent patients, it follows that a normal immune system is protective against the development of TS.8,20,31 This is confirmed by patients who regain normal immune function after cessation of antineoplastic medica tions and experience concomitant improvement in TS lesions.5,19,20 Among transplant patients, modifications in immunosuppressant therapies resulted in an improvement in approximately half of the patients.6,14,15,22 Antiviral medications have also been successful in the treatment of TS. Systemic valganciclovir and valacyclovir and topical acyclovir and cidofovir have been reported to be effective in treating TS.1--14,11,27,28 Of these antiviral medications, topical cidofovir 1% or 3% cream, applied twice daily, and valganciclovir 900 mg, applied twice daily, have been most com m only used.6,12-14,19,22,26 Oral valganciclovir is reported to be the best treatment, with patients showing nearly complete resolution.6,12-14,19,22,26 Other treatments that have been used include topical steroids, topical and systemic antibacterials, topical and systemic retinoids, and topical imiquimod, all of which have either provided minimal benefit or been ineffective.1,5,6,16,20 A small proportion of patients (three of nine reported), experi enced some improvement with the use of topical retinoids
(tretinoin or tazarotene).14,16,1"’22 It is unclear if these topical vitamin A derivatives alter the state of viral infection or simply diminish the cutaneous manifestations of TS. In the case presented here, we show a significant clinical response to valganciclovir, which adds to the reported efficacy of this medication in patients with TS. Valganciclovir is a guanosine analogue that functions by inhibiting polymerase activity. Valganciclovir is traditionally used in cases of herpesvirus infections and is now mainly reserved for the treatment of cytomegalovirus infection. Valganciclovir, like ganciclovir, is phosphorylated by viral thym idine kinases in the cells infected with virus. Herpesviruses express the viral thymidine kinases that act on valganciclovir, and the resultant triphosphate guanosine analogue inhibits viral DNA polymerase. Polyomavirus infection is not predicted to result in the expression of a comparable viral thymidine kinase. For this reason, cidofovir has been the standard antiviral medication used to treat polyomavirus infection, such as BK virus infections.32 Cidofovir acts as a cytosine analogue and inhibits the human DNA polymerases, which are needed for polyomavirus replication. The mechanism by which valganciclovir inhibits polyomavirus replication remains to be elucidated, but one can hypothesize that infection with polyomavirus might lead to changes in human thymidine kinases that allow them to phosphorylate valganciclovir to its active form. The majority of cases of TS have been described in solid organ transplant recipients, particularly those who have received kidney and heart transplants.1,3-6,12-28 The other major group of patients at risk for TS are those with hematologic malignancies receiving antineoplastic che motherapy.1,3-6,1--28 The reasons for the propensity to develop TS in these very specific groups of immunosuppressed patients are unknown. The medications most commonly associated with TS development are those routinely given to transplant recipients and include systemic steroids, tacrolimus, and mycophenolate mofetil.1,3-6,12-28 Methotrexate, cyclophosphamide, and rituximab were the most common antineoplastic medications associated with TS. ’ ’ ---b The immunosuppressive medications associated with TS development are not exclusively used in solid organ transplant patients or patients with hematologic malignancy, yet TS is rare in other settings. This suggests that other factors may be involved in the development of TS apart from immunosuppressive therapies. First, there may be an under lying genetic predisposition to the development of TS, such as a polymorphism in the human leukocyte antigen genes or an interleukin deficiency that allows the TSPyV to replicate. Second, there may be repeated exposure to a reservoir or infectious vector that may precipitate the development of TS.
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For example, a recent study found that TSPyV could be detected in the urine of a renal transplant patient, which might serve as a reservoir for infectious spread.3 Finally, there may be specific combinations of medications that mediate the loss of immune function around the hair follicle. This was demonstrated in one case in which a patient was switched from tacrolimus to cyclosporine and experienced clinical improvement of TS.I:> Like most other polyomaviruses, TSPyV has a genome that encodes five putative genes.7,33 These have been designated as the VP1, VP2, and VP3 capsid antigens and the small and large T antigens.7,33 The TSPyV VP1 antigen has been used to determine the seroprevalence of TSPyV antibodies.8 It is, however, the large T antigen that is perhaps of most clinical interest as it contains binding motifs for the tum or suppressor proteins pRb and tp53.7,33 In cell lines and animals models, this large T antigen induces oncogenic transformation of the cells.7,33 In addition to the inhibition of pRb and tp53, large T antigen has been shown to inhibit apoptosis, perturb cell signaling, induce angiogenesis, and disrupt chromosomal replication fidelity.7,12,33 The small T antigen may also contribute to oncogenesis via interactions with protein phosphatase 2A.7,12,33 Although there are no reported cases of TS leading to clinically relevant tumors, the oncogenic potential of TSPyV bears continued evaluation and may justify more aggressive antiviral therapy in the future.
Conclusion We have presented a case of TS in a patient with SLE and renal transplant-associated immunosuppression. TS is a rare, virus-induced skin condition with skin lesions that can be disfiguring. Although limited anecdotal evidence exists for treatment, our experience with oral valganciclovir presented here supports this as an effective treatment for TS. Through the continued reporting of TS cases and treatment outcomes, we hope to improve clinical recogni tion of this possibly underrecognized condition and provide clinicians with important guidance for effective treatment.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
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2. Tan BH, Busam KJ. Virus-associated trichodysplasia spinulosa. Adv Anat Pathol 2011;18:450-3, doi: 10.1097/PAP.0b013e318234aad2. 3. Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol 2012;148:726-33, doi:10.1001/archdcrmatol.201 1. 3298. 4. Matthews MR, Wang RC, Reddick RL, et al. Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus. J Cutan Pathol 2011;38:420-31, doi:10.1111/ I.1600-0560.2010.01664.X. 5. Wyatt AJ, Sachs DL, Shia J, et al. Virus-associated trichodysplasia spinulosa. Am J Surg Pathol 2005;29:241-6, doi:10.1097/01.pas. 0000149691.83086.dc. 6. Sperling LC, Tomaszewski MM, Thomas DA. Viral-associated trichodysplasia in patients who are immunocompromised. J Am Acad Dermatol 2004;50:318-22, doi:10.1016/S0190-9622(03)01490-7. 7. van der ME, Janssens RW, Lauber C, et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromised patient. PLoS Pathog 2010;6(7): el001024, doi: 10.1371/journal.ppat. 1001024. 8. van der ME, Kazem S, Burgers MM, et al. Seroprevalence of trichodysplasia spinulosa-associated polyomavirus. Emerg Infect Dis 2011;17:1355-63. 9. Nicol JT, Robinot R, Carpentier A, et al. Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus. Clin Vaccine Immunol 2013;20:363-8, doi:10.1128/CV1.00438-12. 10. Kazem S, van der Meijden E, Kooijman S, et al. Trichodysplasia spinulosa is characterized by active polyomavirus infection. J Clin Virol 2012;53:225-30, doi:10.1016/j.icv.2011.11.007. 11. Sadeghi M, Aronen M, Chen T, et al. Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus DNAs and antibodies in blood among the elderly. BMC Infect Dis 2012;12: 383, doi: 10.1186/1471-2334-12-383. 12. Wanat KA, Holler PD, Dentchev T, et al. Viral-associated trichodysplasia: characterization of a novel polyomavirus infection with therapeutic insights. Arch Dermatol 2012;148:219-23, doi: 10.1001/archdermatol.2011.1413. 13. Holzer AM, Hughey LC. Trichodysplasia of immunosuppression treated with oral valganciclovir. J Am Acad Dermatol 2009;60:16972, doi:10.1016/j.jaad.2008.07.051. 14. Benoit T, Bacelieri R, Morrell DS, Metcalf J. Viral-associated trichodysplasia of immunosuppression: report of a pediatric patient with response to oral valganciclovir. Arch Dermatol 2010; 146:871M, doi:10.1001/archdermatol.2010.175. 15. Chastain MA, Millikan LE. Pilomatrix dysplasia in an immunosuppressed patient. J Am Acad Dermatol 2000;43(1 Pt 1):118—22, doi: 10.1067/mjd.2000.100967. 16. Heaphy MR Jr, Shamma HN, Hickmann M, White MJ. Cyclosporine-induced folliculodystrophy. J Am Acad Dermatol 2004;50:310-5, doi:10.1016/S0190-9622(03)00774-6. 17. Campbell RM, Ney A, Gohh R, Robinson-Bostom L. Spiny hyperkeratotic projections on the face and extremities of a kidney transplant recipient. Arch Dermatol 2006;142:1643-8. 18. Khoury F, Kibbi A, Ghosn S. Virus-associated trichodysplasia spinulosa in a child with acute lymphoblastic leukemia [abstract], J Cutan Pathol 2007;34:77.
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19. Osswald SS, Kulick KB, Tomaszewski MM, Sperling LC. Viralassociated trichodysplasia in a patient with lymphoma: a case report and review. J Cutan Pathol 2007;34:721-5, doi:10.1111/ j.l600-0560.2006.00693.x. 20. Sadler GM, Halbert AR, Smith N, Rogers M. Trichodysplasia spinulosa associated with chemotherapy for acute lymphocytic leukaemia. Australas J Dermatol 2007;48:110-4, doi:10.1111/ j.l440-0960.2007.00348.x. 21. Lee JS, Frederiksen P, Kossard S. Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission. Australas J Dermatol 2008;49:57-60, doi:10.1111/j,14400960.2007.00422.x. 22. Schwieger-Briel A, Balma-Mena A, Ngan B, et al. Trichodysplasia spinulosa—a rare complication in immunosuppressed patients. Pediatr Dermatol 2010;27:509-13, doi: 10.1111/j. 1525- 1470.2010.01278.x. 23. Blake BP, Marathe KS, Mohr MR, et al. Viral-associated trichodysplasia of immunosuppression in a renal transplant patient. J Drugs Dermatol 2011;10:422-4. 24. Burns A, Arnason T, Fraser R, et al. Keratotic “spiny” papules in an immunosuppressed child. Trichodysplasia spinulosa (TS). Arch Dermatol 2011;147:1215-20, doi: 10.100 l/archdermatol.2011,286-a. 25. de Luzuriaga AR, Petronic-Rosic V, Finch T, Wasserman J. Trichodysplasia of immunosuppression [abstract]. J Cutan Pathol 2011;38:153.
26. Elaba Z, Hughey SL, Andea A. Trichodysplasia spinulosa in a lung transplant patient [abstract], J Cutan Pathol 2011;38:153. 27. Lee YY, Tucker SC, Prow NA, et al. Trichodysplasia spinulosa: a benign adnexal proliferation with follicular differentiation associated with polyomavirus. Australas J Dermatol 2013 Jan 18, doi:10.1111/ajd. 12012. 28. Brimhall CL, Malone JC. Viral-associated trichodysplasia spinulosa in a renal transplant patient. Arch Dermatol 2012;148:863^, doi:10.1001/archdermatol.2012.29. 29. Berk DR, Lu D, Bayliss SJ. Trichodysplasia spinulosa in an adolescent with cystic fibrosis and lung transplantation. Int J Dermatol 2013;52:1586-8, doi:10.1111/j.l365-4632.2011. 05391.x. 30. Moktefi A, Laude H, Brudy GL, et al. Trichodysplasia spinulosa associated with lupus. Am J Dermatopathol 2013 Aug, doi:10. 1097/DAD.06013e319293f620. 31. Chen T, Mattila PS, Jartti T, et al. Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus. J Infect Dis 2011;204:1523-6, doi:10.1093/infdis/jir614. 32. Moens U, Ludvigsen M, Van Ghelue M. Human polyomaviruses in skin diseases. Patholog Res Int 2011;2011:123491. 33. Van Ghelue M, Khan MT, Ehlers B, Moens U. Genome analysis of the new human polyomaviruses. Rev Med Virol 2012;22:354-77, doi:10.1002/rmv.l711.
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