Trichodysplasia Spinulosa in a 20-Month-Old Girl With a Good Response to Topical Cidofovir 1%
Abstract
Trichodysplasia spinulosa (TS) is a rare entity, characterized by a follicular digitate keratosis predominantly affecting the face and variable degrees of hair loss, most severely facial hair, that occurs in immunosuppressed individuals, and is considered to be a viral infection caused by a human polyomavirus, the “TS-associated polyomavirus.” Histologically it is characterized by hair follicles with excessive inner root-sheath differentiation and intraepithelial viral inclusions. Correlation of these findings with clinical features is required for diagnosis. Treatment with antiviral agents appears to be the most effective. We report the occurrence of TS in a 20-month-old girl with multivisceral transplantation due to short-bowel syndrome secondary to intestinal atresia and gastroschisis. The patient was treated with cidofovir 1% cream, with significant improvement and without any adverse effects. We describe the youngest patient, to our knowledge, with TS.
- TS —
- trichodysplasia spinulosa
Trichodysplasia spinulosa (TS) is a follicular eruption that affects immunocompromised patients, and was first reported by Haycox et al in 1999,1 who described a skin eruption with friable spinous processes, indurated erythematous papules, and eyebrow alopecia in a patient who was receiving cyclosporine after renal and pancreas transplantation. After that, in 2004, Sperling et al2 used the term viral-associated trichodysplasia to report a kidney transplant recipient on a multidrug immunosuppression regimen.
This disease is being increasingly recognized among immunosuppressed patients. TS is characterized by erythematous to skin-colored, follicular-based papules, primarily in the central part of the face, that produce variable degrees of alopecia and dysmorphic features,3 as well as by the histopathologic findings of abnormally maturing anagen follicles with excessive inner root-sheath differentiation.4 Despite having been primarily described in transplant recipients, recently it also has been recognized in patients receiving chemotherapy for leukemia and lymphoma.3
We report an exceptional case of TS in the youngest patient described in the literature, to our knowledge. We also describe the patient’s significant response to topical cidofovir therapy.
Case Report
We report the case of a 20-month-old girl with a history of short-bowel syndrome secondary to intestinal atresia and gastroschisis. She also had hepatopathy due to enteral nutrition. Therefore, the patient had undergone multivisceral transplantation, including liver, stomach, intestine, ascending colon, cecum, and pancreas. After the transplantation, she was placed on an immunosuppressive regimen of prednisone and tacrolimus. Six months before going to dermatology service, the patient had several complications, such as respiratory syncytial virus bronchiolitis and adenovirus, interstitial lung disease, secondary hyperparathyroidism, mild renal failure, hypertension, and intestinal enterovirus infection. There were no data of transplant rejection in any monitoring time.
Approximately 8 months after the transplantation, the patient was evaluated for the development of facial lesions that had been present for 2 to 3 months. She had erythematous follicular papules primarily involving the central area of her face, particularly the nose, but also the glabella, cheeks, eyebrows, forehead, and nasolabial folds, as well as mild alopecia of her eyebrows (Fig 1). She also had small, white spicules protruding from some papules on her nose. The lesions were asymptomatic. The initial suspicion was graft-versus-host disease, a common entity in the setting of multivisceral transplantation, so she was initially treated with topical steroids and topical tacrolimus, which failed to alleviate the condition.
Erythematous follicular papules primarily involving the central area of the patient’s face, particularly her nose, where she also had small, white spicules protruding from some papules and mild alopecia of eyebrows.
A biopsy specimen was obtained, and histologic sections demonstrated abnormally maturing anagen hair follicles, hypertrophic bulbs, and excessive inner root-sheath differentiation with numerous large eosinophilic trichohyalin granules and hypercornification (Fig 2).
A (H&E, x2), B (H&E, x20), Abnormally maturing anagen hair follicles, hypercornification, and hypertrophic bulbs. C (H&E, x40), Excessive inner root-sheath differentiation with numerous large eosinophilic trichohyalin granules.
The histopathologic findings, in the context of the clinical setting, supported a diagnosis of TS. We treated our patient with topical cidofovir 1% cream, once daily. Cidofovir cream is formulated from cidofovir vial; it is made in beeler base and the indicated percentage. The patient had significant improvement over a period of 8 weeks, with noticeably smoother nose and reduction in both the number and size of the papules, without any adverse effects (Fig 3).
Eight weeks after starting topical cidofovir 1% cream. Noticeably smoother nose and reduction in both the number and size of the papules.
Different attempts to wean therapy in clinically improved areas resulted in a recurrence of the papules. Currently, the patient is 3 years old, and she continues on an immunosuppressive regimen and cidofovir 1% cream once daily, without TS lesions while she is under topical cidofovir therapy.
Discussion
TS can be classified as a benign, viral-associated folliculocentric process that presents as keratotic spiny papules typically distributed over the central part of the face.5 It is known in the literature under a variety of names, including trichodysplasia of immunosuppression, viral-associated trichodysplasia spinulosa, pilomatrix dysplasia, spiny hyperkeratosis, or cyclosporine-induced folliculodystrophy.5–7 This variation of names basically denotes a follicular abnormality related to immunosuppression.8 The disease course appears to be intimately linked to immunosuppression,3 characteristically in association with solid-organ transplantation or hematologic neoplasm treated with chemotherapy. This entity has been linked to various immunosuppressive medications, including cyclosporine therapy, tacrolimus, azathioprine, prednisone, mycophenolate mofetil, cyclophosphamide, methotrexate, rituximab, fludarabine, intravenous immunoglobulin A, and vincristine.3 Clinically, patients with TS develop multiple asymptomatic or mildly pruritic skin-colored to erythematous follicular-based papules that typically have hyperkeratotic spicules, and have a predilection for the central part of the face, being able to produce dysmorphic features, most commonly distorting the contours of the nose.3,7 Lesions can progress to involve the trunk and extremities.3,7 Variable degrees of alopecia have been reported, most commonly and severely affecting the eyebrows and occasionally the eyelashes and other hair-bearing areas of the face; the scalp is less commonly involved.3 TS was initially identified in both adult and pediatric patients who had undergone allograft solid-organ transplantation and treated with immunosuppressants to protect against allograft rejection, but soon the disease was also recognized in pediatric and adult patients who were immunocompromised secondary to malignant hematolymphoproliferative disorders.5,9
TS has been reported in a wide range of ages, between 5 and 69 years, with no known gender predilection, and the duration of immunosuppression at the time of the development of the lesions varies from 8 to 48 months.3
The histologic features are unique. Follicular dilatation, absence of a papilla, proliferation of inner root-sheath cells with enlarged trichohyalin granules, and infundibular keratin plugs are typical histologic features of TS.10 There are other less typical histologic findings that include multiple small hair shafts or hair shaft–like material within affected follicles, vacuolated keratinocytes with pyknotic nuclei and coarse keratohyalin granules in the upper layers of the perifollicular epithelium, gray-blue cytoplasmic material in the proliferative inner root-sheath cells, and focal perifolliculitis and a sparse lymphocytic interface dermatitis.10 Correlation between skin biopsy and clinical features is required for definitive diagnosis. However, many times the diagnosis may be missed if the sample does not contain anagen-phase follicles that demonstrate characteristic features.
Electron microscopy of skin biopsy specimens in some instances has revealed 30- to 40-nm-diameter viral particles in the nuclei of inner root-sheath cells and in extracellular keratin, belonging to the Polyomaviridae family.7,11 It was the eighth identified member of the human Polyomaviridae family (called TS-associated polyomavirus).12 The polymerase chain reaction and sequencing confirmation of the human polyomavirus DNA, as well as the results of immunohistochemical staining for specific polyomavirus middle T antigen, support this as a polyomavirus and not a papillomavirus, as it was thought previously.4 Infection is acquired at an early age without apparent disease and probably persists subclinically.13 Immunosuppression, alone or in combination with other no known factors, is the predisposing factor that triggers folliculotropic polyomavirus reactivation, and alters follicular maturation.4,5,8,9,11,
Routine testing with polymerase chain reaction assay, gene-sequencing studies, immunohistochemical stains, or electron microscopy, are not necessary in all cases, as routine histologic staining can be sufficient to make the diagnosis in cases of classic clinical presentations.4 These tools may be valuable in confirming the diagnosis in cases involving more subtle or atypical presentations.4
Medical treatment options of clinical TS lesions remain limited.5 The reduction or change of immunosuppressants has demonstrated clinical improvement,13 whereas topical and oral retinoids are minimally effective. Topical steroids, topical tacrolimus, topical antibiotics, imiquimod cream, keratolytics, benzyl peroxide, and minocycline are ineffective. Oral valganciclovir hydrochloride and 1% to 3% topical cidofovir have been reported to be efficacious3,5,10,11,13–15
Differential diagnoses for TS would include other digitate keratotic conditions, as multiple minute digitate hyperkeratoses, palmoplantar filiform hyperkeratosis, paraneoplastic facial hyperkeratotic spicules associated plasma cell dyscrasias, lichen spinulosus, spiny keratoderma, and even filiform warts, although they could be clinically distinct.6,7
The overall disease course of TS is somewhat unpredictable10: some cases of TS fully resolve after months to years, whereas others are reported with only slight improvement even with different treatments.
Our patient was placed on a once-daily topical regimen of cidofovir 1% cream, with significant improvement of her lesions. This case demonstrates a persistent response to topical cidofovir therapy without any adverse effect, a finding that is consistent with previous reports.2,4,11,14
TS is an emerging entity in the setting of immunosuppression. Given the number of immunocompromised patients, and the likely high prevalence of the causative virus, as seroepidemiological studies indicate that TS-associated polyomavirus is ubiquitous and latently infects 70% of the healthy individuals in adulthood,13,16,17 we believe that TS is probably underdiagnosed, possibly leading to delays in diagnosis. As organ transplantation and immunosuppression are becoming more common, the frequency of TS could increase. Clinicians should be more aware of this condition, which should be considered in the differential diagnoses for cutaneous spiny eruptions arising in the setting of immunosuppression. If the clinical features are suggestive of TS, the obtained biopsy specimens should contain anagen-phase hair follicles.
Herein, we describe a pediatric TS case with significant response to topical cidofovir and confirm its efficacy as an important treatment of this entity. This good clinical response to cidofovir strengthens the hypothesis of a viral etiology for the disease. We report, to our knowledge, the youngest patient with TS described in the literature.
Acknowledgments
We thank Dr Fatima Ros, Pharmacy Department, Hospital Universitario La Paz.
Footnotes
- Accepted July 30, 2015.
- Address correspondence to Raquel Santesteban, Calle Irunlarrea 3, Planta Baja, Pamplona, Navarra, Spain. E-mail: raquel.santestesban{at}hotmail.com
Dr Santesteban drafted the initial manuscript, and reviewed the final manuscript as submitted; Drs Feito, Mayor, and de Lucas attended the patient in the Department of Dermatology for 3 years, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Beato made the pathological diagnosis, reviewed and revised the manuscript, and approved the final manuscript as submitted; and Dr Ramos attended the patient in the Department of Gastroenterology for years, reviewed and revised the manuscript, and approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
References
- Copyright © 2015 by the American Academy of Pediatrics
