Trichodysplasia Spinulosa in a 20-Month-Old Girl With a Good Response to Topical Cidofovir 1%

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 efficacious^{3,5,10,11,13–15}

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.