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Multiple minute digitate hyperkeratosis: A proposed algorithm for the digitate keratoses
Multiple minute digitate hyperkeratosis: A proposed algorithm for the digitate keratoses Tony Philip Caccetta, MBBS (Hons),a Ben Dessauvagie, MBBS (Hons),b Dugald McCallum, FRCPA,b and Sujith Prasad Kumarasinghe, FACDa Perth, Australia Background: Multiple minute digitate hyperkeratosis (MMDH) is a rare disorder of keratinization with many different names. Objective: We present a case of MMDH and review the literature. We propose and discuss the classification the digitate keratoses, which include MMDH, lichen spinulosus, phrynoderma, spiny keratoderma, arsenical keratosis, multiple filiform verrucae, postirradiation digitate keratosis, trichodysplasia spinulosa, and hyperkeratotic spicules. We present a table of suggested and synonymous terms and propose a diagnostic algorithm for these digitate keratoses. Methods: A literature search using PubMed and MEDLINE was performed. This included the search terms ‘‘MMDH,’’ ‘‘familial disseminated filiform hyperkeratosis,’’ ‘‘punctate porokeratotic keratoderma,’’ ‘‘disseminated spiked keratosis,’’ ‘‘minute aggregate keratosis,’’ ‘‘digitate keratosis,’’ ‘‘conical keratosis,’’ ‘‘hyperkeratotic spicules,’’ and ‘‘music box spine dermatosis.’’ A case of MMDH in an 89-year-old woman is described. Results: The digitate keratoses are presented alongside their synonymous terms and are divided into those that are generalized or localized using an algorithm. Limitations: Separate disease entities are likely to arise within the digitate keratoses with increased reporting of immunohistochemical keratin analysis and molecular genetic studies. Conclusion: We report a new case of MMDH and provide a clinical approach to diagnosis of the digitate keratoses. ( J Am Acad Dermatol 2012;67:e49-55.) Key words: arsenical keratosis; digitate keratoses; hyperkeratotic spicules; lichen spinulosus; multiple filiform verrucae; multiple minute digitate hyperkeratosis; phrynoderma; postirradiation digitate keratosis; spiny keratoderma; trichodysplasia spinulosa.
CASE REPORT An 89-year-old woman presented to the dermatology outpatient clinic reporting rough skin and itch of 8 years’ duration. Examination revealed many From the Department of Dermatologya and Anatomical Pathology, PathWest,b Royal Perth Hospital. Funding sources: None. Conflicts of interest: None declared. Given as an oral presentation at the 43rd Annual Scientific Meeting of the Australasian College of Dermatologists, Darwin, Australia, May 16, 2010. Reprint requests: Tony Philip Caccetta, MBBS (Hons), Department of Dermatology, Royal Perth Hospital, Wellington Street, Perth WA 6000, Australia. E-mail: [email protected]. Published online November 8, 2010. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.07.023
Abbreviations used: CK: cytokeratin MMDH: multiple minute digitate hyperkeratosis
digitate keratoses affecting the chest, abdomen, back, and proximal arms and legs (Fig 1). The face, palms, and soles were spared. The lesions were mostly nonfollicular, 1 to 2 mm in diameter, 4 to 5 mm in length, skin colored, and evenly distributed over the trunk and limbs. There were no other clinical features to suggest nutritional deficiency. Her medical history was unremarkable. In particular there was no family history of a digitate keratosis, no malignancy, no retinoid medication, and no arsenic exposure, radiotherapy, or immunosuppression. e49
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A differential diagnosis of multiple minute digitate MMDH, lichen spinulosus, phrynoderma, spiny kerhyperkeratosis (MMDH), lichen spinulosus, atoderma, arsenical keratosis, multiple filiform verand phrynoderma were considered. Punch biopsy rucae, postirradiation digitate keratosis, specimens were taken from 4 lesions. trichodysplasia spinulosa, and hyperkeratotic spicHistopathological examination showed focal ules. We define digitate as a minute fingerlike procolumns of orthokeratotic and parakeratotic hyperjection. Terms such as ‘‘spiked,’’ ‘‘spiny,’’ ‘‘filiform,’’ keratosis, arising from a tented epidermis. Prominent ‘‘piliform,’’ ‘‘aggregate,’’ ‘‘acuminate,’’ ‘‘conical,’’ and keratohyaline granules were ‘‘music box spine’’ may be seen in the stratum found throughout the literaCAPSULE SUMMARY granulosum overlying an ture describing various digiacanthotic epidermis. The tate keratoses. Such a The digitate keratoses are proposed to dermis was unremarkable plethora of terms can lead include multiple minute digitate (Fig 2). Electron microscopy to confusion within the literhyperkeratosis, lichen spinulosus, again demonstrated acanthoature. In this discussion we phrynoderma, spiny keratoderma, sis and hyperkeratosis. review the MMDH literature arsenical keratosis, multiple filiform Keratohyaline granules were and provide a diagnostic alverrucae, postirradiation digitate focally reduced in number. gorithm (Fig 5) with synonykeratosis, trichodysplasia spinulosa, and Odland (lamellar) bodies, mous and suggested terms hyperkeratotic spicules. tonofilaments, and desmofor the digitate keratoses The digitate keratoses are divided into somes were of normal num(Table I). generalized and localized using an ber and morphology (Fig 3). MMDH1-19 is predomialgorithm. nantly a nonfollicular digitate Immunohistochemical stainkeratosis affecting the trunk ing with cytokeratins Our future understanding may lie in and limbs. The face and palAE1/AE3, high moleculare immunohistochemical keratin analysis moplantar surfaces are not weight keratin, cytokeratin and molecular genetics. affected. The lesions include (CK) 5/6 antibodies, CK 14, white, yellow, brown, or cytokeratin CAM 5.2, and CK skin-colored spicules (0.5- to 5.0-mm long and 0.319 stained the lesional cells in the pattern expected of to 3.0-mm diameter) and occasionally flat-topped, normal epidermis (Fig 4). Specifically, there was dome-shaped, or crateriform papules. Cases may be staining of all layers of the epidermis by AE1/AE3 familial or sporadic. There are 18 female and 10 male and high moleculareweight keratin, staining of only cases reported, including our case. The age of onset basal keratinocytes by anticytokeratin 5/6 and CK14, ranges from 15 to 81 years. There has been one case and absent staining with CAM 5.2 and CK19. associated with etretinate use.10 Another case has A malignancy screen was performed (including full preceded breast cancer.14 Histopathology reveals blood count, urea electrolytes creatinine, liver funcfocal columns of orthokeratotic hyperkeratosis aristion tests, serum electrophoresis and free light chains, ing from a tented epidermis. Less commonly there is cancer antigen 15-3 and 19-9, 125 carcinoembryonic parakeratosis and epidermal invagination. The straantigen, and chest x-ray), which revealed negative tum granulosum is often prominent, but may be of findings. Her vitamin A, B12, C, and E; folate; and zinc variable thickness. Electron microscopy may show a levels were within normal limits. A diagnosis of focally reduced number of keratohyaline granules MMDH was made based on the generalized and normal or increased number of Odland (lameldistribution of lesions that spared the face, palms, lar) bodies.4-7 Treatment is often unsuccessful or and soles; the nonfollicular pattern; the absence of only transient, however there have been reports of nutritional deficiency; and supportive histopathology improvement with various topical keratolytics, and and electron microscopy. Her itch was partially topical and oral retinoids. Resolution without treatrelieved with 1% menthol and 1% phenol in aqueous ment has also been reported.9 We favor the term cream. There was partial improvement in the selected ‘‘multiple minute digitate hyperkeratosis’’ over the areas treated with 4% salicylic acid in sorbolene synonymous terms presented in Table I, as this was cream. At 1-year review her lesions persisted and a the term used when first described by Goldstein1 in repeated malignancy screen produced negative 1967. findings. Lichen spinulosus is a follicular digitate keratosis that mainly affects the trunk and limbs. Follicular DISCUSSION keratotic papules 1 to 3 mm in diameter with horny The digitate keratoses are a proposed group of spines are grouped into 2- to 6-cm plaques.20 This acquired and inherited disorders that include d
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Fig 1. Multiple minute digitate hyperkeratosis affecting back.
grouped arrangement aids clinical diagnosis. The age of onset is around adolescence. The grouped follicular digitate keratoses of the HIV-associated follicular syndrome resemble lichen spinulosus, however they have been reported to occur on the face, and may represent a distinct entity of digitate keratosis.21 Histopathology resembles keratosis pilaris, with follicular keratin plugs, however there is a dense lymphocytic perifollicular infiltrate. The cause is unknown. Response to topical keratolytics has been reported. The term ‘‘lichen spinulosus’’ is favored over the synonymous terms in Table I, as it is the best-recognized term. Phrynoderma22 (‘‘toad skin’’) is a follicular digitate keratosis often affecting the posterolateral upper aspect of arms and anterolateral aspect of thighs before spreading to involve the elbows, knees, and neck. It is caused by various nutritional deficiencies (often but not always vitamin A). Other clinical features specific to the nutritional deficiency are often present. Histopathology reveals hyperkeratosis with prominent follicular plugging. Resolution occurs with nutritional supplementation. ‘‘Phrynoderma’’ is a wellrecognized term. Spiny keratoderma23-34 is characterized by discrete keratotic plugs arising from the palms, soles, or both. It may be familial or sporadic. There may or may not be associated malignancy.23 Histopathology is variable showing focal columns of orthokeratotic or parakeratotic hyperkeratosis overlying a hypogranular epidermis of variable contour (invaginated or tented). Electron microscopy may reveal a reduced number of keratohyaline granules and normal Odland bodies. Hashimoto et al34 have shown immunohistochemical staining with AE13 (a hair type keratin), proposing that spiny keratoderma may represent ectopic hair formation. Partial response to treatment with topical keratolytics, topical retinoids, and topical 5-fluorouracil27 has been reported. We prefer the term ‘‘spiny keratoderma’’ over the synonymous terms presented in Table I as it
Fig 2. Light microscopy. A, Low-power image of multiple minute digitate hyperkeratosis exhibiting hyperkeratotic spicule arising from pointed epidermal elevation. Epidermis is expanded by basaloid keratinocytes. B, High-power image showing prominent keratohyaline granules within stratum granulosum. There is both orthokeratosis and parakeratosis within hyperkeratotic spicule. (A and B, Hematoxylin-eosin stain; original magnifications: A, 350; B, 3100.)
is not a porokeratosis, the designation ‘‘music box spine’’ is not well understood, ‘‘multiple minute palmar-plantar digitate hyperkeratosis’’ causes confusion with ‘‘MMDH,’’ and ‘‘filiform hyperkeratosis’’ attempts to group both palmoplantar and disseminated digitate keratoses together, generating further confusion. Arsenical keratoses present with digitate keratoses of the palms and/or soles in those exposed to arsenic. Arsenic exposure may be medicinal, via drinking water, or occupational. These patients are at risk of squamous cell carcinoma of the skin and other internal malignancies, and therefore require close monitoring. Histopathology reveals focal orthokeratotic or parakeratotic hyperkeratosis, often overlying a depressed epidermis. Treatment with topical 5-fluorouracil, oral acitretin, and surgical excision may successfully treat arsenical keratoses and minimize the risk of malignancy. ‘‘Arsenical keratosis’’ is a good descriptive term. Multiple filiform verrucae are usually seen on the face (around the lips, nares, and eyelids commonly), but may occur anywhere. Histology reveals marked
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Fig 3. Electron microscopy. A, Low-power electron micrograph of multiple minute digitate hyperkeratosis (MMDH) showing epidermal acanthosis and focal reduction of keratohyaline granules. B, High-power electron micrograph showing two adjacent keratinocytes within MMDH with desmosomes, tonofibrils, and Odland (lamellar) bodies, all of unremarkable number and morphology.
papillomatosis with inward turning elongated peripheral rete ridges, columns of parakeratosis overlying the papillomatous projections, and an absent to diminished granular layer. Elsewhere the granular layer is thickened with coarse keratohyaline granules. Vacuolated cells (koilocytes) are characteristic of verrucae and basophilic viral inclusions may be present. Electron microscopy may show 45- to 55-nm diameter viral particles, consistent with human papillomavirus. No alternative terms have been proposed. ‘‘Multiple filiform verrucae’’ is a good descriptive term. Postirradiation digitate keratosis is a nonfollicular digitate keratosis confined to sites of irradiation.35-38 Onset may be months to years after irradiation. All reported patients received radiotherapy for breast cancer. Histopathology reveals a focal column of parakeratotic hyperkeratosis overlying an invaginated and hypogranular (or agranular) epidermis. There has been one case reported with orthokeratotic hyperkeratosis. Electron microscopy has shown moth-eaten keratohyaline granules and normal Odland bodies. Treatments have not been reported in the literature. We favor the term ‘‘postirradiation digitate keratosis’’ over the synonymous terms presented in Table I, as this was the term first used when described by Burns35 in 1986. Hyperkeratotic spicules39-47 are follicular or nonfollicular digitate keratoses of the face (nose in particular), and may also involve the scalp, trunk, and limbs. They are often associated with paraproteinemia, multiple myeloma, and cryoglobulinemia, but may be idiopathic.43 More recently two cases were reported associated with Se´zary syndrome.48 Histopathology
Fig 4. Immunohistochemistry. High-power image showing positive membranous staining for broad-spectrum cytokeratin AE1/AE3 in both epidermal and horn cells of multiple minute digitate hyperkeratosis. (Original magnification: 3200.)
reveals focal columns of orthokeratotic or parakeratotic hyperkeratosis with homogenous compact eosinophilic inclusions (immunoglobulin). Skin immunofluorescence may reveal intercellular epidermal immunoglobulin deposition, and if so identical serum monoclonal gammopathy is present. Successful treatment with chemotherapy in those with underlying multiple myeloma has been reported. We prefer the term ‘‘hyperkeratotic spicules’’ over the synonymous terms presented in Table I as ‘‘MMDH associated with paraproteinemia’’ causes confusion with ‘‘MMDH’’ and terms using ‘‘follicular’’ can be inaccurate as hyperkeratotic spicules may be follicular and nonfollicular. Trichodysplasia spinulosa is a follicular digitate keratosis predominantly affecting the face, however it can also affect the trunk and limbs. It is distinct from
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Fig 5. Diagnostic algorithm for digitate keratoses. MMDH, Multiple minute digitate hyperkeratosis.
Table I. Suggested and synonymous terms for digitate keratoses Suggested terms
MMDH1,3,7,11,13-19
Lichen spinulosus
Postirradiation digitate keratosis34
Hyperkeratotic spicules
Trichodysplasia spinulosa46
Spiny keratoderma26,29,31,32
MMDH, Multiple minute digitate hyperkeratosis.
Synonymous terms
Familial disseminated piliform hyperkeratosis2 Disseminated spiked hypereratosis4,6 Minute aggregate keratosis5 Parakeratotic horns8 Transient postinflammatory digitate keratosis9 Digitate keratosis10 Lichen pilaris seu spinulosus Keratosis follicularis spinosa Keratosis spinulosa Postirradiation MMDH36 Postirradiation multiple minute digitate porokeratosis37 Postirradiation conical keratosis35 MMDH associated with paraproteinemia46 Follicular hyperkeratotic spicules39,41-43 Follicular spicules40,44 Cutaneous spicules45 Follicular hyperkeratosis38 Trichodysplasia of immunosuppression48 Viral-associated trichodysplasia spinulosa Pilomatrix dysplasia Cyclosporine-induced folliculodystrophy Punctate porokeratotic keratoderma22,23,25,28 Music box spine dermatosis Multiple minute palmar-plantar digitate hyperkeratosis24 Filiform hyperkeratosis27,30
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lichen spinulosus and phrynoderma, which affect the trunk and limbs, but not the face. Because of its predominance on the face, it is therefore presented as a localized digitate keratosis in our algorithm. It is considered to be a viral infection that occurs in immunosuppressed individuals.49,50 However, viral particles have not been isolated in all patients.49 There may be associated alopecia. Histology reveals dilated hair follicles with proliferation of the inner root sheath cells containing large trichohyaline granules. Electron microscopy may show 30- to 40-nm diameter viral particles, consistent with papovavirus. Treatment success has been reported with oral valganciclovir.48 We favor ‘‘trichodysplasia spinulosa’’ over the synonymous terms presented in Table I, as it appears to be a viral infection that occurs in immunosuppressed individuals, not one or the other, and it is not specific to cyclosporine. The use of many synonymous terms and the previously proposed classifications11,14,17,28 for the digitate keratoses can cause confusion. We propose our suggested terms (Table I) and algorithm (Fig 5) for diagnosing the digitate keratoses. We believe this to be current, however expect that distinct entities will arise, in particular within the morphologically variable group of MMDH and spiny keratoderma, as our understanding improves. Our future understanding may lie in immunohistochemical cytokeratin analysis, as demonstrated by Hashimoto et al34 in spiny keratoderma. Our molecular genetic understanding may improve by comparing the regulation of keratin genes in lesional and interlesional skin with those of normal comparable subjects. REFERENCES 1. Goldstein N. Multiple minute digitate hyperkeratosis. Arch Dermatol 1967;96:692-3. 2. Aufgang A. Hypererkatose piliforme disseminee familiale. Ann Dermatol Venereol 1972;99:381-90. 3. Yoon SW, Gibbs RB. Multiple minute digitate hyperkeratosis. Arch Dermatol 1975;111:1176-7. 4. Frenk E, Mevorah B, Leu F. Disseminated spiked hyperkeratosis: an unusual discrete non-follicular keratinization disorder. Arch Dermatol 1981;117:412-4. 5. Shuttleworth D, Graham-Brown RAC, Hutchinson PE. Minute aggregate keratosesea report of three cases. Clin Exp Dermatol 1985;10:566-71. 6. Nedwich JA, Sullivan JJ. Disseminated spiked hyperkeratosis. Int J Dermatol 1987;26:358-61. 7. Balus L, Donati P, Amantea A, Breathnach AS. Multiple minute digitate hyperkeratosis. J Am Acad Dermatol 1988;18:431-6. 8. Aloi FG, Molinero A, Pippione M. Parakeratotic horns in a patient with Crohn’s disease. Clin Exp Dermatol 1989;14:79-81. 9. Cox NH, Ince P. Transient post-inflammatory digitate keratoses. Clin Exp Dermatol 1989;17:170-2. 10. Carmichael AJ, Tan CY. Digitate keratosesea complication of etretinate used in the treatment of disseminated superficial actinic porokeratosis. Clin Exp Dermatol 1990;15:370-1.
11. Benoldi D, Zucchi A, Allegra F. Multiple minute digitate hyperkeratoses. Clin Exp Dermatol 1993;18:261-2. 12. Judd LE, Wood KP. Disseminated spiked hyperkeratosis. Int J Dermatol 1993;32:446-7. 13. Wilkinson SM, Wilkinson N, Chalmers RJ. Multiple minute digitate keratoses: a transient sporadic variant. J Am Acad Dermatol 1994;31:802-3. 14. Ramselaar C, Toonstra J. Multiple minute digitate hyperkeratosis: report of two cases with an updated review and proposal for a new classification. Eur J Dermatol 1999;9: 460-5. 15. Takagawa S, Satoh T, Yokozeki H, Nishioka K. Multiple minute digitate hyperkeratoses. Br J Dermatol 2000;142:1044-6. 16. Rubegni P, De Aloe G, Piangiani E, Cherubini-Di Simpicio F, Fimiani M. Two sporadic cases of idiopathic multiple minute digitate hyperkeratosis. Clin Dermatol 2000;26:53-5. 17. Pimentel CL, Puig L, Garcia-Muret MP, Fernandez-Figueras MT, Alomar A. Multiple minute digitate hyperkeratosis. J Eur Acad Dermatol Venereol 2002;16:411-27. 18. Guarneri C, Guarneri F, Vaccaro M, Borgia F, Cannavo SP. Multiple digitate hyperkeratoses. Int J Dermatol 2005;44:664-7. 19. Clark JL, Davis G, Bennet D. Innumerable filiform papules. Arch Dermatol 2008;144:1051-6. 20. Friedman SJ. Lichen spinulosus: clinicopathological review of thirty-five cases. J Am Acad Dermatol 1990;22:261-4. 21. Blasdale C, Turner RJ, Leonard N, Ong ELC, Lawrence CM. Spontaneous clinical improvement in HIV-associated follicular syndrome. Clin Exp Dermatol 2004;29:480-2. 22. Girard C, Dereure O, Blatiere V, Guillot B, Bessis D. Vitamin A deficiency phrynoderma associated with chronic giardiasis. Pediatr Dermatol 2006;23:346-9. 23. Herman PS. Punctate porokeratotic keratoderma. Dermatologica 1973;147:206-13. 24. Friedman SJ, Herman PS, Pittelkow MR, Su D. Punctate porokeratotic keratoderma. Arch Dermatol 1988;124:1678-82. 25. Knobler EH, Grossman ME, Rabinowitz AD. Multiple minute palmar-plantar digitate hyperkeratoses. Br J Dermatol 1989; 121:239-42. 26. Kondo S, Shimoura T, Hozumi Y, Aso K. Punctate porokeratotic keratoderma. Acta Derm Venereol 1990;70:478-82. 27. Osman Y, Daly TJ, Don PC. Spiny keratoderma of the palms and soles. J Am Acad Dermatol 1992;26:879-81. 28. Zarour H, Grob JJ, Andrac L, Bonerandi JJ. Palmoplantar orthokeratotic filiform hyperkeratosis in a patient with associated Darier’s disease: classification of filiform hyperkeratosis. Dermatology 1992;185:205-9. 29. Bianchi L, Orlandi A, Iraci S, Spagnoli LG, Nini G. Punctate porokeratotic keratodermaeits occurrence with internal neoplasia. Clin Exp Dermatol 1994;19:139-41. 30. McGovern TW, Gentry RH. Spiny keratoderma: case report, classification, and treatment of music box spine dermatoses. Cutis 1994;54:389-94. 31. Kaddu S, Soyer HP, Kerl H. Palmar filiform hyperkeratosis: a new paraneoplastic syndrome? J Am Acad Dermatol 1995;33: 337-40. 32. Anderson D, Cohen DE, Lee HS, Thellman C. Spiny keratoderma in association with autosomal dominant polycystic kidney disease with liver cysts. J Am Acad Dermatol 1996;34: 935-6. 33. Torres G, Behshad R, Han A, Castrovinci AJ, Gilliam AC. I forgot to shave my hands: a case of spiny keratoderma. J Am Acad Dermatol 2008;58:344-8. 34. Hashimoto K, Toi Y, Horton S, Sun TT. Spiny keratoderma: a demonstration of hair keratin and hair type keratinization. J Cutan Pathol 1999;26:25-30.
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35. Burns DA. Post-irradiation digitate keratoses. Clin Exp Dermatol 1986;11:646-9. 36. Vestey JP, Mallet RB, Rodger A. Post irradiation conical keratosis. J R Soc Med 1989;82:166-7. 37. Mizuno K, Okamoto H, Imamura S. Postirradiation multiple minute digitate hyperkeratoses. Clin Exp Dermatol 1995;20: 425-7. 38. Pujol RM, Perez-Losada E, Matias-Guiu X, Fuentes J, Alonso MC, Alomar A, et al. Postirradiation multiple minute digitate porokeratoses. J Cutan Med Surg 2001;5:126-30. 39. Lukitsch O, Gebhardt KP, Kovary PM. Follicular hyperkeratosis and cryocrystalglobulinemia syndrome. Arch Dermatol 1985; 121:795-8. 40. Bork K, Bockers M, Pfeifle J. Pathogenesis of paraneoplastic follicular hyperkeratotic spicules in multiple myeloma. Arch Dermatol 1990;126:509-13. 41. Requena L, Sarasa JL, Ortiz Masllorens F, Martin L, Pique E, Olivares M, et al. Follicular spicules of the nose: a peculiar cutaneous manifestation of multiple myeloma. J Am Acad Dermatol 1995;32:834-9. 42. Paul C, Fermand JP, Flageul B, Caux F, Duterque M, Dubertret L, et al. Hyperkeratotic spicules and monoclonal gammopathy. J Am Acad Dermatol 1995;33:346-51.
43. Kim TY, Park YM, Jang IG, Yi JY, Kim CW, Song KY. Idiopathic follicular hyperkeratotic spicules. J Am Acad Dermatol 1997; 36:476-7. 44. Braun RP, Skaria AM, Saurat JH, Borradori L. Multiple hyperkeratotic spicules and myeloma. Dermatology 2002;205:210-2. 45. Satta R, Casu G, Dore F, Longinotti M, Cottoni F. Follicular spicules and multiple ulcers: cutaneous manifestations of multiple myeloma. J Am Acad Dermatol 2003;49:736-40. 46. Miller JJ, Anderson BE, Ioffreda MD, Bongiovanni MB, Fogelberg AC. Hair casts and cutaneous spicules in multiple myeloma. Arch Dermatol 2006;142:1665-6. 47. Sripakash K, Yong-Gee S. Multiple minute digitate hyperkeratosis associated with paraproteinemia. Australas J Dermatol 2008;49:233-6. 48. Al-Niaimi F, Cox NH, Taylor WD. Follicular hyperkeratosis as a manifestation of Se´zary syndrome. Br J Dermatol 2010;162: 695-6. 49. Sadler GM, Halbert AR, Smith N, Rogers M. Trichodysplasia spinulosa associated with chemotherapy for acute lymphocytic leukemia. Australas J Dermatol 2007;48:110-4. 50. Holzer AM, Hughey LC. Trichodysplasia of immunosuppression treated with oral valganciclovir. J Am Acad Dermatol 2008;60:169-71.
CASE REPORT An 89-year-old woman presented to the dermatology outpatient clinic reporting rough skin and itch of 8 years’ duration. Examination revealed many From the Department of Dermatologya and Anatomical Pathology, PathWest,b Royal Perth Hospital. Funding sources: None. Conflicts of interest: None declared. Given as an oral presentation at the 43rd Annual Scientific Meeting of the Australasian College of Dermatologists, Darwin, Australia, May 16, 2010. Reprint requests: Tony Philip Caccetta, MBBS (Hons), Department of Dermatology, Royal Perth Hospital, Wellington Street, Perth WA 6000, Australia. E-mail: [email protected]. Published online November 8, 2010. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.07.023
Abbreviations used: CK: cytokeratin MMDH: multiple minute digitate hyperkeratosis
digitate keratoses affecting the chest, abdomen, back, and proximal arms and legs (Fig 1). The face, palms, and soles were spared. The lesions were mostly nonfollicular, 1 to 2 mm in diameter, 4 to 5 mm in length, skin colored, and evenly distributed over the trunk and limbs. There were no other clinical features to suggest nutritional deficiency. Her medical history was unremarkable. In particular there was no family history of a digitate keratosis, no malignancy, no retinoid medication, and no arsenic exposure, radiotherapy, or immunosuppression. e49
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A differential diagnosis of multiple minute digitate MMDH, lichen spinulosus, phrynoderma, spiny kerhyperkeratosis (MMDH), lichen spinulosus, atoderma, arsenical keratosis, multiple filiform verand phrynoderma were considered. Punch biopsy rucae, postirradiation digitate keratosis, specimens were taken from 4 lesions. trichodysplasia spinulosa, and hyperkeratotic spicHistopathological examination showed focal ules. We define digitate as a minute fingerlike procolumns of orthokeratotic and parakeratotic hyperjection. Terms such as ‘‘spiked,’’ ‘‘spiny,’’ ‘‘filiform,’’ keratosis, arising from a tented epidermis. Prominent ‘‘piliform,’’ ‘‘aggregate,’’ ‘‘acuminate,’’ ‘‘conical,’’ and keratohyaline granules were ‘‘music box spine’’ may be seen in the stratum found throughout the literaCAPSULE SUMMARY granulosum overlying an ture describing various digiacanthotic epidermis. The tate keratoses. Such a The digitate keratoses are proposed to dermis was unremarkable plethora of terms can lead include multiple minute digitate (Fig 2). Electron microscopy to confusion within the literhyperkeratosis, lichen spinulosus, again demonstrated acanthoature. In this discussion we phrynoderma, spiny keratoderma, sis and hyperkeratosis. review the MMDH literature arsenical keratosis, multiple filiform Keratohyaline granules were and provide a diagnostic alverrucae, postirradiation digitate focally reduced in number. gorithm (Fig 5) with synonykeratosis, trichodysplasia spinulosa, and Odland (lamellar) bodies, mous and suggested terms hyperkeratotic spicules. tonofilaments, and desmofor the digitate keratoses The digitate keratoses are divided into somes were of normal num(Table I). generalized and localized using an ber and morphology (Fig 3). MMDH1-19 is predomialgorithm. nantly a nonfollicular digitate Immunohistochemical stainkeratosis affecting the trunk ing with cytokeratins Our future understanding may lie in and limbs. The face and palAE1/AE3, high moleculare immunohistochemical keratin analysis moplantar surfaces are not weight keratin, cytokeratin and molecular genetics. affected. The lesions include (CK) 5/6 antibodies, CK 14, white, yellow, brown, or cytokeratin CAM 5.2, and CK skin-colored spicules (0.5- to 5.0-mm long and 0.319 stained the lesional cells in the pattern expected of to 3.0-mm diameter) and occasionally flat-topped, normal epidermis (Fig 4). Specifically, there was dome-shaped, or crateriform papules. Cases may be staining of all layers of the epidermis by AE1/AE3 familial or sporadic. There are 18 female and 10 male and high moleculareweight keratin, staining of only cases reported, including our case. The age of onset basal keratinocytes by anticytokeratin 5/6 and CK14, ranges from 15 to 81 years. There has been one case and absent staining with CAM 5.2 and CK19. associated with etretinate use.10 Another case has A malignancy screen was performed (including full preceded breast cancer.14 Histopathology reveals blood count, urea electrolytes creatinine, liver funcfocal columns of orthokeratotic hyperkeratosis aristion tests, serum electrophoresis and free light chains, ing from a tented epidermis. Less commonly there is cancer antigen 15-3 and 19-9, 125 carcinoembryonic parakeratosis and epidermal invagination. The straantigen, and chest x-ray), which revealed negative tum granulosum is often prominent, but may be of findings. Her vitamin A, B12, C, and E; folate; and zinc variable thickness. Electron microscopy may show a levels were within normal limits. A diagnosis of focally reduced number of keratohyaline granules MMDH was made based on the generalized and normal or increased number of Odland (lameldistribution of lesions that spared the face, palms, lar) bodies.4-7 Treatment is often unsuccessful or and soles; the nonfollicular pattern; the absence of only transient, however there have been reports of nutritional deficiency; and supportive histopathology improvement with various topical keratolytics, and and electron microscopy. Her itch was partially topical and oral retinoids. Resolution without treatrelieved with 1% menthol and 1% phenol in aqueous ment has also been reported.9 We favor the term cream. There was partial improvement in the selected ‘‘multiple minute digitate hyperkeratosis’’ over the areas treated with 4% salicylic acid in sorbolene synonymous terms presented in Table I, as this was cream. At 1-year review her lesions persisted and a the term used when first described by Goldstein1 in repeated malignancy screen produced negative 1967. findings. Lichen spinulosus is a follicular digitate keratosis that mainly affects the trunk and limbs. Follicular DISCUSSION keratotic papules 1 to 3 mm in diameter with horny The digitate keratoses are a proposed group of spines are grouped into 2- to 6-cm plaques.20 This acquired and inherited disorders that include d
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Fig 1. Multiple minute digitate hyperkeratosis affecting back.
grouped arrangement aids clinical diagnosis. The age of onset is around adolescence. The grouped follicular digitate keratoses of the HIV-associated follicular syndrome resemble lichen spinulosus, however they have been reported to occur on the face, and may represent a distinct entity of digitate keratosis.21 Histopathology resembles keratosis pilaris, with follicular keratin plugs, however there is a dense lymphocytic perifollicular infiltrate. The cause is unknown. Response to topical keratolytics has been reported. The term ‘‘lichen spinulosus’’ is favored over the synonymous terms in Table I, as it is the best-recognized term. Phrynoderma22 (‘‘toad skin’’) is a follicular digitate keratosis often affecting the posterolateral upper aspect of arms and anterolateral aspect of thighs before spreading to involve the elbows, knees, and neck. It is caused by various nutritional deficiencies (often but not always vitamin A). Other clinical features specific to the nutritional deficiency are often present. Histopathology reveals hyperkeratosis with prominent follicular plugging. Resolution occurs with nutritional supplementation. ‘‘Phrynoderma’’ is a wellrecognized term. Spiny keratoderma23-34 is characterized by discrete keratotic plugs arising from the palms, soles, or both. It may be familial or sporadic. There may or may not be associated malignancy.23 Histopathology is variable showing focal columns of orthokeratotic or parakeratotic hyperkeratosis overlying a hypogranular epidermis of variable contour (invaginated or tented). Electron microscopy may reveal a reduced number of keratohyaline granules and normal Odland bodies. Hashimoto et al34 have shown immunohistochemical staining with AE13 (a hair type keratin), proposing that spiny keratoderma may represent ectopic hair formation. Partial response to treatment with topical keratolytics, topical retinoids, and topical 5-fluorouracil27 has been reported. We prefer the term ‘‘spiny keratoderma’’ over the synonymous terms presented in Table I as it
Fig 2. Light microscopy. A, Low-power image of multiple minute digitate hyperkeratosis exhibiting hyperkeratotic spicule arising from pointed epidermal elevation. Epidermis is expanded by basaloid keratinocytes. B, High-power image showing prominent keratohyaline granules within stratum granulosum. There is both orthokeratosis and parakeratosis within hyperkeratotic spicule. (A and B, Hematoxylin-eosin stain; original magnifications: A, 350; B, 3100.)
is not a porokeratosis, the designation ‘‘music box spine’’ is not well understood, ‘‘multiple minute palmar-plantar digitate hyperkeratosis’’ causes confusion with ‘‘MMDH,’’ and ‘‘filiform hyperkeratosis’’ attempts to group both palmoplantar and disseminated digitate keratoses together, generating further confusion. Arsenical keratoses present with digitate keratoses of the palms and/or soles in those exposed to arsenic. Arsenic exposure may be medicinal, via drinking water, or occupational. These patients are at risk of squamous cell carcinoma of the skin and other internal malignancies, and therefore require close monitoring. Histopathology reveals focal orthokeratotic or parakeratotic hyperkeratosis, often overlying a depressed epidermis. Treatment with topical 5-fluorouracil, oral acitretin, and surgical excision may successfully treat arsenical keratoses and minimize the risk of malignancy. ‘‘Arsenical keratosis’’ is a good descriptive term. Multiple filiform verrucae are usually seen on the face (around the lips, nares, and eyelids commonly), but may occur anywhere. Histology reveals marked
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Fig 3. Electron microscopy. A, Low-power electron micrograph of multiple minute digitate hyperkeratosis (MMDH) showing epidermal acanthosis and focal reduction of keratohyaline granules. B, High-power electron micrograph showing two adjacent keratinocytes within MMDH with desmosomes, tonofibrils, and Odland (lamellar) bodies, all of unremarkable number and morphology.
papillomatosis with inward turning elongated peripheral rete ridges, columns of parakeratosis overlying the papillomatous projections, and an absent to diminished granular layer. Elsewhere the granular layer is thickened with coarse keratohyaline granules. Vacuolated cells (koilocytes) are characteristic of verrucae and basophilic viral inclusions may be present. Electron microscopy may show 45- to 55-nm diameter viral particles, consistent with human papillomavirus. No alternative terms have been proposed. ‘‘Multiple filiform verrucae’’ is a good descriptive term. Postirradiation digitate keratosis is a nonfollicular digitate keratosis confined to sites of irradiation.35-38 Onset may be months to years after irradiation. All reported patients received radiotherapy for breast cancer. Histopathology reveals a focal column of parakeratotic hyperkeratosis overlying an invaginated and hypogranular (or agranular) epidermis. There has been one case reported with orthokeratotic hyperkeratosis. Electron microscopy has shown moth-eaten keratohyaline granules and normal Odland bodies. Treatments have not been reported in the literature. We favor the term ‘‘postirradiation digitate keratosis’’ over the synonymous terms presented in Table I, as this was the term first used when described by Burns35 in 1986. Hyperkeratotic spicules39-47 are follicular or nonfollicular digitate keratoses of the face (nose in particular), and may also involve the scalp, trunk, and limbs. They are often associated with paraproteinemia, multiple myeloma, and cryoglobulinemia, but may be idiopathic.43 More recently two cases were reported associated with Se´zary syndrome.48 Histopathology
Fig 4. Immunohistochemistry. High-power image showing positive membranous staining for broad-spectrum cytokeratin AE1/AE3 in both epidermal and horn cells of multiple minute digitate hyperkeratosis. (Original magnification: 3200.)
reveals focal columns of orthokeratotic or parakeratotic hyperkeratosis with homogenous compact eosinophilic inclusions (immunoglobulin). Skin immunofluorescence may reveal intercellular epidermal immunoglobulin deposition, and if so identical serum monoclonal gammopathy is present. Successful treatment with chemotherapy in those with underlying multiple myeloma has been reported. We prefer the term ‘‘hyperkeratotic spicules’’ over the synonymous terms presented in Table I as ‘‘MMDH associated with paraproteinemia’’ causes confusion with ‘‘MMDH’’ and terms using ‘‘follicular’’ can be inaccurate as hyperkeratotic spicules may be follicular and nonfollicular. Trichodysplasia spinulosa is a follicular digitate keratosis predominantly affecting the face, however it can also affect the trunk and limbs. It is distinct from
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Fig 5. Diagnostic algorithm for digitate keratoses. MMDH, Multiple minute digitate hyperkeratosis.
Table I. Suggested and synonymous terms for digitate keratoses Suggested terms
MMDH1,3,7,11,13-19
Lichen spinulosus
Postirradiation digitate keratosis34
Hyperkeratotic spicules
Trichodysplasia spinulosa46
Spiny keratoderma26,29,31,32
MMDH, Multiple minute digitate hyperkeratosis.
Synonymous terms
Familial disseminated piliform hyperkeratosis2 Disseminated spiked hypereratosis4,6 Minute aggregate keratosis5 Parakeratotic horns8 Transient postinflammatory digitate keratosis9 Digitate keratosis10 Lichen pilaris seu spinulosus Keratosis follicularis spinosa Keratosis spinulosa Postirradiation MMDH36 Postirradiation multiple minute digitate porokeratosis37 Postirradiation conical keratosis35 MMDH associated with paraproteinemia46 Follicular hyperkeratotic spicules39,41-43 Follicular spicules40,44 Cutaneous spicules45 Follicular hyperkeratosis38 Trichodysplasia of immunosuppression48 Viral-associated trichodysplasia spinulosa Pilomatrix dysplasia Cyclosporine-induced folliculodystrophy Punctate porokeratotic keratoderma22,23,25,28 Music box spine dermatosis Multiple minute palmar-plantar digitate hyperkeratosis24 Filiform hyperkeratosis27,30
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lichen spinulosus and phrynoderma, which affect the trunk and limbs, but not the face. Because of its predominance on the face, it is therefore presented as a localized digitate keratosis in our algorithm. It is considered to be a viral infection that occurs in immunosuppressed individuals.49,50 However, viral particles have not been isolated in all patients.49 There may be associated alopecia. Histology reveals dilated hair follicles with proliferation of the inner root sheath cells containing large trichohyaline granules. Electron microscopy may show 30- to 40-nm diameter viral particles, consistent with papovavirus. Treatment success has been reported with oral valganciclovir.48 We favor ‘‘trichodysplasia spinulosa’’ over the synonymous terms presented in Table I, as it appears to be a viral infection that occurs in immunosuppressed individuals, not one or the other, and it is not specific to cyclosporine. The use of many synonymous terms and the previously proposed classifications11,14,17,28 for the digitate keratoses can cause confusion. We propose our suggested terms (Table I) and algorithm (Fig 5) for diagnosing the digitate keratoses. We believe this to be current, however expect that distinct entities will arise, in particular within the morphologically variable group of MMDH and spiny keratoderma, as our understanding improves. Our future understanding may lie in immunohistochemical cytokeratin analysis, as demonstrated by Hashimoto et al34 in spiny keratoderma. Our molecular genetic understanding may improve by comparing the regulation of keratin genes in lesional and interlesional skin with those of normal comparable subjects. REFERENCES 1. Goldstein N. Multiple minute digitate hyperkeratosis. Arch Dermatol 1967;96:692-3. 2. Aufgang A. Hypererkatose piliforme disseminee familiale. Ann Dermatol Venereol 1972;99:381-90. 3. Yoon SW, Gibbs RB. Multiple minute digitate hyperkeratosis. Arch Dermatol 1975;111:1176-7. 4. Frenk E, Mevorah B, Leu F. Disseminated spiked hyperkeratosis: an unusual discrete non-follicular keratinization disorder. Arch Dermatol 1981;117:412-4. 5. Shuttleworth D, Graham-Brown RAC, Hutchinson PE. Minute aggregate keratosesea report of three cases. Clin Exp Dermatol 1985;10:566-71. 6. Nedwich JA, Sullivan JJ. Disseminated spiked hyperkeratosis. Int J Dermatol 1987;26:358-61. 7. Balus L, Donati P, Amantea A, Breathnach AS. Multiple minute digitate hyperkeratosis. J Am Acad Dermatol 1988;18:431-6. 8. Aloi FG, Molinero A, Pippione M. Parakeratotic horns in a patient with Crohn’s disease. Clin Exp Dermatol 1989;14:79-81. 9. Cox NH, Ince P. Transient post-inflammatory digitate keratoses. Clin Exp Dermatol 1989;17:170-2. 10. Carmichael AJ, Tan CY. Digitate keratosesea complication of etretinate used in the treatment of disseminated superficial actinic porokeratosis. Clin Exp Dermatol 1990;15:370-1.
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43. Kim TY, Park YM, Jang IG, Yi JY, Kim CW, Song KY. Idiopathic follicular hyperkeratotic spicules. J Am Acad Dermatol 1997; 36:476-7. 44. Braun RP, Skaria AM, Saurat JH, Borradori L. Multiple hyperkeratotic spicules and myeloma. Dermatology 2002;205:210-2. 45. Satta R, Casu G, Dore F, Longinotti M, Cottoni F. Follicular spicules and multiple ulcers: cutaneous manifestations of multiple myeloma. J Am Acad Dermatol 2003;49:736-40. 46. Miller JJ, Anderson BE, Ioffreda MD, Bongiovanni MB, Fogelberg AC. Hair casts and cutaneous spicules in multiple myeloma. Arch Dermatol 2006;142:1665-6. 47. Sripakash K, Yong-Gee S. Multiple minute digitate hyperkeratosis associated with paraproteinemia. Australas J Dermatol 2008;49:233-6. 48. Al-Niaimi F, Cox NH, Taylor WD. Follicular hyperkeratosis as a manifestation of Se´zary syndrome. Br J Dermatol 2010;162: 695-6. 49. Sadler GM, Halbert AR, Smith N, Rogers M. Trichodysplasia spinulosa associated with chemotherapy for acute lymphocytic leukemia. Australas J Dermatol 2007;48:110-4. 50. Holzer AM, Hughey LC. Trichodysplasia of immunosuppression treated with oral valganciclovir. J Am Acad Dermatol 2008;60:169-71.