Keratosis As a Novel Entity in the Palmoplantar Keratoderma Category

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OBSERVATION “Nagashima-Type” Keratosis as a Novel Entity in the Palmoplantar Keratoderma Category

Kenji Kabashima, MD, PhD; Jun-ichi Sakabe; Yoko Yamada, MD; Yoshiki Tokura, MD, PhD

Background: “Nagashima-type” keratosis is character- keratotic lesions on his palms and soles that had devel- ized by transgressive and nonprogressive palmoplantar oped when he was an infant and had progressed until 2 keratoderma (PPK) with an autosomal recessive trait. Be- to 3 years earlier. His family history revealed no similar cause its clinical manifestations are similar to but milder disorders. The symptoms and clinical course were typi- than those of mal de Meleda, it was originally described cal for Nagashima-type PPK. A genetic study was per- as a mild form of Meleda-type PPK. Since then, about 20 formed to search for a mutation in the SLURP1 gene, cases have been reported in the Japanese-language lit- which is responsible for mal de Meleda, but no muta- erature. However, to our knowledge, no cases have been tions were detected in the exon or intron sites of reported from countries other than Japan, presumably SLURP1. because Nagashima-type PPK was not recognized as a distinct entity. It is essential to describe the characteristics Conclusion: The results of the present genetic study sug- of this disease in the English-language literature. gest that Nagashima-type keratosis is a novel entity of PPK and is distinct from mal de Meleda. Observations: A 17-year-old boy presented with transgressive, hyperhidrotic, erythematous, and hyper- Arch Dermatol. 2008;144(3):375-379

ALMOPLANTAR KERATO- yond the palmar and/or plantar skin), is derma (PPK) comprises a a rare autosomal recessive skin disorder.2 heterogenous group of dis- The main clinical characteristics are trans- orders, which can be subdi- gressive PPK, hyperhidrosis, and peri- vided into hereditary and oral erythema.1 The disease has its onset acquired forms. Classification of the he- in early infancy and follows a progressive P 1,3 reditary PPK is difficult because of inter- course. Recently, mutations in the gene individual and intraindividual variations SLURP1 (secreted LY6/PLAUR-related pro- and differences in nomenclature. Lucker tein 1) located on chromosome 8q24.3 et al1 classified PPK based on the specific were found to be the cause of MDM.4 mophological appearance and distribu- Cases of recessive severe PPK have been tion of the hyperkeratosis, the presence or reported all over the world, and most have absence of associated features, and the in- been described as Meleda type because of heritance pattern. Additional criteria were their similar clinical symptoms.5-7 On the the presence of skin lesions on areas other other hand, a case of clinically different type of transgressive PPK was described in 1977.8 Nagashima8 initially named this For editorial comment case Meleda-type PPK, but because it was see page 384 less severe than MDM and was nonprogressive after puberty, it was different from than the palms and soles, the age at onset MDM or the Meleda type of PPK. Two ad- of the keratoderma, the severity of the dis- ditional siblings affected by this milder type ease process, and the histologic find- of recessive PPK were described by Mit- ings.1 According to the classification of suhashi et al9 in 1989; these cases were Lucker and colleagues,1 the diffuse auto- then termed Nagashima-type PPK be- somal recessive type of hereditary PPK cause of their uniqueness. About 20 cases without associated features includes mal of Nagashima-type PPK have been re- de Meleda (MDM), Gamborg Nielsen type, ported from Japan, but all of them were Nagashima type, and acral keratoderma.1 written and reviewed in the Japanese lit- Author Affiliations: 10 Department of Dermatology, Mal de Meleda, also referred to as eryth- erature. Therefore, the definition and University of Environmental rokeratodermia varibilis or keratosis pal- characterization of this disease have not and Occupational Health, moplantaris transgrediens (defined as the been well recognized in the world, al- Kitakyushu, Japan. contiguous extension of hyperkeratosis be- though Nagashima-type PPK is included

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C D

Figure 1. Clinical appearance. A and C, Bilateral reddish, palmoplantar hyperkeratotic lesions on the palms and soles. B and D, The lesions extend onto the dorsum of the hands and the Achilles tendon area.

A B

Figure 2. Histologic findings (hematoxylin-eosin, original magnification ϫ10 [A] and ϫ20 [B]). A, A biopsy specimen from the dorsum of the hand shows orthokeratotic hyperkeratosis with acanthosis, hypergranulosis, and mild perivascular inflammatory infiltration. B, A higher-power view also shows moderate lymphocytic infiltration in the upper dermis.

in the diffuse autosomal recessive type of hereditary PPKs REPORT OF A CASE without associated features, even in the English- language reviews.1 We report a typical case of Nagashima- type PPK for the first time (to our knowledge) in the En- A 17-year-old boy presented with bilateral reddish, pal- glish-language literature and present an additional genetic moplantar hyperkeratotic lesions (Figure 1) that ex- analysis. tended into the dorsum of the hands and the Achilles ten-

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Figure 3. Iodide starch test. Five minutes after starch was applied to the palms of the control (A) and the patient (B), excessive starch was wiped off, and photographs were taken.

don area (Figure 1B and D). The condition, which had developed within the first 2 years of life and had pro- Table 1. Primers for Polymerase Chain Reaction and DNA Sequencing gressed until 2 to 3 years earlier, was associated with hyperhidrosis on his palms and soles, accompanied by a dis- Primer Sequence tinct odor and maceration. The patient was otherwise healthy, and his family history was negative for similar SLURP1 Ј Ј disorders. The lesions had been treated with topical 0.1% Forward 5 -GTC AGG CGC CTA AAA TCA AG-3 Reverse 5Ј-AGC AGG TGC CTA GAA TGT GC-3Ј betamethasone valerate ointment and keratolytic mois- SLURP1-S2 turizing creams for the associated contact dermatitis. The Forward 5Ј-AGT GAG TTC CCC AGT GTT GG-3Ј results of a potassium hydrochloride test were negative SLURP1-S3 for fungi on the palms and soles. Forward 5Ј-ACT TCT GAG CAC GGA GC-3Ј Reverse 5Ј-GCT CCG TGC TCA GAA GT-3Ј HISTOLOGIC FINDINGS SLURP1-S4 Forward 5Ј-GCA TTC AAG TCT GTG GCT CA-3Ј Reverse 5Ј-TGA GCC ACA GAC TTG AAT GC-3Ј A biopsy specimen from the erythematous dorsum of the SLURP1-S5 hand showed orthokeratotic hyperkeratosis with acan- Forward 5Ј-CCT CAA GTG CTA CAC CTG CA-3Ј thosis, hypergranulosis, and mild perivascular inflam- Reverse 5Ј-TGC AGG TGT AGC ACT TGA GG-3Ј matory infiltration (Figure 2A). A moderate lympho- SLURP1-S6 cytic infiltrate in the upper dermis was also noted Forward 5Ј-ACC CCA GCT CTG ACA CAG AC-3Ј Reverse 5Ј-GTC TGT GTC AGA GCT GGG GT-3Ј (Figure 2B). There was no viral inclusion, granular de- SLURP1-S7 generation, or epithelial cell abnormalities. Forward 5Ј-GCA ACT CGG AAC TCT GAA CC-3Ј Reverse 5Ј-GGT TCA GAG TTC CGA GTT GC-3Ј IODINE TESTS

Quantification of sweat production was performed by Mi- cler (Eppendorf AG, Hamburg, Germany) using a for- nor iodine-starch tests,11 with some modification. Briefly, ward (5Ј-GTCAGGCGCCTAAAATCAAG-3Ј) and a starch was put on the palms of subjects in a tempera- reverse (5Ј-AGCAGGTGCCTAGAATGTGC-3Ј) primer ture- and moisture-controlled room at 26°C and 50% pair. Initially, the polymerase chain reaction was sub- moisture. Five minutes later, excessive starch was wiped jected to denaturation for 2 minutes at 96°C, followed off, and photographs were taken. Compared with a nor- by 30 cycles of amplification (1 minute at 96°C, 1 minute mal healthy control subject, the patient exhibited a marked at 65°C, and 2 minutes 30 seconds at 72°C). A final elon- change of starch color to purple by sweating (Figure 3). gation step (5 minutes at 72°C) was applied at the end of the 30 cycles. GENETIC ANALYSIS FOR ARS Amplified products were purified with a commer- COMPONENT B (SLURP1) GENE cially available gel extraction kit (QIAquick Gel Extrac- tion Kit; QIAGEN, Valencia, California) after 1.5% aga- The subjects were enrolled and local ethical guidelines rose electrophoresis. Direct sequence was performed with were followed. Genomic DNA was isolated from periph- a cycle sequencing kit (BigDye Terminator Version 3.1 eral blood leukocytes by proteinase K and the phenol/ Cycle Sequencing Kit; Applied Biosystems, Foster City, chloroform/isoamylalcohol extraction procedure. The California) and sequencing primers (Table 1), using cap- SLURP1 gene (EMBL HSARS81S; NCBI X99977) was am- illary electrophoresis (ABI Prism 3130xl Genetic Ana- plified via polymerase chain reaction in the thermal cy- lyzer; Applied Biosystems), and analyzed with a DNA se-

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Patient No./ Other Involved Source Sex/Age Onset Family History Areas Hyperhidrosis Mitsuhashi et al,9 1989 1/M/15 y 1 mo Sister Knees Yes Mitsuhashi et al,9 1989 2/F/13 y Birth Sister of patient 1 Knees and elbows Yes Aso,12 1989 3/F/27 y Infancy Brother Knees and elbows Unknown Shimizu,13 1992 4/F/1 y 2 mo Brother Knee Yes Miyachi et al,14 1994 5/F/11 y 4 mo Isolated case Knees Yes Kitajima et al,15 1994 6/M/6 y 3 y Isolated case Knees and elbows No Kitajima et al,15 1994 7/M/11 mo 2 wk Isolated case Knee Unknown Kitajima et al,15 1994 8/M/1 y 3 mo Sister Knees and elbows Unknown Kitajima et al,15 1994 9/F/5 y 1 y Sister of patient 8 None Unknown Mitsuishi,16 1995 10/M/6 y Birth Brother Knees and elbows Yes Mitsuishi,16 1995 11/M/9 y Birth Brother of patient 10 Knees and elbows Yes Nakamura et al,17 1981 12/M/37 y Infancy Sister Knees and elbows Yes Nakamura et al,17 1981 13/F/34 y Infancy Sister of patient 12 None Unknown Matsunaga et al,18 2000 14/F/3 y Birth Sister Knees Yes Matsunaga et al,18 2000 15/F/10 mo Birth Sister of patient 14 None No Minagawa et al,10 2005 16/M/30 y Infancy Brother Knees and elbows Yes Chikenji et al,19 2005 17/F/12 y Infancy Sister None Yes Chikenji et al,19 2005 18/F/7 y Infancy Sister of patient 17 None Yes Present case 19/M/17 y Infancy Isolated None Yes

a Adapted from a previous review by Minagawa et al.10

quencing analyzer software package (ABI Prism DNA throughout the lives of the patients and extends to the Sequencing Analyzer, Version 5.1; Applied Biosys- dorsal surfaces of the hands and feet.1 Constricting bands tems). The results showed that no exon-intron muta- surrounding the digits are typical and occasionally re- tion was detected in the SLURP1 gene, which is respon- sult in spontaneous amputation,1,3 which has never oc- sible for MDM. curred in patients with the Nagashima type. The Gam- borg Nielsen type of PPK is a moderately severe form that COMMENT is characterized by a thick hyperkeratosis, distinctly de- marcated from normal skin. It differs from the Nagashima- About 20 cases of Nagashima-type PPK have been re- type PPK in that the dorsal aspects of the finger joints ported in Japan.10 We evaluated those cases and modi- are covered by hyperkeratotic plaques and there can be 22 fied the previous Japanese review10 (Table 2). The Na- constricting bands surrounding the fingers. Acral kera- gashima-type PPK is characterized by an autosomal toderma can also easily be differentiated from Nagashima- recessive trait, a nonprogressive course, and less severe type PPK by its specific clinical findings, which include manifestations than those of MDM. The other charac- striate hyperkeratinosis of the palms and soles, hyper- teristics include (1) a male-female ratio of 9:10; (2) an keratotic plaques over the dorsum of the hands and toes, onset of disease from birth to 3 years old; (3) hyperhi- and linear hyperkeratotic lesions over the Achilles ten- drosis as an associated condition; and (4) a high fre- don areas, ankles, elbows, and knees. Another possible quency of tinea pedis complication (7 of 17 cases).20 More- differential diagnosis is symmetrical lividities of the soles, over, a high frequency of involvement of other sites, such a rare dermatosis of unknown etiology, characterized by as elbows and knees, was noted in previous cases (13 of hyperhidrosis and symmetrical, bluish-red plaques on the 19 cases), but not in our case. Because, to our knowl- soles of the feet, but its predilection is not limited to areas edge, Nagashima-type cases have been reported only in of pressure or patterns of innervations.23 Its skin mani- the Japanese literature, this type of PPK is not well known festations are usually localized to the soles, and involve- in Western countries, even though the existence of this ment of palms is rare. Regarding the mode of inherit- disease is recognized.1 In fact, there was a report of a case ance in Nagashima-type PPK, 8 sibling cases have been from Europe21 entitled “An Unusual Case of PPK,” which reported.9,12,13,15-19 One case originated from a consan- was clinically similar to Nagashima-type PPK. There- guineous mating.14 So far, no inheritance to descen- fore, we believe that it is worthwhile to present a typical dants of the affected patients or other family members case of Nagashima-type PPK with clinicopathologic and has been reported, to our knowledge. These previously genetic characterization. reported cases suggest that the mode of inheritance is au- Mal de Meleda shares transgressive PPK and hyper- tosomal recessive. hidrosis with the Nagashima-type keratosis, but MDM Nagashima-type PPK was initally reported as MDM is much more severe than the Nagashima type. It usu- but was described as being less severe and largely non- ally involves perioral erythema and occasionally exhib- progressive after puberty. A SLURP1 mutation was found its brachydactyly, nail abnormalities, and lichenoid in patients with MDM, and SLURP1 is absent at the pro- plaques. In general, MDM follows a progressive course tein level in cases of MDM.24 Furthermore, it has been

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 shown that the SLURP1 gene belongs to a family of se- 2. Hovorka O, Ehlers E. Mal de Meleda. Arch Derm Syph (Berlin). 1897;40:251-256. creted proteins that are expressed in the skin25,26 and is 3. Bergman R, Bitterman-Deutsch O, Fartasch M, Gershoni-Baruch R, Friedman- ␣ 27 Birnbaum R. Mal de Meleda keratoderma with pseudoainhum. Br J Dermatol. an allosteric modulator of the 7 nicotinic receptor. Also, 1993;128(2):207-212. several nicotinic receptors are expressed in the skin and 4. Fischer J, Bouadjar B, Heilig R, et al. Mutations in the gene encoding SLURP-1 skin appendages. On the other hand, 1 case of MDM within mal de Meleda. Hum Mol Genet. 2001;10(8):875-880. out mutation in any exon or intron-exon junction of the 5. Jee SH, Lee YY, Wu YC, Lu YC, Pan CC. Report of a family with mal de Meleda SLURP1 gene has been reported,28 and 2 reports have in Taiwan: a clinical, histopathological and immunological study. Dermatologica. 1985;171(1):30-37. documented MDM-like autosomal recessive PPK un- 6. Laurent R, Prost O, Nicollier M, Marquet SC, Balzer MM, Adessi G. Composite 29 linked to SLURP1, suggesting that genetic heteroge- keratohyaline granules in palmoplantar keratoderma: an ultrastructural study. Arch neity may exist in MDM. These cases of erythrokerato- Dermatol Res. 1985;277(5):384-394. dermia variabilis without link to SLURP1 have shown a 7. Kastl I, Anton-Lamprecht I, Gamborg Nielsen P. Hereditary palmoplantar kera- wide variety of clinical manifestations, such as brachy- tosis of the Gamborg Nielsen type: clinical and ultrastructural characteristics of dactyly, tapered fingers toward the tips, circular con- a new type of autosomal recessive palmoplantar keratosis. Arch Dermatol Res. 28 1990;282(6):363-370. striction, thin nails with longitudinal ridging, scaly bor- 8. Nagashima M. Palmoplantar keratoses [in Japanese]. Jinrui Idengaku Shosho. ders of erythrodermic keratosis, red nails with preserved 1977;9:23-27. lunulae, and perioral erythema,30 which do not usually 9. Mitsuhashi Y, Hashimoto I, Takahashi M. Meleda type of keratosis palmoplan- appear in Nagashima-type PPK. Therefore, at present, we taris [in Japanese]. Hifubyoh Shinryou. 1989;11:298-299. could not find clinical similarities between our case and 10. Minagawa Y, Saito H, Ishiko A. A case of keratosis palmoplantaris transgrediens Nagashima [in Japanese]. Hifuka No Rinsho. 2005;59:1168-1171. other cases of MDM or MDM-like PPK unlinked to 11. Minor V. Ein Neues Verfahren zu der klinischen Untersuchung der SLURP1. It is also possible that SLURP1 mutations may Schweissabsonderung. Z Neurol. 1927;101:302-308. eventually be found farther from the gene than the re- 12. Aso K. “Nagashima type” palmoplantar keratosis [in Japanese]. Hifuka Mook. gion studied herein. Theoretically, therefore, the lack of 1989;15:148-153. SLURP1 mutation in our case does not necessarily ne- 13. Shimizu N. A case of “Meleda type” keratosis palmoplantaris [in Japanese]. Ni- igataken Ishikaiho. 1992;7(2):2-10. gate the possibility that Nagashima-type keratosis is a type 14. Miyachi M, Fukuda T, Kikuchi A, Shimizu H, Tajima S, Nishikawa T. Meleda type of PPK that is distinct from MDM. However, dermatolo- palmoplantar keratosis. Hifubyoh Shinryou. 1994;16(12):1121-1124. gists should keep the concept and characteristics of Na- 15. Kitajima S, Sugano S, Tsuji T. Meleda type of plamoplantar keratosis [in Japanese]. gashima-type keratosis in mind. Future studies should Proc Conference Disord Keratinization. 1994;9:74-76. include either a whole genome mapping plan or focus 16. Mitsuishi K. A case of Nagashima-type keratosis palmoplantaris [in Japanese]. Proc Conference Disord Keratinization. 1995;10:59-60. directly on candidate genes, such as SLURP2, and genes 17. Nakamura M, Igarashi M, Ichikawa M, Oh-I T, Kawasaki S. A sibling case of Na- of similar function. More reports and concise clinical ob- gashima-type of palmoplantar keratosis [in Japanese]. Rinsho Hifuka. 1981; servations with genetic approach may reveal the patho- 52(6):456-460. mechanism underlying PPK. 18. Matsunaga R, Mizoguchi M. A sibling case of Nagashima-type of palmoplantar keratosis. Rinsho Derma (Tokyo). 2000;42(13):2047-2050. 19. Chikenji T, Yagi N, Matsuba S, Takamori K. Sibling cases of keratosis palmo- Accepted for Publication: September 10, 2007. plantaris transgrediens Nagashima [in Japanese]. Proc Conference Disord Correspondence: Kenji Kabashima, MD, PhD, Depart- Keratinization. 2005;20:113-116. ment of Dermatology, University of Environmental and 20. Minagawa Y, Ishiko A. Nagashima type palmoplantar keratoderma [in Japanese]. Occupational Health, 1-1 Iseigaka Yahatanishi-ku, Pract Dermatol. 2005;27:5-10. Kitakyushu, Fu 807-8555, Japan ([email protected] 21. Devos SA, Delescluse J. An unusual case of palmoplantar keratoderma. J Eur Acad Dermatol Venereol. 2003;17(1):68-69. .ac.jp). 22. Gamborg Nielsen P. Mutilating palmo-plantar keratoderma. Acta Derm Venereol. Author Contributions: Study concept and design: 1983;63(4):365-367. Kabashima and Sakabe. Acquisition of data: Kabashima, 23. Pernet G. Symmetrical lividities of the soles of the feet. Br J Dermatol. 1925;37: Sakabe, Yamada, and Tokura. Analysis and interpreta- 311-312. tion of data: Kabashima, Sakabe, and Tokura. Drafting of 24. Favre B, Plantard L, Aeschbach L, et al. SLURP1 is a late marker of epidermal differentiation and is absent in mal de Meleda. J Invest Dermatol. 2007;127 the manuscript: Kabashima, Sakabe, and Tokura. Criti- (2):301-308. cal revision of the manuscript for important intellectual con- 25. Arredondo J, Chernyavsky AI, Jolkovsky DL, Webber RJ, Grando SA. SLURP-2: tent: Kabashima, Yamada, and Tokura. Obtained fund- a novel cholinergic signaling peptide in human mucocutaneous epithelium. J Cell ing: Kabashima. Administrative, technical, and material Physiol. 2006;208(1):238-245. support: Kabashima, Sakabe, and Yamada. Study super- 26. Arredondo J, Chernyavsky AI, Webber RJ, Grando SA. Biological effects of SLURP-1 vision: Kabashima and Tokura. on human keratinocytes. J Invest Dermatol. 2005;125(6):1236-1241. 27. Chimienti F, Hogg RC, Plantard L, et al. Identification of SLURP-1 as an epider- Financial Disclosure: None reported. mal neuromodulator explains the clinical phenotype of mal de Meleda. Hum Mol Additional Contributions: Yoshihiko Mitsuhashi, MD, Genet. 2003;12(22):3017-3024. provided useful discussion. 28. van Steensel MA, van Geel MV, Steijlen PM. Mal de Meleda without mutations in the ARS coding sequence. Eur J Dermatol. 2002;12(2):129-132. 29. Charfeddine C, Mokni M, Kassar S, et al. Further evidence of the clinical and ge- REFERENCES netic heterogeneity of recessive transgressive PPK in the Mediterranean region. J Hum Genet. 2006;51(10):841-845. 1. Lucker GP, Van de Kerkhof PC, Steijlen PM. The hereditary palmoplantar kera- 30. Lestringant GG, Frossard PM, Eckl KM, Reis A, Hennies HC. Genetic and clinical toses: an updated review and classification. Br J Dermatol. 1994;131(1): heterogeneity in transgressive palmoplantar keratoderma. J Invest Dermatol. 2001; 1-14. 116(5):825-827.

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