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March> 1, 2008

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

Author Affiliations

Author Affiliations: Department of Dermatology, University of Environmental and Occupational Health, Kitakyushu, Japan.

Arch Dermatol. 2008;144(3):375-379. doi:10.1001/archderm.144.3.375

Background  “Nagashima-type” keratosis is characterized by transgressive and nonprogressive palmoplantar keratoderma (PPK) with an autosomal recessive trait. Because its clinical manifestations are similar to but milder than those of mal de Meleda, it was originally described as a mild form of Meleda-type PPK. Since then, about 20 cases have been reported in the Japanese-language literature. However, to our knowledge, no cases have been reported from countries other than Japan, presumably because Nagashima-type PPK was not recognized as a distinct entity. It is essential to describe the characteristics of this disease in the English-language literature.

Observations  A 17-year-old boy presented with transgressive, hyperhidrotic, erythematous, and hyperkeratotic lesions on his palms and soles that had developed when he was an infant and had progressed until 2 to 3 years earlier. His family history revealed no similar disorders. The symptoms and clinical course were typical for Nagashima-type PPK. A genetic study was performed to search for a mutation in the SLURP1 gene, which is responsible for mal de Meleda, but no mutations were detected in the exon or intron sites of SLURP1.

Conclusion  The results of the present genetic study suggest that Nagashima-type keratosis is a novel entity of PPK and is distinct from mal de Meleda.

Palmoplantar keratoderma (PPK) comprises a heterogenous group of disorders, which can be subdivided into hereditary and acquired forms. Classification of the hereditary PPK is difficult because of interindividual and intraindividual variations and differences in nomenclature. Lucker et al1 classified PPK based on the specific mophological appearance and distribution of the hyperkeratosis, the presence or absence of associated features, and the inheritance pattern. Additional criteria were the presence of skin lesions on areas other than the palms and soles, the age at onset of the keratoderma, the severity of the disease process, and the histologic findings.1 According to the classification of Lucker and colleagues,1 the diffuse autosomal recessive type of hereditary PPK without associated features includes mal de Meleda (MDM), Gamborg Nielsen type, Nagashima type, and acral keratoderma.1

Mal de Meleda, also referred to as erythrokeratodermia varibilis or keratosis palmoplantaris transgrediens (defined as the contiguous extension of hyperkeratosis beyond the palmar and/or plantar skin), is a rare autosomal recessive skin disorder.2 The main clinical characteristics are transgressive PPK, hyperhidrosis, and perioral erythema.1 The disease has its onset in early infancy and follows a progressive course.1,3 Recently, mutations in the gene SLURP1 (secreted LY6/PLAUR-related protein 1) located on chromosome 8q24.3 were found to be the cause of MDM.4

Cases of recessive severe PPK have been reported all over the world, and most have been described as Meleda type because of their similar clinical symptoms.57 On the other hand, a case of clinically different type of transgressive PPK was described in 1977.8 Nagashima8 initially named this case Meleda-type PPK, but because it was less severe than MDM and was nonprogressive after puberty, it was different from MDM or the Meleda type of PPK. Two additional siblings affected by this milder type of recessive PPK were described by Mitsuhashi et al9 in 1989; these cases were then termed Nagashima-type PPK because of their uniqueness. About 20 cases of Nagashima-type PPK have been reported from Japan, but all of them were written and reviewed in the Japanese literature.10 Therefore, the definition and characterization of this disease have not been well recognized in the world, although Nagashima-type PPK is included in the diffuse autosomal recessive type of hereditary PPKs 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 English-language literature and present an additional genetic analysis.


A 17-year-old boy presented with bilateral reddish, palmoplantar hyperkeratotic lesions (Figure 1) that extended into the dorsum of the hands and the Achilles tendon area (Figure 1B and D). The condition, which had developed within the first 2 years of life and had progressed until 2 to 3 years earlier, was associated with hyperhidrosis on his palms and soles, accompanied by a distinct odor and maceration. The patient was otherwise healthy, and his family history was negative for similar disorders. The lesions had been treated with topical 0.1% betamethasone valerate ointment and keratolytic moisturizing creams for the associated contact dermatitis. The results of a potassium hydrochloride test were negative for fungi on the palms and soles.

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.

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 biopsy specimen from the erythematous dorsum of the hand showed orthokeratotic hyperkeratosis with acanthosis, hypergranulosis, and mild perivascular inflammatory infiltration (Figure 2A). A moderate lymphocytic infiltrate in the upper dermis was also noted (Figure 2B). There was no viral inclusion, granular degeneration, or epithelial cell abnormalities.

Figure 2.
Histologic findings (hematoxylin-eosin,
original magnification ×10 [A] and ×20 [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.

Histologic findings (hematoxylin-eosin, original magnification ×10 [A] and ×20 [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.


Quantification of sweat production was performed by Minor iodine-starch tests,11 with some modification. Briefly, starch was put on the palms of subjects in a temperature- and moisture-controlled room at 26°C and 50% moisture. Five minutes later, excessive starch was wiped off, and photographs were taken. Compared with a normal healthy control subject, the patient exhibited a marked change of starch color to purple by sweating (Figure 3).

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.

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.


The subjects were enrolled and local ethical guidelines were followed. Genomic DNA was isolated from peripheral blood leukocytes by proteinase K and the phenol/chloroform/isoamylalcohol extraction procedure. The SLURP1 gene (EMBL HSARS81S; NCBI X99977) was amplified via polymerase chain reaction in the thermal cycler (Eppendorf AG, Hamburg, Germany) using a forward (5′-GTCAGGCGCCTAAAATCAAG-3′) and a reverse (5′-AGCAGGTGCCTAGAATGTGC-3′) primer pair. Initially, the polymerase chain reaction was subjected to denaturation for 2 minutes at 96°C, followed by 30 cycles of amplification (1 minute at 96°C, 1 minute at 65°C, and 2 minutes 30 seconds at 72°C). A final elongation step (5 minutes at 72°C) was applied at the end of the 30 cycles.

Amplified products were purified with a commercially available gel extraction kit (QIAquick Gel Extraction Kit; QIAGEN, Valencia, California) after 1.5% agarose electrophoresis. Direct sequence was performed with a cycle sequencing kit (BigDye Terminator Version 3.1 Cycle Sequencing Kit; Applied Biosystems, Foster City, California) and sequencing primers (Table 1), using capillary electrophoresis (ABI Prism 3130xl Genetic Analyzer; Applied Biosystems), and analyzed with a DNA sequencing analyzer software package (ABI Prism DNA Sequencing Analyzer, Version 5.1; Applied Biosystems). The results showed that no exon-intron mutation was detected in the SLURP1 gene, which is responsible for MDM.

Table 1. 
Primers for Polymerase Chain Reaction and DNA Sequencing
Primers for Polymerase Chain Reaction and DNA Sequencing

About 20 cases of Nagashima-type PPK have been reported in Japan.10 We evaluated those cases and modified the previous Japanese review10 (Table 2). The Nagashima-type PPK is characterized by an autosomal recessive trait, a nonprogressive course, and less severe manifestations than those of MDM. The other characteristics include (1) a male-female ratio of 9:10; (2) an onset of disease from birth to 3 years old; (3) hyperhidrosis as an associated condition; and (4) a high frequency of tinea pedis complication (7 of 17 cases).20 Moreover, a high frequency of involvement of other sites, such as elbows and knees, was noted in previous cases (13 of 19 cases), but not in our case. Because, to our knowledge, Nagashima-type cases have been reported only in the Japanese literature, this type of PPK is not well known in Western countries, even though the existence of this disease is recognized.1 In fact, there was a report of a case from Europe21 entitled “An Unusual Case of PPK,” which was clinically similar to Nagashima-type PPK. Therefore, we believe that it is worthwhile to present a typical case of Nagashima-type PPK with clinicopathologic and genetic characterization.

Table 2. Reported Cases of “Nagashima-Type” Keratosisa
Table 2. Reported Cases of “Nagashima-Type” Keratosisa

Mal de Meleda shares transgressive PPK and hyperhidrosis with the Nagashima-type keratosis, but MDM is much more severe than the Nagashima type. It usually involves perioral erythema and occasionally exhibits brachydactyly, nail abnormalities, and lichenoid plaques. In general, MDM follows a progressive course throughout the lives of the patients and extends to the dorsal surfaces of the hands and feet.1 Constricting bands surrounding the digits are typical and occasionally result in spontaneous amputation,1,3 which has never occurred in patients with the Nagashima type. The Gamborg Nielsen type of PPK is a moderately severe form that is characterized by a thick hyperkeratosis, distinctly demarcated from normal skin. It differs from the Nagashima-type PPK in that the dorsal aspects of the finger joints are covered by hyperkeratotic plaques and there can be constricting bands surrounding the fingers.22 Acral keratoderma can also easily be differentiated from Nagashima-type PPK by its specific clinical findings, which include striate hyperkeratinosis of the palms and soles, hyperkeratotic plaques over the dorsum of the hands and toes, and linear hyperkeratotic lesions over the Achilles tendon areas, ankles, elbows, and knees. Another possible differential diagnosis is symmetrical lividities of the soles, a rare dermatosis of unknown etiology, characterized by hyperhidrosis and symmetrical, bluish-red plaques on the soles of the feet, but its predilection is not limited to areas of pressure or patterns of innervations.23 Its skin manifestations are usually localized to the soles, and involvement of palms is rare. Regarding the mode of inheritance in Nagashima-type PPK, 8 sibling cases have been reported.9,12,13,1519 One case originated from a consanguineous mating.14 So far, no inheritance to descendants of the affected patients or other family members has been reported, to our knowledge. These previously reported cases suggest that the mode of inheritance is autosomal recessive.

Nagashima-type PPK was initally reported as MDM but was described as being less severe and largely nonprogressive after puberty. A SLURP1 mutation was found in patients with MDM, and SLURP1 is absent at the protein level in cases of MDM.24 Furthermore, it has been shown that the SLURP1 gene belongs to a family of secreted proteins that are expressed in the skin25,26 and is an allosteric modulator of the α7 nicotinic receptor.27 Also, several nicotinic receptors are expressed in the skin and skin appendages. On the other hand, 1 case of MDM without mutation in any exon or intron-exon junction of the SLURP1 gene has been reported,28 and 2 reports have documented MDM-like autosomal recessive PPK unlinked to SLURP1,29 suggesting that genetic heterogeneity may exist in MDM. These cases of erythrokeratodermia variabilis without link to SLURP1 have shown a wide variety of clinical manifestations, such as brachydactyly, tapered fingers toward the tips, circular constriction, thin nails with longitudinal ridging,28 scaly borders of erythrodermic keratosis, red nails with preserved lunulae, and perioral erythema,30 which do not usually appear in Nagashima-type PPK. Therefore, at present, we could not find clinical similarities between our case and other cases of MDM or MDM-like PPK unlinked to SLURP1. It is also possible that SLURP1 mutations may eventually be found farther from the gene than the region studied herein. Theoretically, therefore, the lack of SLURP1 mutation in our case does not necessarily negate the possibility that Nagashima-type keratosis is a type of PPK that is distinct from MDM. However, dermatologists should keep the concept and characteristics of Nagashima-type keratosis in mind. Future studies should include either a whole genome mapping plan or focus directly on candidate genes, such as SLURP2, and genes of similar function. More reports and concise clinical observations with genetic approach may reveal the pathomechanism underlying PPK.

Correspondence: Kenji Kabashima, MD, PhD, Department of Dermatology, University of Environmental and Occupational Health, 1-1 Iseigaka Yahatanishi-ku, Kitakyushu, Fu 807-8555, Japan (kkabashi@med.uoeh-u.ac.jp).

Accepted for Publication: September 10, 2007.

Author Contributions:Study concept and design: Kabashima and Sakabe. Acquisition of data: Kabashima, Sakabe, Yamada, and Tokura. Analysis and interpretation of data: Kabashima, Sakabe, and Tokura. Drafting of the manuscript: Kabashima, Sakabe, and Tokura. Critical revision of the manuscript for important intellectual content: Kabashima, Yamada, and Tokura. Obtained funding: Kabashima. Administrative, technical, and material support: Kabashima, Sakabe, and Yamada. Study supervision: Kabashima and Tokura.

Financial Disclosure: None reported.

Additional Contributions: Yoshihiko Mitsuhashi, MD, provided useful discussion.

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