Journal of Dermatology 2015; 42: 889–892
doi: 10.1111/1346-8138.12916
CONCISE COMMUNICATION
Low-dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work Toshifumi NOMURA,1,* Reine MORIUCHI,2,* Masae TAKEDA,1 Shotaro SUZUKI,1 Kazuhiro KIKUCHI,2 Takamasa ITO,2 Hiroshi SHIMIZU,1 Satoko SHIMIZU2 1
Department of Dermatology, Hokkaido University Graduate School of Medicine, 2Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan
ABSTRACT Punctate palmoplantar keratoderma type 1 (PPKP1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss-of-function mutations in AAGAB have recently been reported as a cause of PPKP1. Despite the discovery of the genetic cause of PPKP1, pathogenesis-based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP1. In this study, we analyzed a Japanese woman with PPKP1 and identified a novel frame-shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB. Moreover, low-dose etretinate was effective in improving the PPKP1 lesions in our patient. Our published work review identified only eight cases of PPKP1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP1.
Key words:
AAGAB, adapalene, etretinate, punctate palmoplantar keratoderma type 1, retinoid.
INTRODUCTION Punctate palmoplantar keratoderma type 1 (PPKP1, Online Mendelian Inheritance in Man no. 148600), also known as the Buschke–Fischer–Brauer type, is a rare autosomal dominant form of palmoplantar keratoderma, clinically characterized by multiple punctate hyperkeratotic papules affecting the palmar and plantar skin.1 These circumscribed papules gradually coalesce and increase in number with age, and the patients generally exhibit a chronic intractable course with deteriorated quality of life.1 Histological findings include marked orthokeratotic hyperkeratosis and hypergranulosis associated with a well-defined central epidermal depression.1 Loss-of-function mutations in AAGAB, encoding a- and c-adaptin binding protein p34, have recently been reported as a cause of PPKP1.1,2 The protein is involved in clathrin-mediated vesicle transport, which plays a crucial role in the endocytosis and recycling of receptor tyrosine kinases (RTK) such as epidermal growth factor receptor and Axl.1,3 Therefore, AAGAB null mutations have been speculated to result in the increased half-life of several RTK in basal keratinocytes, leading to hyperproliferative hyperkeratosis on the palmoplantar regions of PPKP1 patients.1,3 To date, 28 mutations have been identified in 54 families with PPKP1.4,5 Despite the discovery of the genetic cause of
PPKP1, however, pathogenesis-based therapies are still unavailable. Instead, current management of the disease is mainly directed toward reduction of hyperkeratosis, using topical keratolytics, topical vitamin D3 and/or topical or systemic retinoids. However, only a very limited number of case reports describe successful treatment with these therapeutic modalities for PPKP1.5–11 Here, we report a Japanese case of PPKP1 with a novel AAGAB null mutation who showed significant improvement with low-dose etretinate.
CASE REPORT A 54-year-old Japanese woman presented with a four-decade history of numerous small hyperkeratotic lesions on the palms and soles. They had gradually increased in number since the symptoms first emerged in her teenage years. Topical application of 20% urea cream had not been effective for the lesions. She had a previous medical history of hyperthyroidism but was otherwise healthy. The patient had a family history of the disorder, with her daughter also being affected. Physical examination revealed hundreds of asymptomatic punctate hyperkeratotic lesions of up to 5 mm in diameter on the palmoplantar regions (Fig. 1a). On the soles, the lesions mainly affected the weight-bearing areas, coalescing to form larger
Correspondence: Toshifumi Nomura, M.D., Ph.D., Department of Dermatology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. Email: [email protected] *These authors contributed equally to this work. Received 4 February 2015; accepted 20 March 2015.
© 2015 Japanese Dermatological Association
889
T. Nomura et al.
(b)
(a)
(c)
(d)
Figure 1. (a) Numerous punctate keratotic papules on the soles. Note that the papules are coalesced into larger lesions on the heels. (b) Well-demarcated amorphous yellowish-orange areas without dotted vessels are observed under dermoscopy. Each of the areas is surrounded by a whitish halo. (c) Histology of the lesion shows hyperkeratosis, hypergranulosis and mild acanthosis with a well-defined central epidermal depression (hematoxylin–eosin, original magnification 920). (d) Significant decreases in the number of keratotic papules and flattening of them are noted at 12 weeks after the initiation of treatment with oral etretinate (Tigason) at 20 mg/day (0.4 mg/kg per day).
lesions (Fig. 1a). Dermoscopic examination revealed circumscribed structureless yellowish-orange areas each of which was surrounded by a whitish halo (Fig. 1b). The histology of a papule sampled from the left palm showed hypergranulosis, hyperkeratosis and mild acanthosis with a well-defined central epidermal depression (Fig. 1c). Taken together, these led to the clinical diagnosis of PPKP1. Genomic DNA of the patient was obtained from peripheral blood using the QIAamp DNA Blood Maxi Kit (Qiagen, Germantown, MD, USA) and was subjected to AAGAB mutation analysis. The patient gave her written informed consent for mutation analysis in compliance with principles of the Declaration of Helsinki. This study was approved by the medical ethics committee of the Hokkaido University Graduate School of Medicine. The entire coding regions of AAGAB (NM_024666.4) was amplified and sequenced as described previously,1 which led to the identification of a previously unreported frame-shift mutation, c.195_198del4 (Fig. 2), in exon 2 of the gene. The 4-bp deletion gives rise to a premature termination codon (PTC) at 43 amino acids downstream of the mutation (p.Lys66Phefs*43). This mutation was not detected in 50 ethnically matched control individuals. These findings collectively supported the diagnosis of PPKP1. The initial 11-week treatment of topical adapalene gel 0.1% (Differin gel; Galderma, Fort Worth, TX, USA) produced no improvement. After discontinuation of the topical adapalene, oral etretinate (Tigason; Chugai Pharmaceutical, Tokyo, Japan) was administrated at 20 mg/day (0.4 mg/
890
Figure 2. A heterozygous 4-bp deletion mutation in AAGAB is carried by the patient, resulting in c.195_198del4 (p.Lys66Phefs*43) (lower panel). The normal control sequence from exon 2 of the gene, corresponding to codons 184–204, is also shown (upper panel).
kg per day), which dramatically reduced the number of keratotic papules and flattened the papules in the patient by 12 weeks after the initiation of the systemic therapy (Fig. 1d). Overall, the treatment was well tolerated, as the patient reported only mild skin desquamation on the palms and soles.
DISCUSSION Because of the disease’s rarity, there are no evidence-based treatments established for PPKP1. To date, only eight cases with PPKP1 showing successful response to a topical or systemic treatment have been reported (Table 1).5–11 Notably, six
© 2015 Japanese Dermatological Association
Etretinate for punctate palmoplantar keratoderma
Table 1. Summary of punctate palmoplantar keratoderma type 1 cases showing successful response to topical or systemic treatment Age (years)/ sex
Ethnicity
Treatment
Treatment duration for initial control
80/F
Japanese
Etretinate, 30 mg/day
1 month
77/M 41/F 65/F 49/M 46/F 61/F 54/F
Japanese N/A Caucasian N/A N/A German Japanese
Etretinate, 30 mg/day Alitretinoin, 30 mg/day Acitretin, 25 mg/day Acitretin, N/A Chemotherapy Topical tazarotene Etretinate, 20 mg/day
N/A 8 months 2 months 3 months N/A 3 months 7 weeks
AAGGAB mutation c.174del (p.Asn59Ilefs*51) N/A N/A N/A N/A c.481C>T (pArg161*) N/A c.195_198del (p.Lys66Phefs*43)
Reference 5 6 7 8 9 10 11 This study
N/A, not available.
of the cases were successfully treated with systemic acitretin, etretinate or alitretinoin (Table 1).5–9 The treatment duration for initial control of the disease by systemic retinoids varied from 1 to 8 months, and the retinoid doses used for these cases were 20–30 mg/day (Table 1). The therapy was well tolerated by all but one patient, who received 30 mg/day of etretinate and developed diarrhea. In our case, it is of note that oral etretinate even at doses of less than 0.5 mg/kg per day significantly resolved the lesions within 12 weeks. Thus, this study may indicate that short-term oral etretinate has the potential to alleviate the lesions dramatically even at low doses, although further studies are needed to confirm this finding. In contrast, neither topical urea nor adapalene was effective in our patient. Although there is one case report that describes effective treatment with topical tazarotene, a third-generation retinoid, for PPKP1,11 oral etretinate showed superior effectiveness to topical adapalene in our case. Adapalene, a synthetic naphthoic acid derivative with retinoid activity, binds to the nuclear retinoic acid receptors (RAR), and the RAR–adapalene complex inhibits the differentiation of keratinocytes by regulating gene transcription.12 Thus, this third-generation retinoid can reduce hyperkeratosis and is now widely used for the treatment of acne vulgaris, mainly affecting facial skin.12 Marked thickening of the stratum corneum in lesional skin of PPKP1 is expected to reduce the penetration of adapalene into keratinocytes, which may make systemic retinoids superior to topical adapalene in the management of PPKP1. In this study, we also identified a novel frame-shift mutation in AAGAB that yields a PTC and that presumably causes the haploinsufficiency of p34. This study brings the total number of AAGAB mutations to 29, but no genotype–phenotype correlations have been reported in PPKP1.5 Moreover, it still remains unknown whether there are any differences in response to current therapies for PPKP1 according to the type of mutation in AAGAB. Because oral etretinate was also reported to be effective in a patient with PPKP1 who carries the different AAGAB mutation c.174delC,5 it seems that the context of the AAGAB mutation carried by patients does not affect the outcome of etretinate treatment for PPKP1.
© 2015 Japanese Dermatological Association
Moreover, previous studies suggest that aging and environmental factors could play greater roles in determining the disease severity than could the context of the AAGAB mutation.5 Therefore, it may also be important to remove environmental factors that could exacerbate the disease phenotype, such as low-humidity conditions and mechanical friction, in the treatment of PPKP1. Dermoscopic findings of PPKP1 have not been reported to date. In the present case, well-demarcated structureless yellowish-orange areas surrounded by a whitish halo were observed under dermoscopy, whereas dotted vessels, commonly seen in verruca vulgaris, were not noted. Because PPKP1 can clinically mimic verruca vulgaris, dermoscopic observation may be useful for the differential diagnosis of these diseases. In summary, short-term low-dose oral etretinate was effective for the lesions of PPKP1 in our patient. Although further studies are warranted to ascertain the best approach to management of PPKP1 and to translate the discovery of the genetic cause into pathogenesis-based therapies in PPKP1, systemic retinoids seem to be the most promising current treatment for this refractory disease.
ACKNOWLEDGMENTS: We are grateful to the patient for her participation in this study. This work was supported by a Grant-inAid for Young Scientists (B) 25860925 (to T. N.) from the Japan Society for the Promotion of Science. CONFLICT OF INTEREST:
The authors declare that there
are no conflicts of interest.
REFERENCES 1 Pohler E, Mamai O, Hirst J et al. Haploinsufficiency for AAGAB causes clinically heterozygous forms of palmoplantar keratoderma. Nat Genet 2012; 44: 1272–1276. 2 Giehl KA, Eckstein GN, Pasternack SM et al. Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fisher-Brauer. Am J Hum Genet 2012; 91: 754–759.
891
T. Nomura et al.
3 Pohler E, Zamiri M, Harkins CP et al. Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. J Invest Dermatol 2013; 133: 2805–2808. 4 Pohler E, Huber M, Boonen SE et al. New and recurrent AAGAB mutations in punctate palmoplantar keratoderma. Br J Dermatol 2014; 171: 433–436. 5 Nomura T, Yoneta A, Pohler E et al. Punctate palmoplantar keratoderma type 1: a novel AAGAB mutation and efficacy of etretinate. Acta Derm Venereol 2015; 95: 110–111. 6 Horikoshi M, Kuroda K, Tajima S. Punctate palmoplantar keratoderma with pigmentary lesions on the dorsa of feet and ankles: successful treatment with a combination of low-dose oral etretinate and topical calcipotriol. J Dermatol 2004; 31: 469–472. 7 Raone B, Raboni R, Patrizi A. Alitretinoin: a new treatment option for hereditary punctate palmoplantar keratoderma (Brauer-BuschkeFischer syndrome). J Am Acad Dermatol 2014; 71: e48–e49.
892
8 Erkek E, Erdogan S, Tuncez F et al. Type 1 hereditary punctate keratoderma associated with widespread lentigo simplex and successfully treated with low-dose oral acitretin. Arch Dermatol 2006; 142: 1076–1077. 9 Al-Mutairi N, Joshi A, Nour-Eldin O. Punctate palmoplantar keratoderma (Buschke-Fischer-Braurer disease) with psoriasis: a rare association showing excellent response to acitretin. J Drugs Dermatol 2005; 4: 627–634. 10 Kiritsi D, Chmel N, Arnold AW, Jakob T, Bruckner-Tuderman L, Has C. Novel and recurrent AAGAB mutations: clinical variability and molecular consequences. J Invest Dermatol 2013; 133: 2483– 2486. 11 Kong MS, Harford R, O’Neill JT. Keratosis punctata palmoplantaris controlled with topical retinoids: a case report and review of the literature. Cutis 2004; 74: 173–179. 12 Piskin S, Uzunali E. A review of the use of adapalene for the treatment of acne vulgaris. Ther Clin Risk Manag 2007; 3: 621–624.
© 2015 Japanese Dermatological Association
doi: 10.1111/1346-8138.12916
CONCISE COMMUNICATION
Low-dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work Toshifumi NOMURA,1,* Reine MORIUCHI,2,* Masae TAKEDA,1 Shotaro SUZUKI,1 Kazuhiro KIKUCHI,2 Takamasa ITO,2 Hiroshi SHIMIZU,1 Satoko SHIMIZU2 1
Department of Dermatology, Hokkaido University Graduate School of Medicine, 2Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan
ABSTRACT Punctate palmoplantar keratoderma type 1 (PPKP1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss-of-function mutations in AAGAB have recently been reported as a cause of PPKP1. Despite the discovery of the genetic cause of PPKP1, pathogenesis-based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP1. In this study, we analyzed a Japanese woman with PPKP1 and identified a novel frame-shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB. Moreover, low-dose etretinate was effective in improving the PPKP1 lesions in our patient. Our published work review identified only eight cases of PPKP1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP1.
Key words:
AAGAB, adapalene, etretinate, punctate palmoplantar keratoderma type 1, retinoid.
INTRODUCTION Punctate palmoplantar keratoderma type 1 (PPKP1, Online Mendelian Inheritance in Man no. 148600), also known as the Buschke–Fischer–Brauer type, is a rare autosomal dominant form of palmoplantar keratoderma, clinically characterized by multiple punctate hyperkeratotic papules affecting the palmar and plantar skin.1 These circumscribed papules gradually coalesce and increase in number with age, and the patients generally exhibit a chronic intractable course with deteriorated quality of life.1 Histological findings include marked orthokeratotic hyperkeratosis and hypergranulosis associated with a well-defined central epidermal depression.1 Loss-of-function mutations in AAGAB, encoding a- and c-adaptin binding protein p34, have recently been reported as a cause of PPKP1.1,2 The protein is involved in clathrin-mediated vesicle transport, which plays a crucial role in the endocytosis and recycling of receptor tyrosine kinases (RTK) such as epidermal growth factor receptor and Axl.1,3 Therefore, AAGAB null mutations have been speculated to result in the increased half-life of several RTK in basal keratinocytes, leading to hyperproliferative hyperkeratosis on the palmoplantar regions of PPKP1 patients.1,3 To date, 28 mutations have been identified in 54 families with PPKP1.4,5 Despite the discovery of the genetic cause of
PPKP1, however, pathogenesis-based therapies are still unavailable. Instead, current management of the disease is mainly directed toward reduction of hyperkeratosis, using topical keratolytics, topical vitamin D3 and/or topical or systemic retinoids. However, only a very limited number of case reports describe successful treatment with these therapeutic modalities for PPKP1.5–11 Here, we report a Japanese case of PPKP1 with a novel AAGAB null mutation who showed significant improvement with low-dose etretinate.
CASE REPORT A 54-year-old Japanese woman presented with a four-decade history of numerous small hyperkeratotic lesions on the palms and soles. They had gradually increased in number since the symptoms first emerged in her teenage years. Topical application of 20% urea cream had not been effective for the lesions. She had a previous medical history of hyperthyroidism but was otherwise healthy. The patient had a family history of the disorder, with her daughter also being affected. Physical examination revealed hundreds of asymptomatic punctate hyperkeratotic lesions of up to 5 mm in diameter on the palmoplantar regions (Fig. 1a). On the soles, the lesions mainly affected the weight-bearing areas, coalescing to form larger
Correspondence: Toshifumi Nomura, M.D., Ph.D., Department of Dermatology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. Email: [email protected] *These authors contributed equally to this work. Received 4 February 2015; accepted 20 March 2015.
© 2015 Japanese Dermatological Association
889
T. Nomura et al.
(b)
(a)
(c)
(d)
Figure 1. (a) Numerous punctate keratotic papules on the soles. Note that the papules are coalesced into larger lesions on the heels. (b) Well-demarcated amorphous yellowish-orange areas without dotted vessels are observed under dermoscopy. Each of the areas is surrounded by a whitish halo. (c) Histology of the lesion shows hyperkeratosis, hypergranulosis and mild acanthosis with a well-defined central epidermal depression (hematoxylin–eosin, original magnification 920). (d) Significant decreases in the number of keratotic papules and flattening of them are noted at 12 weeks after the initiation of treatment with oral etretinate (Tigason) at 20 mg/day (0.4 mg/kg per day).
lesions (Fig. 1a). Dermoscopic examination revealed circumscribed structureless yellowish-orange areas each of which was surrounded by a whitish halo (Fig. 1b). The histology of a papule sampled from the left palm showed hypergranulosis, hyperkeratosis and mild acanthosis with a well-defined central epidermal depression (Fig. 1c). Taken together, these led to the clinical diagnosis of PPKP1. Genomic DNA of the patient was obtained from peripheral blood using the QIAamp DNA Blood Maxi Kit (Qiagen, Germantown, MD, USA) and was subjected to AAGAB mutation analysis. The patient gave her written informed consent for mutation analysis in compliance with principles of the Declaration of Helsinki. This study was approved by the medical ethics committee of the Hokkaido University Graduate School of Medicine. The entire coding regions of AAGAB (NM_024666.4) was amplified and sequenced as described previously,1 which led to the identification of a previously unreported frame-shift mutation, c.195_198del4 (Fig. 2), in exon 2 of the gene. The 4-bp deletion gives rise to a premature termination codon (PTC) at 43 amino acids downstream of the mutation (p.Lys66Phefs*43). This mutation was not detected in 50 ethnically matched control individuals. These findings collectively supported the diagnosis of PPKP1. The initial 11-week treatment of topical adapalene gel 0.1% (Differin gel; Galderma, Fort Worth, TX, USA) produced no improvement. After discontinuation of the topical adapalene, oral etretinate (Tigason; Chugai Pharmaceutical, Tokyo, Japan) was administrated at 20 mg/day (0.4 mg/
890
Figure 2. A heterozygous 4-bp deletion mutation in AAGAB is carried by the patient, resulting in c.195_198del4 (p.Lys66Phefs*43) (lower panel). The normal control sequence from exon 2 of the gene, corresponding to codons 184–204, is also shown (upper panel).
kg per day), which dramatically reduced the number of keratotic papules and flattened the papules in the patient by 12 weeks after the initiation of the systemic therapy (Fig. 1d). Overall, the treatment was well tolerated, as the patient reported only mild skin desquamation on the palms and soles.
DISCUSSION Because of the disease’s rarity, there are no evidence-based treatments established for PPKP1. To date, only eight cases with PPKP1 showing successful response to a topical or systemic treatment have been reported (Table 1).5–11 Notably, six
© 2015 Japanese Dermatological Association
Etretinate for punctate palmoplantar keratoderma
Table 1. Summary of punctate palmoplantar keratoderma type 1 cases showing successful response to topical or systemic treatment Age (years)/ sex
Ethnicity
Treatment
Treatment duration for initial control
80/F
Japanese
Etretinate, 30 mg/day
1 month
77/M 41/F 65/F 49/M 46/F 61/F 54/F
Japanese N/A Caucasian N/A N/A German Japanese
Etretinate, 30 mg/day Alitretinoin, 30 mg/day Acitretin, 25 mg/day Acitretin, N/A Chemotherapy Topical tazarotene Etretinate, 20 mg/day
N/A 8 months 2 months 3 months N/A 3 months 7 weeks
AAGGAB mutation c.174del (p.Asn59Ilefs*51) N/A N/A N/A N/A c.481C>T (pArg161*) N/A c.195_198del (p.Lys66Phefs*43)
Reference 5 6 7 8 9 10 11 This study
N/A, not available.
of the cases were successfully treated with systemic acitretin, etretinate or alitretinoin (Table 1).5–9 The treatment duration for initial control of the disease by systemic retinoids varied from 1 to 8 months, and the retinoid doses used for these cases were 20–30 mg/day (Table 1). The therapy was well tolerated by all but one patient, who received 30 mg/day of etretinate and developed diarrhea. In our case, it is of note that oral etretinate even at doses of less than 0.5 mg/kg per day significantly resolved the lesions within 12 weeks. Thus, this study may indicate that short-term oral etretinate has the potential to alleviate the lesions dramatically even at low doses, although further studies are needed to confirm this finding. In contrast, neither topical urea nor adapalene was effective in our patient. Although there is one case report that describes effective treatment with topical tazarotene, a third-generation retinoid, for PPKP1,11 oral etretinate showed superior effectiveness to topical adapalene in our case. Adapalene, a synthetic naphthoic acid derivative with retinoid activity, binds to the nuclear retinoic acid receptors (RAR), and the RAR–adapalene complex inhibits the differentiation of keratinocytes by regulating gene transcription.12 Thus, this third-generation retinoid can reduce hyperkeratosis and is now widely used for the treatment of acne vulgaris, mainly affecting facial skin.12 Marked thickening of the stratum corneum in lesional skin of PPKP1 is expected to reduce the penetration of adapalene into keratinocytes, which may make systemic retinoids superior to topical adapalene in the management of PPKP1. In this study, we also identified a novel frame-shift mutation in AAGAB that yields a PTC and that presumably causes the haploinsufficiency of p34. This study brings the total number of AAGAB mutations to 29, but no genotype–phenotype correlations have been reported in PPKP1.5 Moreover, it still remains unknown whether there are any differences in response to current therapies for PPKP1 according to the type of mutation in AAGAB. Because oral etretinate was also reported to be effective in a patient with PPKP1 who carries the different AAGAB mutation c.174delC,5 it seems that the context of the AAGAB mutation carried by patients does not affect the outcome of etretinate treatment for PPKP1.
© 2015 Japanese Dermatological Association
Moreover, previous studies suggest that aging and environmental factors could play greater roles in determining the disease severity than could the context of the AAGAB mutation.5 Therefore, it may also be important to remove environmental factors that could exacerbate the disease phenotype, such as low-humidity conditions and mechanical friction, in the treatment of PPKP1. Dermoscopic findings of PPKP1 have not been reported to date. In the present case, well-demarcated structureless yellowish-orange areas surrounded by a whitish halo were observed under dermoscopy, whereas dotted vessels, commonly seen in verruca vulgaris, were not noted. Because PPKP1 can clinically mimic verruca vulgaris, dermoscopic observation may be useful for the differential diagnosis of these diseases. In summary, short-term low-dose oral etretinate was effective for the lesions of PPKP1 in our patient. Although further studies are warranted to ascertain the best approach to management of PPKP1 and to translate the discovery of the genetic cause into pathogenesis-based therapies in PPKP1, systemic retinoids seem to be the most promising current treatment for this refractory disease.
ACKNOWLEDGMENTS: We are grateful to the patient for her participation in this study. This work was supported by a Grant-inAid for Young Scientists (B) 25860925 (to T. N.) from the Japan Society for the Promotion of Science. CONFLICT OF INTEREST:
The authors declare that there
are no conflicts of interest.
REFERENCES 1 Pohler E, Mamai O, Hirst J et al. Haploinsufficiency for AAGAB causes clinically heterozygous forms of palmoplantar keratoderma. Nat Genet 2012; 44: 1272–1276. 2 Giehl KA, Eckstein GN, Pasternack SM et al. Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fisher-Brauer. Am J Hum Genet 2012; 91: 754–759.
891
T. Nomura et al.
3 Pohler E, Zamiri M, Harkins CP et al. Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. J Invest Dermatol 2013; 133: 2805–2808. 4 Pohler E, Huber M, Boonen SE et al. New and recurrent AAGAB mutations in punctate palmoplantar keratoderma. Br J Dermatol 2014; 171: 433–436. 5 Nomura T, Yoneta A, Pohler E et al. Punctate palmoplantar keratoderma type 1: a novel AAGAB mutation and efficacy of etretinate. Acta Derm Venereol 2015; 95: 110–111. 6 Horikoshi M, Kuroda K, Tajima S. Punctate palmoplantar keratoderma with pigmentary lesions on the dorsa of feet and ankles: successful treatment with a combination of low-dose oral etretinate and topical calcipotriol. J Dermatol 2004; 31: 469–472. 7 Raone B, Raboni R, Patrizi A. Alitretinoin: a new treatment option for hereditary punctate palmoplantar keratoderma (Brauer-BuschkeFischer syndrome). J Am Acad Dermatol 2014; 71: e48–e49.
892
8 Erkek E, Erdogan S, Tuncez F et al. Type 1 hereditary punctate keratoderma associated with widespread lentigo simplex and successfully treated with low-dose oral acitretin. Arch Dermatol 2006; 142: 1076–1077. 9 Al-Mutairi N, Joshi A, Nour-Eldin O. Punctate palmoplantar keratoderma (Buschke-Fischer-Braurer disease) with psoriasis: a rare association showing excellent response to acitretin. J Drugs Dermatol 2005; 4: 627–634. 10 Kiritsi D, Chmel N, Arnold AW, Jakob T, Bruckner-Tuderman L, Has C. Novel and recurrent AAGAB mutations: clinical variability and molecular consequences. J Invest Dermatol 2013; 133: 2483– 2486. 11 Kong MS, Harford R, O’Neill JT. Keratosis punctata palmoplantaris controlled with topical retinoids: a case report and review of the literature. Cutis 2004; 74: 173–179. 12 Piskin S, Uzunali E. A review of the use of adapalene for the treatment of acne vulgaris. Ther Clin Risk Manag 2007; 3: 621–624.
© 2015 Japanese Dermatological Association
