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Akiyama, Masashi

Kojima, Daiei

Kono, Michihiro

Okuno, Yusuke

Suga, Yasushi

Takeichi, Takuya

Tsukamoto, Katsuhiko

Journal of Dermatological Science

English

Nagoya Repository

1 Takeichi et al. Journal of Dermatological Science Manuscript No. JDS-2016-203-R1 Revised Version Letter to the Editor  A combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment for hyperkeratosis and itching in Olmsted syndrome associated with a TRPV3 mutation  Takuya Takeichi1,*, Katsuhiko Tsukamoto2, Yusuke Okuno3,4, Daiei Kojima4, Michihiro Kono1, Yasushi Suga5 and Masashi Akiyama1,*  1Department of Dermatology, 4Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; 2Department of Dermatology, Yamanashi Prefectural Central Hospital, Kofu, Japan; 3Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan; 5Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan  *Correspondence: Takuya Takeichi, Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Telephone: 81-52-744-2314 E-mail: takeichi@med.nagoya-u.ac.jp Masashi Akiyama E-mail: makiyama@med.nagoya-u.ac.jp  2 Takeichi et al. Funding statement: None The authors have no conflicts of interest to declare.  Running title: Combination therapy for OS from TRPV3 mutation Abbreviations: OS, Olmsted syndrome KEY WORDS: Olmsted syndrome, TRPV3 Word count: 999/1000 words in the main text, 10/10 references, 2 figures   3 Takeichi et al. To the Editor: Most cases of Olmsted syndrome (OS, OMIM#614594) are inherited in autosomal dominantly, although autosomal recessive and X-linked cases have been reported [1]. Pathogenic mutations in TRPV3 cause the dominant and recessive subtypes of OS, and those in MBTPS2 lead to the X-linked form of OS [2]. Clinically, there are 2 major skin manifestations of OS: symmetrical keratoderma on the palms and soles, and symmetrical hyperkeratotic plaques around bodily orifices. Several additional cutaneous manifestations have been reported: constriction bands on the fingers and toes (pseudoainhum), diffuse alopecia, skin infections, onychodystrophy and increased risk of squamous cell carcinoma [1, 3]. TRPV3 encodes a transient receptor potential (TRP) vanilloid cation channel that is primarily expressed in the skin, hair follicles, brain and spinal cord. Mutant TRPV3 may function dominant-positively to increase the constitutive TRPV3 activity and elevate Ca2+ in keratinocytes, leading to severe keratoderma and intolerant itching sensation [4]. TRPV3 is a Ca2+ entry pathway tightly associated with the TGF-α/EGFR signaling complex orchestrating keratinocyte terminal differentiation [4]. There are no specific or satisfactory treatments for OS. Specific treatments for pain and itching are essential to reduce the morbidity of the disease [5, 6]. Here, we report a pedigree of OS in which severe itching and hyperkeratosis were effectively controlled by a topical ointment of calcipotriol/betamethasone dipropionate with low-dose systemic retinoids. A 39-year-old male presented with partial hyperkeratosis in both soles from his infancy. Clinical examination revealed mild hypotrichosis with some thinning of the hair (Fig. 1A). Light microscopy of cut and plucked hairs did not reveal any gross abnormalities. Focal palmar hyperkeratosis was seen along the friction-prone sites of his 4 Takeichi et al. dominant right hand. His palms showed slight hyperhidrosis. Plantar hyperkeratosis was observed on the big toes and on the edges of the soles (Fig. 1B). Histologically, marked hyperkeratosis without granular degeneration was seen (Fig. 1D). He was treated with a low-dose etretinate (10 mg/day) in combination with a topical calcipotriol/betamethasone dipropionate ointment, leading to sufficient control without adverse effects. To reduce a risk of adverse effects of etretinate treatments including liver dysfunction, conjunctivitis, cheilitis, and hair loss, the patient chose the low-dose etretinate treatment. After 4 months of treatment, his plantar skin became smoother and greatly improved (Fig. 1C). In contrast to the proband, his 5-year-old daughter had a history of hyperkeratosis from 1 month of age. Examinations showed slight hypotrichosis with thin, curly hair (Fig. 1E). We found scaly hyperkeratosis with peripherally inflamed erythema on the palms, and severe diffuse hyperkeratosis on the soles (Fig. 1F and H). All fingers showed moderate contracture, and X-ray of the right hand revealed increased permeability in the distal phalanx (Fig. 1I). Her palms and soles exhibited moderate hyperhidrosis. Notably, she had severe itching on the erythematous lesions of the palms and soles. We used moderate dose of systemic etretinate (10 mg/day), leading to mild improvement of her eruptions (Fig. 1G). Following informed consent and ethical approval, and with all research conforming to the Declaration of Helsinki principles, genomic DNA from the father was subjected to whole-exome sequencing analysis. Whole-exome sequencing revealed a previously reported heterozygous missense mutation in TRPV3 (c.2017C>T; p.Leu673Phe), which was detected by Sanger sequencing in the affected daughter. The mutation was not present in DNA from the unaffected mother, nor in 777 ethnically 5 Takeichi et al. matched control chromosomes (data not shown). TRPV3 channel contains six transmembrane domains with an intramembrane region between the fifth (S5) and sixth (S6) segments, and both C and N terminus are intracellularly located (Figure 2). The mutation p.Leu673Phe in TRPV3 here has been reported previously as a pathogenic substitution in an individual with OS [7]. In addition, a missense mutation of the adjacent methionine residue, p.Met672IIe, has been reported [8]. They are not located in TRP box of the TRP domain of TRPV3, but are highly conserved amino acids among diverse species [7]. Thus far, no strong correlation has been observed between a specific mutation in TRPV3 and the severity of OS. There were differences in the phenotype between our pedigree and the other p.Leu673Phe case with regard to the presence or absence of erythromelalgia. The clinical features across all cases of OS, including those with the same TRPV3 pathology, show some variation, for example, in terms of periorificial keratoderma, leucoplakia, diffuse alopecia and pseudoainhum. In the present pedigree, there was intrafamilial phenotypic heterogeneity with respect to the severity and distribution of eruptions in two affected individuals. We hypothesized that mutations in other genes or environmental factors might have affected their phenotypes through modifier effects. Our pedigree had severe itching on the palms and the soles, especially on the erythematous lesions. TRPV3 is known to play essential roles in skin keratinization, hair growth and possibly itching sensation in humans [4]. Topical treatments including emollients, keratolytics, wet dressings, boric acid, tar, retinoic acid, shale oil and corticosteroids are attempted, producing poor to moderate improvement [5]. In several OS patients, systemic retinoids, corticosteroid or methotrexate were used, producing poor to moderate relief [4]. 6 Takeichi et al. Our cases were significantly improved by the topical calcipotriol/betamethasone dipropionate and low-dose systemic retinoids. This has two important clinical implications: It suggests that topical calcipotriol/betamethasone dipropionate is a potentially useful treatment for OS and that combination therapy of topical calcipotriol/betamethasone dipropionate and low-dose systemic retinoids is a promising treatment for OS. Oral retinoids have been described as efficient therapeutic agents for severe ichthyotic disorders; however, we sometimes hesitate to use systemic retinoid treatments because they have several adverse effects. Topical calcipotriol/betamethasone dipropionate is an effective treatment for psoriasis vulgaris [9]. Akasaka et al. reported that efficient oral etretinate and local injection of bleomycin as therapeutic options for punctate palmoplantar keratoderma type 1 [10]. In the present case, a combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment was effective for skin lesions of OS caused by TRPV3 mutation. Although it is difficult to evaluate its efficacy from only the present case, our finding suggests this combination therapy might be a useful and powerful tool for controlling severe itching and improving quality of life for OS patients.  Acknowledgments This study was supported by JSPS KAKENHI Grants Numbers 15H04887, 15K15415, 15H06280, 16K19717. The work was also supported by the Japan Intractable Diseases Research Foundation. The authors acknowledge the Human Genome Center, Institute of Medical Science, the University of Tokyo (http://sc.hgc.jp/shirokane.html) for providing super-computing resources. 7 Takeichi et al.    8 Takeichi et al. Figure legends Figure 1. Various clinical features are seen in the present family with autosomal dominant Olmsted syndrome. (A) The father has mild hypotrichosis and thinning of hair on the scalp. (B) He shows diffuse hyperkeratosis on the plantar aspect of the big toe (before treatment). (C) After combination treatment, the hyperkeratosis is improved and thick scales are not seen on the big toe. (D) A skin biopsy sample from the right sole shows marked hyperkeratosis without granular degeneration. Scale bar: 100 μm. (E) His daughter has slight hypotrichosis with thin, curly hair. (F) Her palms show scaly hyperkeratotic plaques with erythema on their edges (before treatment). (G) After moderate dose of etretinate treatment, her palmar hyperkeratosis is improved mildly. (H) Her soles show diffuse, severe hyperkeratosis. (I) An X-ray image of her right hand shows increased permeability in the distal phalanx.  Figure 2. Schematic of the TRPV3 domain structure. The yellow areas mark the transmembrane segments (from S1 to S6). The intramembrane region (green area), the transient receptor potential domain (TRP) and the ankyrin repeat domain (ARD) are indicated. The present mutation is marked by a red arrow. The black numbers indicate the numbering of the amino acids in the TRPV3 amino acid sequence.   9 Takeichi et al. References [1] Wilson NJ, Cole C, Milstone LM, Kiszewski AE, Hansen CD, O'Toole EA, et al. Expanding the Phenotypic Spectrum of Olmsted Syndrome. J Invest Dermatol 135:2879-2883,2015. [2] Haghighi A, Scott CA, Poon DS, Yaghoobi R, Saleh-Gohari N, Plagnol V, et al. A missense mutation in the MBTPS2 gene underlies the X-linked form of Olmsted syndrome. J Invest Dermatol 133:571-573,2013. [3] Agarwala MK, George R, Pramanik R, McGrath JA. Olmsted syndrome in an Indian male with a new de novo mutation in TRPV3. Br J Dermatol 174:209-211,2016. [4] Lin Z, Chen Q, Lee M, Cao X, Zhang J, Ma D, et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet 90:558-564,2012. [5] Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet J Rare Dis; 10:33,2015. [6] Zhi YP, Liu J, Han JW, Huang YP, Gao ZQ, Yang Y, et al. Two familial cases of Olmsted-like syndrome with a G573V mutation of the TRPV3 gene. Clin Exp Dermatol 41:510-513,2016. [7] Duchatelet S, Guibbal L, de Veer S, Fraitag S, Nitschké P, Zarhrate M, et al. Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations. Br J Dermatol 171:675-678,2014. [8] Ni C, Yan M, Zhang J, Cheng R, Liang J, Deng D, et al. A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome. Sci Rep 6:21815,2016. [9] Lovato P, Norsgaard H, Tokura Y, Røpke MA. Calcipotriol and betamethasone dipropionate exert additive inhibitory effects on the cytokine expression of inflammatory dendritic cell-Th17 cell axis in psoriasis. J Dermatol Sci 81:153-164,2016. [10] Akasaka E, Okawa Y, Nakano H, Takiyoshi N, Rokunohe D, Toyomaki Y, et al. Two Japanese familial cases of punctate palmoplantar keratoderma caused by a novel AAGAB mutation, 10 Takeichi et al. c.191_194delCAAA. J Dermatol Sci 78:156-158,2015. 

A combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment for hyperkeratosis and itching in Olmsted syndrome associated with a TRPV3 mutation

A combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment for hyperkeratosis and itching in Olmsted syndrome associated with a TRPV3 mutation

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