Plantar Pain in Pachyonychia Congenita

Commentaries 11 expression negated acute UVR-induced H3 acetylation and 5 Kim M-K, Shin J-M, Eun HC et al. The role of p300 histone acetyl- MMP1 expression, demonstrating that P300 was required for transferase in UV-induced histone modifications and MMP-1 gene 4 H3 acetylation at the MMP1 promoter.5 In this issue of the transcription. PLOS ONE 2009; :e4864. 6 Ding S, Chen J, Zeng Q et al. Chronic sun exposure is associated BJD, Ding et al.6 find global increases in H3 acetylation, in a with distinct histone acetylation changes in human skin. Br J Dermatol photo-exposed skin site relative to a protected site in middle- 2018; 179:110–17. aged volunteers, including H3 acetylation at the MMP1 promoter and increases in MMP1 and P300 expression. As the exposed-to-protected site differences were not evident in Supporting Information 4 younger volunteers, skin’s acute UVR epigenetic response Additional Supporting Information may be found in the online was therefore shown to become a more permanent feature version of this article at the publisher’s website: over time. Audio S1. Author audio. This work highlights the existence of a mechanism in photodamaged skin that promotes H3 acetylation over deacetylation at the MMP1 promoter, maintaining MMP1 overexpression and contributing to collagen fragmentation. The DNA damage marker c-H2Ax (another histone modifica- Plantar pain in pachyonychia congenita tion) interacts with P300 at the MMP1 promoter,5 suggestive of a direct role for DNA damage in the induction of H3 acety- DOI: 10.1111/bjd.16700 lation. Could unrepaired DNA damage in photodamaged skin be promoting H3 acetylation over deacetylation? H3 acetyla- Linked Article: Brill et al. Br J Dermatol 2018; 179:154–162. tion now offers a route to investigate gene expression perturbations in photodamaged skin and help unravel the mechanisms driving collagen fragmentation. Pachyonychia congenita (PC) is a rare autosomal dominant Altered H3 acetylation was identified at 308 gene promoters disorder classified into five subtypes based on mutations in in older photo-exposed skin by Ding et al.,6 and global H3 keratin genes (KRT6A, KRT6B, KRT6C, KRT16 and KRT17). The acetylation was a more prominent feature of photo-exposed main clinical features include the triad of severe debilitating skin than H4 acetylation and H3K4 or H3K9 methylation. plantar pain, plantar keratoderma and hypertrophic nail dys- However, direct comparisons with other histone modifications trophy as well as oral leukokeratosis, cysts, palmoplantar and DNA methylation are needed before H3 acetylation is hyperhidrosis, palmar calluses and follicular hyperkeratosis. determined as the major epigenetic change in photodamaged The pathogenic mechanisms leading to palmoplantar kerato- skin. In addition, identification of the gene network driving derma in PC are complex. Recent studies have highlighted dys- collagen degradation is required to assess the relative impor- regulated epithelial inflammation and oxidative stress as À/À tance of MMP1 epigenetic changes to collagen fragmentation. important mechanisms. Work on Krt16 mice and PC biop- Nonetheless, acetylation of H3 is likely a conduit for a few sies have shown that genes involved in inflammation and innate hundred gene expression perturbations in photodamaged skin, immunity, in particular danger-associated molecular patterns including the key collagen degradation enzyme MMP1. (DAMPs) and regulators of skin barrier formation, are significantly elevated in diseased skin and show an exaggerated response to mechanical and chemical stimuli.1,2 These Conflicts of Interest responses may be in part triggered by increases in oxidative À/À Dr David Gunn is a Unilever employee. stress observed in mouse paws of K16 mice thought to be linked to impaired activation of nuclear factor erythroid-derived 2 related factor 2 (Nrf2), a master regulator of cellular UNN Unilever R&D, Colworth Science Park, D. A. G 3 Sharnbrook, U.K. responses to oxidative stress. E-mail: [email protected] Plantar pain is the most debilitating clinical feature of PC leading to significant disability and suffering. Patients describe burning, throbbing or sharp, shooting pain sensations. Manage- References ment includes paring of calluses, and comfortable footwear. 1 Kurdistani SK, Tavazoie S, Grunstein M. Mapping global histone Chronic pain pathways are divided into neuropathic pain acetylation patterns to gene expression. Cell 2004; 117:721–33. caused by nerve damage or disease and nociceptive pain stimu- 2 Horvath S. DNA methylation age of human tissues and cell types. lated by tissue damage. About 50% of patients find nonsteroidal Genome Biol 2013; 14:R115. anti-inflammatory drugs help the pain (PC Project, personal 3 Fligiel SE, Varani J, Datta SC et al. Collagen degradation in aged/ communication), suggesting that there is a nociceptive compo- photodamaged skin in vivo and after exposure to matrix metallopro- nent. The first study to characterize PC pain used pain question- teinase-1 in vitro. J Invest Dermatol 2003; 120:842–8. 4 Kim M-K, Lee DH, Lee S et al. UV-induced DNA damage and his- naires and quantitative sensory testing in 35 patients and tone modification may involve MMP-1 gene transcription in human concluded that the majority of patients with PC experience pain 4 skin in vivo. J Dermatol Sci 2014; 73:169–71. that has a neuropathic component. In this issue of the BJD,

Silviu Brill and colleagues from the Tel Aviv Medical Centre pre- References sent the results of a second, larger study using pain question- ~ naires and sensory testing in 62 patients with mutations in 1 Lessard JC, Pina-Paz S, Rotty JD et al. Keratin 16 regulates innate immunity in response to epidermal barrier breach. Proc Natl Acad Sci KRT6A or KRT16 compared with 45 controls.5 The authors found USA2013; 110:19537–42. an association between PC and moderate-to-severe chronic 2 Cao YA, Hickerson RP, Seegmiller BL et al. Gene expression profiling pain, thermal and mechanical hypoaesthesia and mechanical in pachyonychia congenita skin. J Dermatol Sci 2015; 77:156–65. hyperalgesia, as well as reduced conditioned pain modulation, 3 Kerns ML, Hakim J, Lu RG et al. Oxidative stress and dysfunctional all further supporting the notion that the chronic pain experi- NRF2 underlie pachyonychia congenita phenotypes. J Clin Invest enced by patients with PC is at least in part of neuropathic ori- 2016; 126:2356–66. gin. The extent and mechanisms leading to nerve damage is 4 Wallis T, Poole CD, Hoggard B. Can skin disease cause neuropathic pain? A study in pachyonychia congenita. Clin Exp Dermatol unclear, although it may be postulated that activation of DAMPs 2016; 41:26–33. and the resulting inflammatory response as well as oxidative 5 Brill S, Sprecher E, Smith FJD et al. Chronic pain in pachyonychia stress may be driving forces. Furthermore, evidence for altered congenita: evidence for neuropathic origin. Br J Dermatol 2018; 6 sensory innervation in patients with PC exists. Histological 179:154–62. characterization of cutaneous innervation in affected and unaf- 6 Pan B, Byrnes K, Schwartz M et al. Peripheral neuropathic fected plantar skin from patients with PC and control subjects changes in pachyonychia congenita. Pain 2016; 157:2843–58. found significantly reduced sweat gland innervation, a reduced 7 Zhao Y, Gartner U, Smith FJ, McLean WH. Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachy- number of Meissner corpuscles and increased Merkel cell den- onychia congenita. J Invest Dermatol 2011; 131:1045–52. sity and blood vessel numbers in affected skin. 8 Leachman SA, Hickerson RP, Schwartz ME et al. First-in-human Together, these studies provide evidence that mechanisms mutation-targeted siRNA phase Ib trial of an inherited skin disor- leading to pain in PC extend beyond keratinocyte function der. Mol Ther 2010; 18:442–6. and involve alterations in sensory innervation and neuropathic 9 Hickerson RP, Leake D, Pho LN et al. Rapamycin selectively inhibits pathways. Novel treatment strategies to date have focused on expression of an inducible keratin (K6a) in human keratinocytes and reducing expression of KRT6A using simvastatin, mutant-target- improves symptoms in pachyonychia congenita patients. J Dermatol Sci 2009; 56:82–8. ing short interfering RNA and sirolimus, a mammalian target 10 Swartling C, Vahlquist A. Treatment of pachyonychia congenita with of rapamycin (mTOR) inhibitor that selectively blocks transla- plantar injections of botulinum toxin. Br J Dermatol 2006; 154:763–5. 7–9 tion of KRT6 mRNA. Data presented by Brill and colleagues 11 Tateda S, Kanno H, Ozawa H et al. Rapamycin suppresses micro- further support the notion that additional treatment strategies glial activation and reduces the development of neuropathic pain aimed at reducing neuropathic pain should be trialled. Botuli- after spinal cord injury. J Orthop Res 2017; 35:93–103. num toxin injection, which requires regional anaesthesia, has a significant effect on PC pain.10 Sirolimus may also have a direct effect on damaged nerves.11 Dermatologists caring for patients with PC should consider treating both the neuropathic Dermoscopy and confocal microscopy: and nociceptive components of PC pain. Referral to a pain come together, right now? specialist should also be considered. DOI: 10.1111/bjd.16699 Conflicts of interest Linked Article: Borsari et al. Br J Dermatol 2018; 179:163–172. E.O.T. is a consultant to Palvella Therapeutics, a company that is developing topical sirolimus as a treatment for pachyony- It is often stated that the earlier the diagnosis of melanoma, chia congenita (fees go to university). the better the prognosis. This is well illustrated by melanoma restricted to the epidermis (melanoma in situ, MIS), in which Acknowledgment case there is no risk of recurrence after excision. The significant advances in diagnostics achieved by dermoscopy and Thank you to Roger Kaspar who gave feedback on the com- newer imaging techniques, such as reflectance confocal micro- mentary. scopy (RCM), now make it possible to detect melanoma even before it has become invasive. Dermoscopy and RCM criteria Centre for Cell Biology and Cutaneous M.A. KRUPICZOJC for melanoma diagnosis have now been established through Research, Blizard Institute, Barts and the E.A. O’TOOLE iD numerous studies. However, most of these studies included London School of Medicine and Dentistry, invasive melanomas, with histopathological alterations occur- Queen Mary University of London, London ring in the dermis not expected to be found in MIS. As a E1 2AT, U.K. result, some of the criteria established previously for invasive Correspondence: E.A. O’Toole. melanoma could not be used for MIS, and a specific diagnostic E-mail: [email protected] dermoscopic or RCM study on MIS was lacking.