Importance Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3 (TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation. Objective To examine the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3 mutations. Design, Setting, and Participants In this case series, 3 patients from 2 unrelated families who had TRPV3-mutation-associated PPK were treated with erlotinib from May 5, 2018, through May 13, 2019. Main Outcomes and Measures Clinical follow-up included evaluation of PPK progression, pain and interventions for pain, as well as erlotinib dose adjustment based on treatment effect, plasma levels, and tolerance. Results The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies. Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis. All patients experienced depression and did not engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared. All patients were able to touch the ground with their feet, wear shoes, and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the patients resumed social activities. These improvements were sustained across 12 months of treatment and follow-up. The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted. Conclusions and Relevance The findings of this study report improvement of PPK in patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib. Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention.

中文翻译：

---

使用表皮生长因子受体抑制剂厄洛替尼治疗由TRPV3突变引起的Olmsted综合征患者的足plant角化病。

重要性Olmsted综合征是一种遗传性皮肤病，其特征是从婴儿期开始发展而缺乏有效的治疗方法，其手掌部的掌性角膜疼痛（PPK）令人痛苦和残缺。它最常见是由瞬时受体电位香草酸3（TRPV3）基因突变引起的。在动物模型和角质形成细胞系中，TRPV3信号传导导致表皮生长因子受体（EGFR）反式激活。目的探讨用盐酸厄洛替尼抑制剂阻断EGFR反式激活治疗TRMV3突变引起的Olmsted综合征患者的PPK的可能性。设计，设置和参加者在此病例系列中，从2018年5月5日至2019年5月13日，使用厄洛替尼治疗来自2个无关家庭的3例TRPV3突变相关PPK的患者。主要结果和措施临床随访包括评估PPK进展，疼痛和疼痛干预措施，以及根据治疗效果，血浆水平和耐受性调整厄洛替尼剂量。结果3例患者（2例年龄分别为15和17岁的兄弟和一个13岁的女孩）患有严重的掌plant角化过度，无法忍受的红斑性肌痛，严重的生长迟缓，食欲不振和失眠，自婴儿期起尽管采取了多种治疗方法，但病情一直在恶化。由于过度角化，由于剧烈疼痛和关节受限，两名患者被限制在轮椅上。所有患者都患有抑郁症，没有参加社交活动。在开始使用厄洛替尼治疗的3个月内，角化过度和疼痛消失。所有患者都可以用脚触摸地面，穿鞋并行走。厌食症和失眠症得以缓解，并伴有生长的改善。此外，患者恢复了社交活动。这些改善在12个月的治疗和随访中得以维持。厄洛替尼的剂量低于肿瘤学中使用的剂量，并且仅注意到轻度至中度的不良反应。结论与相关性这项研究的结果报告了厄洛替尼治疗TRPV3突变引起的Olmsted综合征患者的PPK改善。厄洛替尼疗法靶向EGFR反式激活可能会导致缺乏有效干预的孤儿疾病的临床缓解。厄洛替尼的使用剂量低于肿瘤学中使用的剂量，并且仅注意到轻度至中度的不良反应。结论与相关性这项研究的结果报告了厄洛替尼治疗TRPV3突变引起的Olmsted综合征患者的PPK改善。厄洛替尼疗法靶向EGFR反式激活可能会导致缺乏有效干预的孤儿疾病的临床缓解。厄洛替尼的使用剂量低于肿瘤学中使用的剂量，并且仅注意到轻度至中度的不良反应。结论与相关性这项研究的结果报告了厄洛替尼治疗TRPV3突变引起的Olmsted综合征患者的PPK改善。厄洛替尼疗法靶向EGFR反式激活可能会导致缺乏有效干预的孤儿疾病的临床缓解。