Mutations in keratin genes cause a diverse spectrum of skin, hair and mucosal disorders. Cutaneous disorders include epidermolysis bullosa simplex, palmoplantar keratoderma, epidermolytic ichthyosis and pachyonychia congenita. Both clinical and laboratory observations confirm a major role for keratins in maintaining epidermal cell–cell adhesion. When normal tissue homeostasis is disturbed, for example, during wound healing and cancer, keratins play an important non-mechanical role. Post-translational modifications including glycosylation and phosphorylation of keratins play an important role in protection of epithelial cells from injury. Keratins also play a role in modulation of the immune response. A current focus in the area of keratins and disease is the development of new treatments including small inhibitory RNA (siRNA) to mutant keratins and small molecules to modulate keratin expression.

Keratins and skin disease.

This chapter reviews the embryology and development, anatomy and cell biology, physiology, biochemistry, biophysics, and pharmacology of the nail unit.

Structure and Function of the Nail Unit

Proteomic profiling reveals candidate markers for arsenic-induced skin keratosis.

Pachyonychia congenita (PC) is an autosomal dominant skin disorder caused by heterozygous mutations of the keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Patients typically present with dystrophic nails, leucokeratoses, cysts and painful palmoplantar keratoderma that can be both debilitating and disfiguring. Painful keratoderma is a common clinical presentation in patients with PC, especially in those with KRT6A and KRT16 mutations. Affected individuals often have difficulty ambulating, and require systemic pain medications. To date, there is no Food and Drug Administration (FDA)-approved treatment for PC. A number of topical and systemic treatments have previously been evaluated for painful plantar keratoderma, but none has been found to be efficacious. Frequently used management for plantar keratoderma in patients with PC includes regular grooming such as paring/trimming, as well as topical application of products containing salicylic acid, lactic acid or urea. Off-label use of botulinum toxin and topical and systemic retinoids has been tried without success. Consequently, PC is a disease with unmet medical needs, and a targeted therapy is needed for the treatment of painful plantar keratoderma. We report two patients treated with topical sirolimus cream with rapid improvement of pain and ability to ambulate. Two unrelated white middle-aged women both presented with painful plantar keratoderma and dystrophic nails. Both patients had mild hyperlipidaemia and hypertension, but were otherwise healthy. Both patients carried a mutation in the KRT6A protein; Patient 1 had the mutation p.Glu472Lys and Patient 2 had p.Phe174Ser. Despite taking prescribed analgesia regularly, the patients were able to manage only seated office jobs because of severe foot pain. Patient 1 had difficulty ambulating for > 5 min without assistance and was nearly wheelchair-bound. Their condition had failed to respond to multiple topical treatments containing salicylic acid and lactic acid. Based on recent studies, we decided to start topical sirolimus treatment. To avoid systemic toxicities, we compounded 1% sirolimus ointment for both of our patients to be used twice daily on both feet (Fig. 1). The patients used an average of 2.5–4.5 mg sirolimus daily for about 4 months, and kept a daily diary to document the severity of pain upon standing or walking, their level of physical activity and their use of pain medications. Patient 2 had notable improvement of symptoms and thinning of the keratoderma on both feet within 2 weeks. The overall severity of pain reduced rapidly within 4 weeks of initiating treatment (Fig. 2). Patient 2 also noted similar results. Both patients were able to ambulate much better without support, although increased pain was reported with increased daily activities, especially on the preferred weight-bearing side. Because of the reduced keratoderma, they also required fewer podiatry sessions. Two months after treatment initiation, the thickness and size of the callus was markedly reduced (Fig. 1b). Laboratory studies, including complete blood cell counts, metabolic panels, lipid profiles and serum sirolimus level were obtained at each clinic visit for three consecutive months, with no systemic exposure or toxicities detected. The clinical response was consistent during the 4 months of treatment. Patient 2 reported that her symptoms started to worsen approximately 2 weeks after the treatment was discontinued. Our preliminary results suggest that topical sirolimus could be a safe and effective treatment for painful keratoderma in PC. Sirolimus, or rapamycin, is a mammalian target of rapamycin (mTOR) inhibitor. As an immunosuppressant, Correspondence: Dr Joyce M. Teng, Clinical Professor of Dermatology and Pediatrics, Stanford University School of Medicine, 700 Welch Road, Suite 301 G, CA 94304, USA E-mail: jteng3@stanford.edu

Novel treatment of painful plantar keratoderma in pachyonychia congenita using topical sirolimus.

Summary

This is a report of the research presented at the 11th Annual Meeting of the International Pachyonychia Congenita Consortium, held on 6 May 2014 in Albuquerque, NM, U.S.A. This year's meeting was divided into five corners concerning pachyonychia congenita (PC) research: (i) ‘PC Pathogenesis Cornered’, an overview of recent keratin research, for PC and other skin disorders; (ii) ‘From All Corners of …’, an outline of other genetic disorders that we can learn from; (iii) ‘Fighting For Our Corner’, an outline of National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases programmes and U.S. funding opportunities applicable to rare skin disorders; (iv) ‘The PC Corner’, focusing on recent clinical studies related to PC; and (v) ‘Clinical Corners: Turning the Corner?’, an update on ongoing PC clinical trials.

/pdf/pachyonychia-congenita-cornered-report-on-the-11th-annual-30ptbxq3gu.pdf

Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting

Background
Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17.

/pdf/the-molecular-genetic-analysis-of-the-expanding-pachyonychia-b38vx5zg1z.pdf

The molecular genetic analysis of the expanding pachyonychia congenita case collection

Allergic Bronchopulmonary Aspergillosis in Identical Twins: Effectiveness of Dupilumab.

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The molecular genetic analysis of the expanding pachyonychia congenita case collection

Allergic Bronchopulmonary Aspergillosis in Identical Twins: Effectiveness of Dupilumab.