sirolimus and Pachyonychia-Congenita

Pachyonychia congenital (PC) is a rare genetic disorder of cornification and is classified into five types on the basis of keratin gene involved. There are no established treatment options available for PC. Sirolimus in both topical and oral form has been studied in management of PC. We report a young female with a novel genetic mutation in KRT6A gene who presented with painful palmoplantar hyperkeratosis and onychogryphosis, which was cosmetically disfiguring. She was prescribed oral sirolimus after all investigations. There was significant improvement in pain within a week. Pain relief was sustained at 1 year follow-up with topical treatment only. Serial nail avulsion surgeries were also done with showed significant cosmetic improvement in the nails. Medical therapies can be combined with surgery for a better cosmetic outcome and improvement in patient quality of life.

Topics: Administration, Topical; Combined Modality Therapy; Female; Genetic Predisposition to Disease; Humans; Keratin-6; Mutation; Nails; Nicotinic Acids; Pachyonychia Congenita; Rare Diseases; Salicylic Acid; Sirolimus; Treatment Outcome; Young Adult

Topics: Administration, Cutaneous; Antibiotics, Antineoplastic; Female; Humans; Keratoderma, Palmoplantar; Middle Aged; Pachyonychia Congenita; Pain; Sirolimus

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.

Topics: Administration, Cutaneous; Capsaicin; Congresses as Topic; Dermatologic Agents; Humans; Mutation; Off-Label Use; Pachyonychia Congenita; Sirolimus

The macrolide sirolimus (rapamycin) selectively blocks translation of mRNAs containing a terminal 5' oligopyrimidine (TOP) tract by altering the activity of mammalian target of rapamycin (mTOR) and inhibiting downstream mTOR pathway components involved in TOP mRNA translation. The skin disorder pachyonychia congenita (PC) is caused by mutations in the inducible keratins (K) including K6a, K6b, K16 and K17. Published sequence data suggest the 5' untranslated regions of K6a and K6b mRNAs contain 5' TOP motifs and therefore may be sensitive to rapamycin treatment.. Determine if mTOR inhibitors (rapamycin, temsirolimus or everolimus) are viable drug candidates for treatment of PC and other disorders caused by inappropriate expression of K6a and K6b.. 5' RACE analysis was used to map the transcriptional start sites for K5, K6a, K6b, K14, K16 and K17. The sensitivity of these keratins to mTOR inhibitors was determined by Western and qPCR analysis following treatment of a human HaCaT keratinocyte cell line with rapamycin, temsirolimus or everolimus. A small off-label study was undertaken using orally administered rapamycin in three PC patients and the effects were monitored by clinical examination, photography, a validated Dermatology Life Quality Index (DLQI) and a pain and activity diary.. Sequence comparison and 5' RACE analysis of the 5' untranslated regions of K6a and K6b revealed putative TOP regulatory elements. Treatment of a human HaCaT keratinocyte cell line with mTOR inhibitors (rapamycin, temsirolimus or everolimus) resulted in selective K6a repression. Furthermore, treatment of this HaCaT cell line with siRNAs targeting components of the mTOR pathway altered the levels of K6a expression. To test the ability of rapamycin to ameliorate PC symptoms, an off-label study was conducted. PC patient clinical responses to oral rapamycin showed a therapeutic response in callus character as well as subjective improvement. Of particular note, rapamycin greatly reduced the presence of painful cutaneous thromboses after reaching therapeutic serum levels. The well-known rapamycin side effects led to the early withdrawal of all of the patients from the study.. Rapamycin selectively blocks K6a expression in human keratinocytes. The improvement of symptoms in PC patients following rapamycin treatment suggests rapamycin (or rapamycin analogs) may be a therapeutic option, particularly if topical formulations can be developed that avoid the side effects associated with systemic administration.

Topics: 5' Untranslated Regions; Administration, Oral; Base Sequence; Cell Line; Dose-Response Relationship, Drug; Everolimus; Female; Gene Expression Regulation; Humans; Keratin-6; Keratinocytes; Molecular Sequence Data; Pachyonychia Congenita; Pain; Pain Measurement; Protein Kinases; Quality of Life; RNA 5' Terminal Oligopyrimidine Sequence; RNA Interference; RNA, Messenger; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Transcription Initiation Site; Transcription, Genetic; Treatment Outcome