The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Frances J D Smith - One of the best experts on this subject based on the ideXlab platform.
-
revisiting Pachyonychia congenita a case cohort study of 815 patients
British Journal of Dermatology, 2020Co-Authors: Liat Samuelov, Frances J D Smith, Eli Sprecher, Charles HansenAbstract:BACKGROUND Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. OBJECTIVES To harness the same resource to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. METHODS In total, 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry were surveyed for clinical findings associated with PC. Data were analysed using various statistical methods, including the Student's t-test, χ2 -test and anova tests for differences in means/proportions. Spearman correlation and logistic regression were used for phenotype-genotype correlations. RESULTS KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids. KRT17 mutations were most commonly associated with cysts and natal teeth. Using logistic regression, we found that oral leucokeratosis was correlated with earlier toenail involvement, walking aids, nursing difficulties and hoarseness. Cysts were correlated with oral leucokeratosis, natal teeth and ear wax. Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation. Hoarseness was correlated with an increased number of involved fingernails. CONCLUSIONS Here, we establish phenotype-genotype correlations in the largest cohort of patients with PC described to date and reveal novel and clinically useful predictors of disease course and manifestations. What's already known about this topic? Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. The establishment of an international registry containing the clinical and molecular data of patients with PC led to the development of a disease classification based on the mutant gene and associated features. What does this study add? Data were collected via an international registry to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. This is the largest cohort of patients with PC described to date. The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years. Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function. Linked Editorial: Steele and O'Toole. Br J Dermatol 2020; 182:521-522. Linked Comment: Mordaunt. Br J Dermatol 2020; 182:537.
-
Management of Plantar Keratodermas Lessons from Pachyonychia Congenita
Journal of the American Podiatric Medical Association, 2017Co-Authors: Rebecca M. Porter, Albert A. Bravo, Frances J D SmithAbstract:Plantar keratodermas can arise due to a variety of genetically inherited mutations. The need to distinguish between different plantar keratoderma disorders is becoming increasingly apparent because there is evidence that they do not respond identically to treatment. Diagnosis can be aided by observation of other clinical manifestations, such as palmar keratoderma, more widespread hyperkeratosis of the epidermis, hair and nail dystrophies, or erythroderma. However, there are frequent cases of plantar keratoderma that occur in isolation. This review focuses on the rare autosomal dominant keratin disorder Pachyonychia congenita, which presents with particularly painful plantar keratoderma for which there is no specific treatment. Typically, patients regularly trim/pare/file/grind their calluses and file/grind/clip their nails. Topical agents, including keratolytics (eg, salicylic acid, urea) and moisturizers, can provide limited benefit by softening the skin. For some patients, retinoids help to thin calluses but may lead to increased pain. This finding has stimulated a drive for alternative treatment options, from gene therapy to alternative nongenetic methods that focus on novel findings regarding the pathogenesis of Pachyonychia congenita and the function of the underlying genes.
-
Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium.
The British journal of dermatology, 2017Co-Authors: Laure Rittié, Eli Sprecher, Roger L. Kaspar, Frances J D SmithAbstract:The International Pachyonychia Congenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for Pachyonychia congenita, a rare autosomal dominant skin disorder. The research presented at the 13th Annual Research Symposium of the IPCC, held on 10-11 May 2016, in Scottsdale, AZ, U.S.A., is reported here.
-
Keratin 17 Mutations in Four Families from India with Pachyonychia Congenita.
Indian journal of dermatology, 2017Co-Authors: Manoj Kumar Agarwala, Neil J Wilson, Mary E Schwartz, Pankaj Salphale, Dincy Peter, Susanne Pulimood, Frances J D SmithAbstract:Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The main features are palmoplantar keratoderma, plantar pain, and nail dystrophy. Cysts of various types, follicular hyperkeratosis, oral leukokeratosis, hyperhidrosis, and natal teeth may also be present. Four unrelated Indian families presented with a clinical diagnosis of PC. This was confirmed by genetic testing; mutations in KRT17 were identified in all affected individuals.
-
first case of Pachyonychia congenita in the czech republic
Dermatologic Therapy, 2015Co-Authors: Anna Jirakova, Frances J D Smith, Mary E Schwartz, Lucie Rajska, Filip Rob, Martina Džambova, Zuzana Secnikova, Dana Gopfertova, Torello Lotti, Jana HercogovaAbstract:Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by hypertrophic nail dystrophy, oral leukokeratosis, and painful palmoplantar keratoderma. It is associated with a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The International PC Research Registry (IPCRR) confirms that as of January 2014 there have been 547 cases of PC genetically confirmed. It is estimated that there are between 2000 and 10,000 cases of PC in the world. However, the exact prevalence of PC is not yet established. We report a case of PC-K6a, p.Arg164Pro, in a 40-year-old man. Initially he was diagnosed with onychomycosis and was treated with systemic antifungals. This is the first genetically confirmed case of PC in the Czech Republic.
Mary E Schwartz - One of the best experts on this subject based on the ideXlab platform.
-
Genetic variants in Pachyonychia congenita-associated keratins increase susceptibility to tooth decay.
Public Library of Science (PLoS), 2018Co-Authors: Olivier Duverger, Mary E Schwartz, Jenna C Carlson, Chelsea M Karacz, Michael A Cross, Mary L Marazita, John R Shaffer, Maria I. MorassoAbstract:Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of Pachyonychia congenita
-
proteomic profiling of Pachyonychia congenita plantar callus
Journal of Proteomics, 2017Co-Authors: Robert H Rice, Mary E Schwartz, Blythe Durbinjohnson, Michelle Salemi, David M Rocke, Brett S. PhinneyAbstract:Abstract Callus samples from the ball and the arch of the foot, collected on tape circles, were compared by shotgun proteomic profiling. Pachyonychia congenita subjects were sampled who exhibited a mutation in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, and the proteins were digested and analyzed by tandem mass spectrometry. In comparison with samples from unaffected control subjects, those from subjects with KRT6A or KRT16 mutations displayed the most differences in profile from normal, while those from subjects with KRT6C or KRT17 mutations showed few differences from normal. The profiles from subjects with KRT6B mutations were intermediate in protein profile differences. Degree of departure from the normal profile could be estimated by expression of numerous proteins in callus from the ball of the foot that were consistently different. By contrast, the protein profile from the arch of the foot was hardly affected. The results provide a foundation for noninvasive monitoring of the efficacy of treatments with quantitative assessment of departure from the normal phenotype. Significance Pachyonychia congenita is an orphan disease in which the connection between the basic defect (keratin mutation) and debilitating symptoms (severe plantar pain) is poorly understood. Present work addresses the degree to which the protein profile is altered in the epidermis where the severe pain originates. The results indicate that the mutated keratins differ greatly in the degree to which they elicit perturbations in protein profile. In those cases with markedly altered protein levels, monitoring the callus profile may provide an objective measure of treatment efficacy.
-
Keratin 17 Mutations in Four Families from India with Pachyonychia Congenita.
Indian journal of dermatology, 2017Co-Authors: Manoj Kumar Agarwala, Neil J Wilson, Mary E Schwartz, Pankaj Salphale, Dincy Peter, Susanne Pulimood, Frances J D SmithAbstract:Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The main features are palmoplantar keratoderma, plantar pain, and nail dystrophy. Cysts of various types, follicular hyperkeratosis, oral leukokeratosis, hyperhidrosis, and natal teeth may also be present. Four unrelated Indian families presented with a clinical diagnosis of PC. This was confirmed by genetic testing; mutations in KRT17 were identified in all affected individuals.
-
first case of Pachyonychia congenita in the czech republic
Dermatologic Therapy, 2015Co-Authors: Anna Jirakova, Frances J D Smith, Mary E Schwartz, Lucie Rajska, Filip Rob, Martina Džambova, Zuzana Secnikova, Dana Gopfertova, Torello Lotti, Jana HercogovaAbstract:Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by hypertrophic nail dystrophy, oral leukokeratosis, and painful palmoplantar keratoderma. It is associated with a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The International PC Research Registry (IPCRR) confirms that as of January 2014 there have been 547 cases of PC genetically confirmed. It is estimated that there are between 2000 and 10,000 cases of PC in the world. However, the exact prevalence of PC is not yet established. We report a case of PC-K6a, p.Arg164Pro, in a 40-year-old man. Initially he was diagnosed with onychomycosis and was treated with systemic antifungals. This is the first genetically confirmed case of PC in the Czech Republic.
-
Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting
The British journal of dermatology, 2014Co-Authors: Edel A. O'toole, Mary E Schwartz, Roger L. Kaspar, Eli Sprecher, Laure RittiéAbstract: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.
Roger L. Kaspar - One of the best experts on this subject based on the ideXlab platform.
-
Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium.
The British journal of dermatology, 2017Co-Authors: Laure Rittié, Eli Sprecher, Roger L. Kaspar, Frances J D SmithAbstract:The International Pachyonychia Congenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for Pachyonychia congenita, a rare autosomal dominant skin disorder. The research presented at the 13th Annual Research Symposium of the IPCC, held on 10-11 May 2016, in Scottsdale, AZ, U.S.A., is reported here.
-
oxidative stress and dysfunctional nrf2 underlie Pachyonychia congenita phenotypes
Journal of Clinical Investigation, 2016Co-Authors: Michelle L. Kerns, Jill M.c. Hakim, Roger L. Kaspar, Yajuan Guo, Andreas Berroth, Pierre A. CoulombeAbstract:Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with Pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.
-
Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting
The British journal of dermatology, 2014Co-Authors: Edel A. O'toole, Mary E Schwartz, Roger L. Kaspar, Eli Sprecher, Laure RittiéAbstract: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.
-
Report of the 10th Annual International Pachyonychia Congenita Consortium Meeting
The Journal of investigative dermatology, 2014Co-Authors: Maurice A.m. Van Steensel, Frances J D Smith, Pierre A. Coulombe, Leonard M. Milstone, Roger L. Kaspar, Eli Sprecher, I Mclean, Dennis R. Roop, Mary E SchwartzAbstract:The International Pachyonychia Congenita Consortium (IPCC) was founded in 2004 in Park City, Utah, USA. Its goal is to find a cure for Pachyonychia congenita, a rare keratinizing disorder. From February 14th–17th, 2013, the group convened in Park City for their tenth annual meeting. The 2013 meeting focused on how to best move forward with clinical trials and on learning from work in other scientific areas, with an emphasis on understanding mechanisms of pain and hyperkeratosis. Considerable time was spent on discussing the best way to move forward with development of new treatments and how to obtain or develop tools that can measure treatment outcomes in PC.
-
development of skin humanized mouse models of Pachyonychia congenita
Journal of Investigative Dermatology, 2011Co-Authors: Marta Garcia, Sancy A. Leachman, Roger L. Kaspar, Robyn P. Hickerson, Fernando Larcher, Eulalia Baselga, Marcela Del RioAbstract:Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized Pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p.Asn171Lys mutation of the keratin 6a gene (KRT6A), we were able to regenerate PC-derived human skin that appeared phenotypically normal, but developed sustained PC features after the use of an acute hyperproliferative stimulus (i.e., tape stripping). In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p.Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease.
Eli Sprecher - One of the best experts on this subject based on the ideXlab platform.
-
identification of clinically useful predictive genetic variants in Pachyonychia congenita
Clinical and Experimental Dermatology, 2021Co-Authors: F. J. D. Smith, Eli Sprecher, Liat Samuelov, Ofer Sarig, Noam Adir, M Pavlovsky, J Schwartz, D HansenAbstract:BACKGROUND Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants. AIMS We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity. METHODS We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ2 and Kruskal-Wallis tests. RESULTS We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation. CONCLUSIONS We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.
-
revisiting Pachyonychia congenita a case cohort study of 815 patients
British Journal of Dermatology, 2020Co-Authors: Liat Samuelov, Frances J D Smith, Eli Sprecher, Charles HansenAbstract:BACKGROUND Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. OBJECTIVES To harness the same resource to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. METHODS In total, 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry were surveyed for clinical findings associated with PC. Data were analysed using various statistical methods, including the Student's t-test, χ2 -test and anova tests for differences in means/proportions. Spearman correlation and logistic regression were used for phenotype-genotype correlations. RESULTS KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids. KRT17 mutations were most commonly associated with cysts and natal teeth. Using logistic regression, we found that oral leucokeratosis was correlated with earlier toenail involvement, walking aids, nursing difficulties and hoarseness. Cysts were correlated with oral leucokeratosis, natal teeth and ear wax. Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation. Hoarseness was correlated with an increased number of involved fingernails. CONCLUSIONS Here, we establish phenotype-genotype correlations in the largest cohort of patients with PC described to date and reveal novel and clinically useful predictors of disease course and manifestations. What's already known about this topic? Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. The establishment of an international registry containing the clinical and molecular data of patients with PC led to the development of a disease classification based on the mutant gene and associated features. What does this study add? Data were collected via an international registry to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. This is the largest cohort of patients with PC described to date. The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years. Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function. Linked Editorial: Steele and O'Toole. Br J Dermatol 2020; 182:521-522. Linked Comment: Mordaunt. Br J Dermatol 2020; 182:537.
-
chronic pain in Pachyonychia congenita evidence for neuropathic origin
British Journal of Dermatology, 2018Co-Authors: Silviu Brill, F. J. D. Smith, Eli Sprecher, N Geva, H Gruener, Hadas Nahmanaverbuch, Ruth DefrinAbstract:BACKGROUND Pachyonychia congenita (PC) is a rare autosomal dominant skin disease, with chronic pain being the most prominent complaint. Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy. OBJECTIVES Here, for the first time, we aim to evaluate systematically the sensory function of patients with PC vs. controls, in order to investigate the pathophysiology of PC. METHODS Patients (n = 62) and controls (n = 45) completed the McGill and Douleur Neuropathique-4 (DN4) questionnaires. Sensory testing included detection and pain thresholds, pathological sensations, conditioned pain modulation (CPM) and temporal summation of pain. RESULTS A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing. In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet. CPM was reduced among the patients, and was associated with more enhanced mechanical hyperalgesia in the feet. The specific gene and nature of the causative mutation did not affect any of these features. CONCLUSIONS Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC. The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC.
-
Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium.
The British journal of dermatology, 2017Co-Authors: Laure Rittié, Eli Sprecher, Roger L. Kaspar, Frances J D SmithAbstract:The International Pachyonychia Congenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for Pachyonychia congenita, a rare autosomal dominant skin disorder. The research presented at the 13th Annual Research Symposium of the IPCC, held on 10-11 May 2016, in Scottsdale, AZ, U.S.A., is reported here.
-
Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting
The British journal of dermatology, 2014Co-Authors: Edel A. O'toole, Mary E Schwartz, Roger L. Kaspar, Eli Sprecher, Laure RittiéAbstract: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.
F. J. D. Smith - One of the best experts on this subject based on the ideXlab platform.
-
identification of clinically useful predictive genetic variants in Pachyonychia congenita
Clinical and Experimental Dermatology, 2021Co-Authors: F. J. D. Smith, Eli Sprecher, Liat Samuelov, Ofer Sarig, Noam Adir, M Pavlovsky, J Schwartz, D HansenAbstract:BACKGROUND Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants. AIMS We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity. METHODS We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ2 and Kruskal-Wallis tests. RESULTS We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation. CONCLUSIONS We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.
-
chronic pain in Pachyonychia congenita evidence for neuropathic origin
British Journal of Dermatology, 2018Co-Authors: Silviu Brill, F. J. D. Smith, Eli Sprecher, N Geva, H Gruener, Hadas Nahmanaverbuch, Ruth DefrinAbstract:BACKGROUND Pachyonychia congenita (PC) is a rare autosomal dominant skin disease, with chronic pain being the most prominent complaint. Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy. OBJECTIVES Here, for the first time, we aim to evaluate systematically the sensory function of patients with PC vs. controls, in order to investigate the pathophysiology of PC. METHODS Patients (n = 62) and controls (n = 45) completed the McGill and Douleur Neuropathique-4 (DN4) questionnaires. Sensory testing included detection and pain thresholds, pathological sensations, conditioned pain modulation (CPM) and temporal summation of pain. RESULTS A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing. In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet. CPM was reduced among the patients, and was associated with more enhanced mechanical hyperalgesia in the feet. The specific gene and nature of the causative mutation did not affect any of these features. CONCLUSIONS Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC. The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC.
-
The molecular genetic analysis of the expanding Pachyonychia congenita case collection
The British journal of dermatology, 2014Co-Authors: Neil J Wilson, Mary E Schwartz, W H I Mclean, Leonard M. Milstone, Edel A. O'toole, Eli Sprecher, Charles Hansen, A.a. Shepherd, E. Al‐asadi, F. J. D. SmithAbstract: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.
-
Trust Strategic Award (098439/Z/12/Z to
2014Co-Authors: W H I Mclean, Frances J D Smith, F. J. D. Smith, E. Sprecher, Accepted For PublicationAbstract:The molecular genetic analysis of the expanding Pachyonychia congenita case collectio
-
Pachyonychia congenita patients with mutations in krt6a have more extensive disease compared with patients who have mutations in krt16
British Journal of Dermatology, 2012Co-Authors: Katrina Spaunhurst, F. J. D. Smith, Anna Hogendorf, Bharathi Lingala, Myron Schwartz, Agnieszka Cywinskabernas, K J Zeman, Jean Y TangAbstract:Background Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type). Objectives To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16. Methods In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations. Results Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P Conclusion Phenotypic differences between patients with KRT6A and KRT16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.
