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The British Journal of Dermatology Jul 2018
Topics: Chronic Pain; Humans; Keratoderma, Palmoplantar; Pachyonychia Congenita; Peripheral Nervous System Diseases
PubMed: 30156287
DOI: 10.1111/bjd.16700 -
Archives of Disease in Childhood Mar 2021
PubMed: 31836634
DOI: 10.1136/archdischild-2019-318392 -
KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies.European Journal of Human Genetics :... Nov 2022We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two...
We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma, folliculitis, alopecia, sparse eyebrows, dental anomalies and variable acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters on soles and/or arms, rough sparse hair on scalp and keratosis pilaris. By exome sequencing we detected homozygous KRT17 c.281G>A (p.(Arg94His)) in affected individuals, and linkage mapping indicated a single locus. Heterozygous variants in KRT17 cause PC2 (PC-K17) with main characteristics of pachyonychia, subungual keratosis, palmoplantar keratoderma, hyperhidrosis, oral leukokeratosis and epidermal cysts, or steatocystoma multiplex, both with dominant inheritance. The causative variant has been reported in heterozygous state in a family afflicted with severe steatocystoma multiplex and in a sporadic PC2 case, and thus we also define a third phenotype related to the variant. Both exome sequencing and linkage mapping demonstrated recessive inheritance whereas Sanger sequencing indicated heterozygosity for the causal variant, reiterating caution for simple targeted sequencing for genetic testing. Testing parents for variants found in sibs could uncover recessive inheritance also in other KRT genes.
Topics: Humans; Eyebrows; Hyperhidrosis; Keratin-17; Mutation; Nails, Malformed; Pachyonychia Congenita; Steatocystoma Multiplex; Tooth Abnormalities; Pedigree
PubMed: 35676340
DOI: 10.1038/s41431-022-01128-4 -
Journal of Proteomics Aug 2017Callus samples from the ball and the arch of the foot, collected on tape circles, were compared by shotgun proteomic profiling. Pachyonychia congenita subjects were...
UNLABELLED
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.
Topics: Bony Callus; Epidermis; Foot; Humans; Keratins; Mutation; Pachyonychia Congenita; Proteome; Proteomics; Tandem Mass Spectrometry
PubMed: 28648685
DOI: 10.1016/j.jprot.2017.06.017 -
Indian Journal of Dermatology,... 2023Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain...
Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain reporting in pachyonychia congenita clinical studies, it is difficult to evaluate the efficacy of treatment outcomes for painful plantar keratodermas. Objectives To objectively analyse associations between plantar pain and activity levels in pachyonychia congenita patients using a wristband tracker. Methods Pachyonychia congenita patients and matched normal controls wore wristband activity trackers and completed a daily digital survey to record their highest and total pain scores (0-10 scale) each day for 28 consecutive days during four different seasons. Results Twenty four participants (12 pachyonychia congenita patients and 12 matched normal controls) completed the study. Pachyonychia congenita patients walked 1801.30 fewer steps/day (95% CI, -3666.4, 64.1) than normal controls (P = 0.072) and had greater average total [5.26; SD, 2.10] and highest (6.92; SD, 2.35) daily pain than normal controls [0.11 (SD, 0.47), 0.30 (SD, 0.22), respectively] (P < 0.001, both). On average, for each one unit increase in daily highest pain level, pachyonychia congenita activity decreased 71.54 steps/day (SE, 38.90, P = 0.066). Limitation The study had a small number of participants, limiting statistical power. Only pachyonychia congenita patients, ages 18 years or older, with keratin 6a, keratin 16, and keratin 17 mutations were included, limiting generalizability. Conclusion Pachyonychia congenita patients were less active with significantly higher pain than normal controls. There was an inverse correlation between pain and activity. Our findings suggest that wristband tracker technology may be used to evaluate treatment efficacy in future trials on severe plantar pain; therapeutic interventions that decrease plantar pain should correlate with significant increases in activity using wristband trackers.
Topics: Humans; Pachyonychia Congenita; Quality of Life; Fitness Trackers; Shoes; Keratin-6; Pain; Mutation; Walking
PubMed: 37317732
DOI: 10.25259/IJDVL_939_2022 -
Skinmed 2014
Topics: History, 19th Century; History, 20th Century; Humans; Steatocystoma Multiplex
PubMed: 25632643
DOI: No ID Found -
Dermatologic Therapy Sep 2019Pachyonychia 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... (Review)
Review
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
PubMed: 31364784
DOI: 10.1111/dth.13045 -
Pharmaceutics Oct 2021Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold... (Review)
Review
Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.
PubMed: 34684016
DOI: 10.3390/pharmaceutics13101722 -
The Journal of Clinical Investigation Jun 2016Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated...
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.
Topics: Animals; Disease Models, Animal; Glutathione; Humans; Isothiocyanates; Keratin-16; Keratoderma, Palmoplantar; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Pachyonychia Congenita; Phenotype; Phosphorylation; RNA, Messenger; Sulfoxides
PubMed: 27183391
DOI: 10.1172/JCI84870 -
Pain Dec 2016We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and...
We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and control subjects. Plantar biopsies from 10 genetically confirmed patients with PC (with a mutation in KRT6A) were performed at the ball of the foot (affected skin) and the arch (unaffected) and were compared to biopsies from corresponding locations in 10 control subjects. Tissue was processed to visualize intraepidermal nerve fibers (IENF) (PGP9.5), subsets of IENF (CGRP, substance P, tyrosine hydroxylase), myelinated nerve fiber (neurofilament H, NFH), blood vessels (CD31), Meissner corpuscles, and Merkel cells (MCs). Structures were quantified using stereology or validated quantification methods. We observed that PC-affected plantar skin had significantly lower sweat gland innervation (sweat gland nerve fiber density) and reduced numbers of Meissner corpuscles compared to PC-unaffected or anatomically matched control skin. In contrast, Merkel cell densities and blood vessel counts were higher in PC-affected skin compared to either control or PC-unaffected skin. There were no differences in myelinated nerve fiber densities, SP, or CGRP between the groups. Pressure pain thresholds in PC-affected skin were lower compared to PC-unaffected and anatomically matched control skin. Additionally, MC densities in callused plantar skin from healthy runners with callus and one subject with a nonpainful palmoplantar keratoderma (AQP5 mutation) were similar to PC-unaffected and control skin consistent with callus alone not being sufficient to increase MC number. These findings suggest that alterations in PC extend beyond keratinocytes and may provide strategies to study neuropathic pain in PC.
Topics: Adult; Aged; Animals; Aquaporin 5; Biopsy; Female; Humans; Keratin-20; Keratin-6; Male; Merkel Cells; Middle Aged; Mutation; Nerve Fibers, Myelinated; Neurofilament Proteins; Pachyonychia Congenita; Pain Threshold; Peripheral Nervous System Diseases; Skin; Ubiquitin Thiolesterase
PubMed: 27776012
DOI: 10.1097/j.pain.0000000000000711