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Current Opinion in Cell Biology Dec 2023The keratin cytoskeleton protects epithelia against mechanical, nonmechanical, and physical stresses, and participates in multiple signaling pathways that regulate cell... (Review)
Review
The keratin cytoskeleton protects epithelia against mechanical, nonmechanical, and physical stresses, and participates in multiple signaling pathways that regulate cell integrity and resilience. Keratin gene mutations cause multiple rare monoallelic epithelial diseases termed keratinopathies, including the skin diseases Epidermolysis Bullosa Simplex (EBS) and Pachyonychia Congenita (PC), with limited available therapies. The disease-related keratin mutations trigger posttranslational modifications (PTMs) in keratins and their associated proteins that can aggravate the disease. Recent findings of drug high-throughput screening have led to the identification of compounds that may be repurposed, since they are used for other human diseases, to treat keratinopathies. These drugs target unique PTM pathways and sites, including phosphorylation and acetylation of keratins and their associated proteins, and have shed insights into keratin regulation and interactions. They also offer the prospect of testing the use of drug mixtures, with the long view of possible beneficial human use coupled with increased efficacy and lower side effects.
Topics: Humans; Keratins; Cytoskeleton; Epidermolysis Bullosa Simplex; Mutation; Protein Processing, Post-Translational
PubMed: 37925932
DOI: 10.1016/j.ceb.2023.102264 -
Clinical and Experimental Dermatology May 2024Pachyonychia congenita is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma, and hypertrophic...
Pachyonychia congenita is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma, and hypertrophic nail dystrophy. Plantar pain can be debilitating and have a profound impact on quality of life. Current therapeutic options for pain in PC are limited to lifestyle adjustment and mechanical techniques, with a small subgroup of patients benefiting from oral retinoids. This review investigates the pathogenesis of pain in pachyonychia congenita and provides a summary of the current and future therapeutic options.
PubMed: 38805703
DOI: 10.1093/ced/llae199 -
The British Journal of Dermatology Mar 2020
Topics: Humans; Pachyonychia Congenita; Rare Diseases; Skin; Skin Diseases
PubMed: 32107781
DOI: 10.1111/bjd.18817 -
Actas Dermo-sifiliograficas Apr 2024Nail disorders in newborns can show independently or as components of systemic illnesses or genodermatoses. The examination of these abnormalities is complex and... (Review)
Review
Nail disorders in newborns can show independently or as components of systemic illnesses or genodermatoses. The examination of these abnormalities is complex and sometimes challenging. However, familiarity with these disorders can significantly contribute to uncovering potential underlying conditions. This review includes the physiological nail changes seen within the first few months of life, such as Beau's lines, onychoschizia, koilonychia, congenital nail fold hypertrophy of the first digit, and onychocryptosis. This review also focuses on the most relevant congenital disorders reported and how to perform differential diagnosis. Finally, this review highlights those hereditary diseases in which nail involvement is crucial for diagnosis, such as nail-patella syndrome, congenital pachyonychia, or congenital dyskeratosis, among others.
PubMed: 38663727
DOI: 10.1016/j.ad.2024.04.002 -
Journal of the American Podiatric... Sep 2017Plantar keratodermas can arise due to a variety of genetically inherited mutations. The need to distinguish between different plantar keratoderma disorders is becoming... (Comparative Study)
Comparative Study Review
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.
Topics: Comorbidity; Disease Management; Female; Humans; Keratoderma, Palmoplantar; Male; Pachyonychia Congenita; Pain Management; Prognosis; Quality of Life; Risk Assessment; Severity of Illness Index; Sick Role
PubMed: 29077501
DOI: 10.7547/16-043 -
Pediatrics and Neonatology Jul 2023Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). PC is an...
BACKGROUND
Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). PC is an extremely rare condition. To our knowledge, this is the largest genotype-phenotype study of PC in a Vietnamese population to date.
MATERIALS AND METHODS
We investigated keratin gene mutations and clinical features of seven Vietnamese children with PC.
RESULTS
The seven Vietnamese patients were from six different families (two patients in the same family) from across Northern, Central, and Southern Vietnam. All children displayed PC symptoms before 1 year of age, but diagnosis was delayed in 4/7 patients. Thick fingernails, thick toenails, oral leukokeratosis, and follicular hyperkeratosis were the most common features recorded by all seven patients. Plantar keratoderma and thick fingernails were the clinical features associated with the most significant effect on daily function. All patients had mutations in KRT6A (PC-K6a) focused on the 1A and 2B domains. We found three distinct types of mutations (K6a R466P, K6a N171K, and K6a N172del). One mutation (N172del) was common to 5/7 (71.4%) of the patients.
CONCLUSIONS
Individuals displaying nail dystrophy, oral leukokeratosis, follicular hyperkeratosis, and plantar keratoderma should be referred for genetic testing given the high likelihood of a PC-K6a-related mutation in patients with this constellation of clinical signs.
Topics: Humans; Child; Pachyonychia Congenita; Keratin-6; Southeast Asian People; Vietnam; Genotype; Phenotype; Mutation; Keratins; Exanthema; Leukoplakia, Oral
PubMed: 36658016
DOI: 10.1016/j.pedneo.2022.09.018 -
Postepy Dermatologii I Alergologii Feb 2021Keratinization means cytodifferentiation of keratinocytes turning into corneocytes in the stratum corneum. Disorders of keratinization (hyperkeratosis, parakeratosis and... (Review)
Review
Keratinization means cytodifferentiation of keratinocytes turning into corneocytes in the stratum corneum. Disorders of keratinization (hyperkeratosis, parakeratosis and dyskeratosis) are causing many dermatological diseases, including various types of ichthyoses, pachyonychia congenita, pityriasis rubra pilaris, all subtypes of psoriasis, pityriasis lichenoides, dyskeratosis congenita, leukoplakia and keratosis follicularis, which apart from skin lesions may affect the eye's adnexae causing ectropion, entropion, blepharitis, madarosis, and trichiasis, the ocular surface causing keratitis, conjunctivitis, corneal ulceration and episcleritis, which in turn cause uveitis and various fundoscopic changes (proliferative retinopathy, retinal vasculopathy, macular oedema and birdshot chorioretinopathy). Knowledge of ocular symtoms associated with pathological keratinization is crucial, preventing sight-threatening complications such as corneal perforation, lagophthalmus, phthisis bulbi, retinal neovascularization, retinal vasculopathy and optic nerve atrophy. This review encourages dermatologists to monitor patients for ocular symptoms and encourage ophthalmologists to monitor patients for dermatological symptoms.
PubMed: 34408561
DOI: 10.5114/ada.2021.104272 -
Current Opinion in Pediatrics Aug 2014Nail diseases in infants and children are an uncommon cause of consultation and are often difficult to diagnose and to manage. This review will cover nail diseases that... (Review)
Review
PURPOSE OF REVIEW
Nail diseases in infants and children are an uncommon cause of consultation and are often difficult to diagnose and to manage. This review will cover nail diseases that are most commonly seen in clinical practice, including congenital and hereditary disorders and inflammatory, infective, and neoplastic nail diseases. The purpose of the review is to help the reader to recognize nail disorders at an early age and to manage them appropriately.
RECENT FINDINGS
Two recent large studies have reported the clinical findings of genetic disorders involving the nails, that is, pachyonychia congenita and epidermolysis bullosa. Only a few articles gave a comprehensive review of a disease, as occurred for onychomycosis, while the majority of the reports published in the recent literature involve single cases.
SUMMARY
Nail diseases in children and neonates are not easy to diagnose by nonexperts. Basic knowledge of the anatomy and biology of the nail facilitates their diagnosis as the understanding of their pathophysiology. This review gives hints at the most common nail diseases that affect infants and children.
Topics: Age Factors; Antifungal Agents; Child; Child, Preschool; Diagnosis, Differential; Early Diagnosis; Humans; Infant; Nail Diseases; Nails; Nails, Malformed; Practice Guidelines as Topic; Sex Factors
PubMed: 24886951
DOI: 10.1097/MOP.0000000000000116 -
The British Journal of Dermatology Mar 2020Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy... (Review)
Review
BACKGROUND
Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy and very painful palmoplantar keratoderma (PPK). PC dramatically impacts quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound-repair-associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature.
OBJECTIVES
This review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms.
METHODS
We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK.
RESULTS
There are three main stages of progression of PPK-like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1-Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis.
CONCLUSIONS
The progress made suggests new avenues to explore for the treatment of PC-based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16 and KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.
Topics: Animals; Homeostasis; Kelch-Like ECH-Associated Protein 1; Keratin-16; Keratoderma, Palmoplantar; Mice; Mutation; NF-E2-Related Factor 2; Pachyonychia Congenita; Quality of Life
PubMed: 31021398
DOI: 10.1111/bjd.18033 -
The Journal of Investigative Dermatology Apr 2024Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been... (Review)
Review
Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.
Topics: Humans; Pachyonychia Congenita; Keratoderma, Palmoplantar; Administration, Cutaneous; Apoptosis; Cell Differentiation; Mutation
PubMed: 38099888
DOI: 10.1016/j.jid.2023.10.030