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The Journal of Investigative Dermatology Feb 2023Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is...
Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is caused by dominant mutations in keratin (K) K6A, K6B, K6C, K16, or K17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive. In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. Abnormal late terminal keratinization was associated with elevated TGM1 activity. In addition, the calcium ion permeable channel TRPV3 was significantly increased in PC-lesional skin, suggesting a predominant role of the TRPV3/EGFR signaling complex in PC. We hypothesized that this complex contributes to promoting TGM1 activity and induces the expression and shedding of EGFR ligands. To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL. Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC.
Topics: Humans; ErbB Receptors; Erlotinib Hydrochloride; Keratoderma, Palmoplantar; Mutation; Pachyonychia Congenita; Pain; Quality of Life
PubMed: 36116508
DOI: 10.1016/j.jid.2022.08.045 -
The Journal of Pathology Feb 2019Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of... (Review)
Review
Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of biological processes, including cell proliferation and growth, skin inflammation and hair follicle cycling. Aberrant overexpression of K17 is found in various diseases ranging from psoriasis to malignancies such as breast, cervical, oral squamous and gastric carcinomas. Moreover, genetic mutation in KRT17 is related to tissue-specific diseases, represented by steatocystoma multiplex and pachyonychia congenita. In this review, we summarize our findings concerning the regulatory mechanisms of K17 overexpression in psoriasis and compare them to the literature relating to other diseases. We discuss data that proinflammatory cytokines, including interleukin-17 (IL-17), IL-22, interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-β) and transcription factors glioma-associated oncogene homolog 1/2 (Gli1/2), Nrf2 and p53 can regulate K17 by transcriptional and translational control. Moreover, post-translational modification, including phosphorylation and ubiquitination, is involved in the regulation of K17 stability and biological functions. We therefore review the current understanding of the K17 regulatory mechanism and its pathogenic role in diseases from dermatoses to cancer. Prospects for anti-K17 therapy in diagnosis, prognosis and disease treatment are also discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Animals; Cell Transformation, Neoplastic; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Inflammation Mediators; Keratin-17; Neoplasms; Protein Processing, Post-Translational; Signal Transduction; Skin Diseases; Transcription Factors
PubMed: 30306595
DOI: 10.1002/path.5178 -
American Journal of Medical Genetics.... Oct 2014Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current knowledge of oral... (Review)
Review
Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current knowledge of oral manifestations and orofacial function in EDs. The review will focus on the most common forms where dental manifestations can be crucial for a differential diagnosis of ED among individuals with hypodontia and oligodontia, and preferably where the investigations included persons who had a genetically verified diagnosis. Disturbances in tooth development are common and can appear as tooth agenesis, variations in size and shape of teeth, defects in the mineralized tissues, and problems in tooth eruption. Abnormalities in number, size, and shape of teeth, and reduced salivary secretion, present in isolated oligodontia as well as in hypohidrotic ED and incontinentia pigmenti. In some more rare EDs these symptoms appear in combination with clefts of lip and/or palate in some affected individuals. Leukokeratosis in the oral mucosa presents in 70% of genetically confirmed cases of pachyonychia congenita. Also, orofacial function is often affected in ED, due to malformations, an incomplete dentition, and low salivary secretion which can compromise chewing, swallowing, and speech. In conclusion, there is a clinical overlap in oral signs and symptoms between isolated oligodontia and the most common EDs. Studies with genetically confirmed diagnoses and larger cohorts, as well as multicenter collaboration and the establishing of international registries, would create a basis for refined diagnostics, where oral examinations should be an integrated part of clinical assessment.
Topics: Anodontia; Ectodermal Dysplasia; Humans; Salivation; Tooth; Tooth Abnormalities
PubMed: 24719393
DOI: 10.1002/ajmg.a.36571 -
Archives of Plastic Surgery Nov 2023Pachyonychia congenita is a rare genetic disorder characterized by hypertrophic nail plates, hyperkeratotic nail beds, and thickened hyponychium of the fingers and toes,...
Pachyonychia congenita is a rare genetic disorder characterized by hypertrophic nail plates, hyperkeratotic nail beds, and thickened hyponychium of the fingers and toes, impairing manual dexterity and resulting in poor aesthetics. The current body of literature describes various treatment modalities, but no singular approach has been defined as the gold standard. In this case, the authors employed different surgical techniques for treating pachyonychia congenita to evaluate the most effective approach. A 3-year-old boy presented with hypertrophic nail growth involving all digits of both hands and feet. Three surgical procedures were performed on the patient's fingers and toes using germinal matrix excision (GME) alone, GME plus partial sterile matrix excision (pSME), or GME plus complete sterile matrix excision (cSME). The digits treated with GME + cSME exhibited no recurrence of nail growth. Those treated with GME alone exhibited recurrence of hypertrophic nail growth, although their growth slowed. Excision of GME + cSME prevented recurrence of hypertrophic nails, while GME alone or with pSME led to slower-growing hypertrophic nails. Complete excision of the germinal and sterile matrices with skin graft closure may be a definitive treatment for pachyonychia congenita, but further studies are needed to validate these findings.
PubMed: 38143838
DOI: 10.1055/s-0043-1771520 -
JAMA Dermatology Nov 2021This survey study examines the prevalence and characteristics of itch in pachyonychia congenita.
This survey study examines the prevalence and characteristics of itch in pachyonychia congenita.
Topics: Humans; Pachyonychia Congenita; Prevalence; Pruritus
PubMed: 34468688
DOI: 10.1001/jamadermatol.2021.3335 -
The British Journal of Dermatology Mar 2020
Topics: Homeostasis; Humans; Keratoderma, Palmoplantar; Pachyonychia Congenita; Skin
PubMed: 31814103
DOI: 10.1111/bjd.18688 -
Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.The British Journal of Dermatology Mar 2020Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17)....
BACKGROUND
Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction.
OBJECTIVES
To characterize patients with PC with symptomatic mucosal involvement.
METHODS
We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction.
CONCLUSIONS
It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.
Topics: Child; Child, Preschool; Humans; Infant; Keratin-6; Keratins; Keratoderma, Palmoplantar; Mutation; Pachyonychia Congenita
PubMed: 31777952
DOI: 10.1111/bjd.18742 -
Orphanet Journal of Rare Diseases Mar 2015Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and... (Review)
Review
Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefèvre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and itching is important to reduce the morbidity of the disease. The disease is debilitating and progressive keratoderma and auto-amputation of digits can prevent patients from grasping and walking, and confine them to a wheelchair. New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms. The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy.
Topics: Humans; Metalloendopeptidases; Mutation; Skin Diseases, Genetic; TRPV Cation Channels
PubMed: 25886873
DOI: 10.1186/s13023-015-0246-5 -
Indian Journal of Dermatology 2016
PubMed: 27688452
DOI: 10.4103/0019-5154.190110 -
The British Journal of Dermatology Nov 2014This 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,...
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
PubMed: 25124823
DOI: 10.1111/bjd.13341