RARE DISEASE
Pachyonychia congenita
Pachyonychia congenita
Pachyonychia congenita
Synonyms: PC
Synonyms: PC
Synonyms: PC
Drug discovery
9
drugs
With orphan designations
Overview
Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, or KRT17 keratin genes [1][6][12]. Characterized by painful plantar keratoderma, hypertrophic nail dystrophy, and variable manifestations (oral leukokeratosis, cysts, follicular hyperkeratosis), symptom onset typically occurs in infancy or early childhood [6][11][16]. Diagnosis relies on clinical evaluation and genetic testing [1][7].
Therapies
Mechanical intervention: Regular callus debridement, orthotics, and footwear modifications [1][8]
Pharmacologic: Topical keratolytics (urea/salicylic acid), oral retinoids (limited efficacy), rosuvastatin (emerging evidence) [3][13][16]
Surgical: Nail avulsion/cyst excision for refractory cases [1][8]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare skin diseases
Research Papers
113 drug discovery papers about Pachyonychia congenita, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
113 drug discovery papers about Pachyonychia congenita, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
oligonucleotides
2023-09-18 | Proteomic profiling reveals KRT6C as a probable hereterodimer partner for KRT9: New insights into re-classifying epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c) as a group of genetic cutaneous disorders.
Epidermolytic palmoplantar keratoderma (EPPK), a highly penetrant autosomal dominant genodermatosis, is characterized by diffuse keratoses on palmplantar epidermis. The keratin 9 gene (KRT9) is responsible for EPPK. To date, phenotypic therapy is the primary treatment for EPPK. Because KRT9 pairs with a type II keratin-binding partner to function in epidermis, identifying the interaction partner is an essential first step in revealing EPPK pathogenesis and its fundamental treatment. In this study, we proved that keratin 6C (KRT6C) is a probable hereterodimer partner for KRT9. In silico model for KRT6C/KRT9 shows a typical coiled-coil structure in their 2B domains. Proteomics analysis shows that KRT6C/KRT9 pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating cytoskeleton organization and keratinization. This study shows that co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis provide a sensitive approach, which compensates for inevitable inadequacies of anti-keratin 6C antibody and helps discover the probable hereterodimer partner KRT6C for KRT9. The acknowledgement of KRT6C/KRT9 pairwise relationship may help re-classify EPPK and PC-K6c (a milder form of pachyonychia congenita, caused by KRT6C) as a group of hereditary defects at a molecular-based level, and lay foundation for deciphering the keratin network contributing to EPPK and PC-K6c. SIGNIFICANCE OF THE STUDY: What is already known about this topic? KRT9 and KRT6C are disease-causing factors for epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c), respectively. EPPK and PC-K6c have some symptom similarities. Keratins are the major structural proteins in epithelial cells. Each of the type I keratin is matched by a particular type II keratin to assemble a coiled-coil heterodimer. The hereterodimer partner for KRT9 is unknown. What does this study add? We discovered and proved that KRT6C is a probable hereterodimer partner for KRT9 in palmplantar epidermis in a native endogenous environment by using co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis, etc. The proteomics analysis shows that KRT6C/KRT9 keratin pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating intermediate filament-based cytoskeleton organization and keratinization processes. What are the implications of this work? The new understanding of probable KRT6C/KRT9 pairwise correlation may help re-classify the genetic cutaneous disorders EPPK and PC-K6c as a group of hereditary defects at a molecular-based level, and lay foundation for pathogenic mechanism research in EPPK and PC-K6c. The densely related network components derived from the proteomic data using Metascape in the study and pairwise regulation fashion of specific keratin pairs should attract more attention in the further explorations when investigators concern the physiological functions of keratins and the pathogenesis of related skin diseases.
2022-01-17 | Highly branched poly(β-amino ester)s for gene delivery in hereditary skin diseases.
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
2018-10-11 | Keratin 17 in disease pathogenesis: from cancer to dermatoses
Abstract 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.
2003-12-01 | In vivo alteration of the keratin 17 gene in hair follicles by oligonucleotide-directed gene targeting.
Abstract: Using intradermal injection of a chimeric RNA–DNA oligonucleotide (RDO) or a single‐stranded oligonucleotide (ssODN) into murine skin, we attempted to make a dominant mutation (R94P) in the conserved α‐helical domain of keratin 17 (K17), the same mutation found in pachyonychia congenichia type 2 (PC‐2) patients with phenotypes ranging from twisted hair to multiple pilosebaceous cysts. Both K17A‐RDO and K17‐ssODN contained a single base mismatch (C G C to C C C) to alter the normal K17 sequence to cause an amino acid substitution (R94P). The complexes consisting of oligonucleotides and cationic liposomes were injected to C57Bl/6 murine skin at 2 and 5 day after birth. Histological examination of skin biopsies at postnatal day 8 from several mice showed consistent twisted hair shafts or broken hair follicles at the sebaceous gland level and occasional rupture of the hair bulb or epidermal cyst‐like changes. In the injected area, the number of full anagen hair follicles decreased by 50%. Injection of the control oligonucleotide, identical to K17A‐RDO but containing no mismatch to the normal sequence, did not result in any detectable abnormality. The frequency of gene alteration was lower than 3%, according to the restriction fragment length polymorphism (RFLP) analysis of the genomic DNA isolated by dissection of hair follicles from slides. Although intradermal injection of K17A‐RDO or K17‐ssODN caused a dominant mutation in K17 affecting hair growth and morphology, these phenotypic changes were transient either due to the compensation of K17 by other keratins or the replacement of the mutated cells by normal surrounding cells during hair growth.
proteins
2026-07-21 | Autosomal Recessive Palmoplantar Epidermal Differentiation Disorder Caused by Homozygous Stop-Gain Variant in KRT16 Gene.
Palmoplantar epidermal differentiation disorders (pEDDs) comprise a heterogeneous group of disorders characterized by hyperkeratotic thickening of the palms and soles due to pathogenic variants in genes that regulate palmoplantar epidermal differentiation and keratinization. Among these, KRT16-pEDD is caused by heterozygous mutations in the KRT16 gene and may present clinically either as isolated palmoplantar keratoderma (PPK) or as part of the broader phenotype of pachyonychia congenita. This report describes a rare bi-allelic pattern of inheritance involving a presumed loss-of-function variant in KRT16, thereby extending the clinical and genetic spectrum of KRT16-related disorders, and highlighting important implications for variant interpretation and genetic counseling.
2023-04-17 | 894 Towards a genetically- and phenotypically-relevant mouse model for pachyonychia congenita
Pachyonychia congenita(PC) is a rare disorder that features palmoplantar keratoderma(PPK) as its most significant symptom. PPK are thick calluses arising in palmar and plantar skin that are painful to the point of debilitation in PC and related disorders. PC is caused by dominantly-acting small mutations that affect the coding sequence of KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Unlike the case for many other keratinopathies, cell fragility is not a key driver of the genesis of PPK lesions in PC. There currently is no effective treatment for this disorder. We previously generated a mouse strain, Krt16 null, that develops PC-like PPK in footpad skin (J. Invest. Dermatol. 132:1384-91, 2012). The study of these mice has yielded novel insight into the pathophysiology of PC. However, given that most cases of PC involve dominantly-acting missense alleles in KRT16 and other PC genes, Krt16null mice are not genetically relevant to PC nor are they amenable to developing or testing mutant allele-specific therapies. To address this deficiency, we used CRISPR-Cas9 to introduce a R123C point mutation in the Krt16 gene of mice. This allele accounts for >20% of the KRT16-based cases of PC (33/157) and is associated with a classic PC presentation. The Krt16 R123C allele shows Mendelian inheritance and does not compromise viability in mouse offspring. At 5 months of age, mice homozygous for the Krt16 R123C allele show raised footpads but do not feature obvious hyperkeratosis or acanthosis upon histological examination of footpad skin. These findings contrast with Krt16 null mice, which frequently die pre-weaning (66% penetrance) and develop striking PPK-like lesions in footpad skin by two months of age (100% penetrance). Further analysis of Krt16 R123C mice will shed new light into the enigmatic disorder that PC represents.
2019-09-23 | The non-neuronal and nonmuscular effects of botulinum toxin: an opportunity for a deadly molecule to treat disease in the skin and beyond.
There is growing evidence that botulinum neurotoxins (BoNTs) exhibit biological effects on various human cell types with a host of associated clinical implications. This review aims to provide an update on the non-neuronal and nonmuscular effects of botulinum toxin. We critically analysed recent reports on the structure and function of cellular signalling systems subserving biological effects of BoNTs. The BoNT receptors and intracellular targets are not unique for neurotransmission. They have been found in both neuronal and non-neuronal cells, but there are differences in how BoNT binds to, and acts on, neuronal vs. non-neuronal cells. The non-neuronal cells that express one or more BoNT/A-binding proteins, and/or cleavage target synaptosomal-associated protein 25, include: epidermal keratinocytes; mesenchymal stem cells from subcutaneous adipose; nasal mucosal cells; urothelial cells; intestinal, prostate and alveolar epithelial cells; breast cell lines; neutrophils; and macrophages. Serotype BoNT/A can also elicit specific biological effects in dermal fibroblasts, sebocytes and vascular endothelial cells. Nontraditional applications of BoNT have been reported for the treatment of the following dermatological conditions: hyperhidrosis, Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita, multiple eccrine hydrocystomas, eccrine angiomatous hamartoma, eccrine sweat gland naevi, congenital eccrine naevus, Raynaud phenomenon and cutaneous leiomyomas. Experimental studies have demonstrated the ability of BoNT/A to protect skin flaps, facilitate wound healing, decrease thickness of hypertrophic scars, produce an anti-ageing effect, improve a mouse model of psoriasiform dermatitis, and have also revealed extracutaneous effects of BoNT arising from its anti-inflammatory and anticancer properties. BoNTs have a much wider range of applications than originally understood, and the individual cellular responses to the cholinergic impacts of BoNTs could provide fertile ground for future studies.
2019-05-25 | A treatment protocol for botulinum toxin injections in the treatment of pachyonychia congenita‐associated keratoderma
Severely debilitating plantar keratoderma pain is the most distressing clinical feature of pachyonychia congenita (PC). Several earlier publications have reported therapeutic success with plantar injections of botulinum toxin (Btx). To describe our 4-year experience during which we administered a total of 30 plantar Btx injections to five patients with PC following an optimized protocol. Five patients with PC (age 21-54 years) who were treated at our medical centre from April 2015 to June 2018 were included in the study. After an ultrasound-guided nerve block performed by an anaesthesiologist, the patients received plantar intradermal injections of Btx A. To ascertain the effect of the treatment, we used a dedicated quality-of-life questionnaire for patients with PC (PCQoL) and asked the patients to evaluate the intensity of eight parameters pertaining to their symptoms at baseline and before every treatment session. At study closure, patients were asked to evaluate the maximal improvement in the same eight parameters throughout the study period. All patients demonstrated a decrease in PCQoL scores during the follow-up period. All patients showed a significant improvement in PCQoL after the first treatment session and at the last evaluation (P = 0·043). The scores with the best improvement concerned morning feet burning and long-distance walking (> 500 m). The scores were significantly lower if the intervals between Btx injections were <100 days. Btx treatment of PC-associated keratoderma following an optimized protocol leads to a major change in patients' quality of life. What's already known about this topic? Plantar pain is considered by patients to be the most severe and debilitating manifestation of pachyonychia congenita (PC). Over the past few years, a number of reports have shown that plantar injections of botulinum toxin (Btx) reduce or even eliminate pain, blistering and callosities in patients with PC. However, the injection technique, doses of Btx and methods of anaesthesia varied between reports and patients. What does this study add? Here we report our 4-year experience in providing 30 treatments to five patients following an optimized protocol. Btx was found to provide a quantifiable improvement in all patients treated. What is the translational message? Btx treatment of PC-associated keratoderma using a structured approach, which includes the use of a sufficient dose of Btx (200-400 U of onabotulinumtoxinA or 500-1000 U of abobotulinumtoxinA), and regular intervals between treatment sessions (of < 100 days), leads to a major change in patients' quality of life.
2018-12-19 | Neuroendocrine Controls of Keratin Expression in Human Skin
The human skin serves as a source for a large number of neurohormones and neuropeptides, which affect skin biology on multiple different levels. Intriguingly, this includes the control of keratin expression by neurohormones such as thyrotropin-releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1-ligands. While this neuroendocrine regulation of human keratin biology in situ is likely to be involved in the maintenance of skin and hair follicle homeostasis and may participate in skin pathology, this regulation remains to be appreciated and explored by mainstream keratin research. Here, we review recent progress in this frontier of neuroendocrine and keratin skin research, define the many open questions in the field, and elaborate how neurohormones may be harnessed to treat selected genodermatoses and other skin disorders accompanied by abnormal keratin expression.
small molecules
2026-07-21 | Keratin 16 puts the brakes on type I interferon signalling.
A recent study by Cohen et al. identified stress-induced keratin 16 (KRT16) as an active regulator of skin innate immunity. By sequestering 14-3-3ε, KRT16 suppresses retinoic acid-inducible gene I-mediated type I interferon (IFN) signalling. KRT16 loss in pachyonychia congenita amplifies inflammatory IFN signalling, highlighting the KRT16-IFN signalling axis as a potential therapeutic target.
2026-07-02 | Case Report: Successful topical simvastatin therapy in a 2-year-old girl with keratin 16-associated palmoplantar epidermal differentiation disorder
Palmoplantar epidermal differentiation disorder associated with pachyonychia congenita is a rare autosomal dominant genodermatosis characterized by painful palmoplantar hyperkeratosis and nail dystrophy. Treatment options remain limited, particularly in young children, in whom systemic therapies carry safety concerns. Herein, we report a 2-year-old girl who presented with palmoplantar hyperkeratosis since 1 month of age, with progressive nail dystrophy involving all 20 nails. Whole-exome sequencing identified a hemizygous multi-exon deletion in keratin 16 (ClinVar: SUB16259296; OMIM: #167200), and orthogonal validation using amplicon-based high-throughput sequencing confirmed a 437-nucleotide deletion predicted to result in a frameshift with premature termination codon (PTC). American College of Medical Genetics and Genomics classification supported likely pathogenicity. Twice-daily application of topical 2.5% simvastatin/cholesterol cream for 11 weeks produced substantial improvement in plantar hyperkeratosis, resolution of painful fissures, and visibly improved morphology of nascent nail growth. No local or systemic adverse effects were observed. This case provides preliminary evidence that topical simvastatin may be an effective and well-tolerated therapy for keratin 16-associated palmoplantar epidermal differentiation disorder in young children, and highlights the potential importance of topical drug delivery in achieving therapeutic efficacy for this genetic subtype.
2026-04-08 | Keratin 16 inhibits type I interferon responses in differentiating keratinocytes of stressed and diseased skin.
The stress-induced keratin 16 intermediate filament gene, KRT16, and K16 protein are spatially restricted to the suprabasal layers of the epidermis and widely used as biomarkers in psoriasis, hidradenitis suppurativa, atopic dermatitis, and other inflammatory disorders. Pathogenic variants in KRT16 cause pachyonychia congenita (PC), a rare genetic condition in which tissue homeostasis is disrupted in palmoplantar epidermis, nail, oral mucosa, and other KRT16-expressing epithelial appendages. How K16 may regulate the molecular mechanisms underlying these conditions is poorly understood. Here, we show that K16 negatively regulates type I interferon (IFN) signaling and innate immune responses in skin. Clinically, the signature palmoplantar keratoderma lesions in individuals with PC showed enhanced type I IFN signaling. In mouse skin in vivo, loss of Krt16 led to exacerbation of imiquimod-induced psoriasiform disease and heightened recruitment of neutrophils in a phorbol ester-induced model of acute sterile inflammation. In KRT16-null human keratinocytes, loss of K16 amplified IFN signaling including phosphorylated interferon regulatory factor 7 (IRF7) and interferon-stimulated gene 15 (ISG15) after treatment with synthetic dsRNA poly(I:C). Mechanistically, K16 interacted with effectors of the RIG-I-like receptor (RLR) pathway, including 14-3-3ɛ, and inhibited the 14-3-3ɛ:RIG-I interaction upstream of IFN activation in mouse and immortalized human keratinocytes ex vivo. Topical application of the Janus kinase inhibitor cream ruxolitinib to palmoplantar keratoderma lesions of Krt16-null mice reduced lesion severity. These findings uncover a previously unrecognized paradigm for keratin-dependent regulation of innate immunity, with implications for our understanding of inflammatory skin diseases and potential treatments for PC.
2026-04-01 | Miliaria Crystallina in a Case of Pachyonychia Congenita: An Unusual and Underreported Association
Abstract Pachyonychia congenita (PC) is a rare genodermatosis characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, and oral leukokeratosis. We report the case of a 5-year-old boy with classical features of PC along with the rare co-occurrence of extensive miliaria crystallina, a combination reported only once previously. The patient presented with thickened nails from infancy, widespread follicular hyperkeratosis, recurrent summer-onset vesicular lesions, and oral leukokeratosis. Histopathology confirmed features of both PC and miliaria. Based on clinical, dermoscopic, and histopathological findings, a diagnosis of PC was established. The patient responded well to a combination of oral isotretinoin, urea-based keratolytics, and topical steroid-antibiotic therapy. This case highlights a rare and unusual presentation of PC and underscores the importance of recognizing such associations for accurate diagnosis and management.
2026-02-26 | KRT6A Variant Underlies Pachyonychia Congenita: Insights Into Protein Aggregation and PPAR Signaling.
Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to identify the causative mutation in a PC family and investigate the underlying pathogenic mechanism. We performed exome sequencing on this PC pedigree and validated candidate variations using Sanger sequencing. In silico predictions and in vitro experiments showed that the heterozygous missense variant c.512A>G in KRT6A was pathogenic, inducing protein aggregation and disrupting filamentous network structures. Enrichment analysis suggested that the PPAR signaling pathway played a crucial role in PC, with decreased expression of PPARβ/δ in HeLa cells. Comparative analysis of PC patients carrying the p.Asn171 variant revealed marked heterogeneity in clinical manifestations. Notably, oral leukokeratosis, a common phenotype in KRT6A mutation carriers, was not observed in the patients in this study. Interestingly, one patient presented with small papules around the lips and nasal bridge. We conclude that the c.512A>G variant in KRT6A is the genetic cause of this PC family, diagnosed as PC-K6a subtype. This study expands the phenotypic spectrum of congenital PC and suggests the PPAR signaling pathway as a potential therapeutic target.
gene therapies
2023-09-28 | Pachyonychia Congenita: Clinical Features and Future Treatments.
Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.
oligonucleotides
2023-09-18 | Proteomic profiling reveals KRT6C as a probable hereterodimer partner for KRT9: New insights into re-classifying epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c) as a group of genetic cutaneous disorders.
Epidermolytic palmoplantar keratoderma (EPPK), a highly penetrant autosomal dominant genodermatosis, is characterized by diffuse keratoses on palmplantar epidermis. The keratin 9 gene (KRT9) is responsible for EPPK. To date, phenotypic therapy is the primary treatment for EPPK. Because KRT9 pairs with a type II keratin-binding partner to function in epidermis, identifying the interaction partner is an essential first step in revealing EPPK pathogenesis and its fundamental treatment. In this study, we proved that keratin 6C (KRT6C) is a probable hereterodimer partner for KRT9. In silico model for KRT6C/KRT9 shows a typical coiled-coil structure in their 2B domains. Proteomics analysis shows that KRT6C/KRT9 pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating cytoskeleton organization and keratinization. This study shows that co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis provide a sensitive approach, which compensates for inevitable inadequacies of anti-keratin 6C antibody and helps discover the probable hereterodimer partner KRT6C for KRT9. The acknowledgement of KRT6C/KRT9 pairwise relationship may help re-classify EPPK and PC-K6c (a milder form of pachyonychia congenita, caused by KRT6C) as a group of hereditary defects at a molecular-based level, and lay foundation for deciphering the keratin network contributing to EPPK and PC-K6c. SIGNIFICANCE OF THE STUDY: What is already known about this topic? KRT9 and KRT6C are disease-causing factors for epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c), respectively. EPPK and PC-K6c have some symptom similarities. Keratins are the major structural proteins in epithelial cells. Each of the type I keratin is matched by a particular type II keratin to assemble a coiled-coil heterodimer. The hereterodimer partner for KRT9 is unknown. What does this study add? We discovered and proved that KRT6C is a probable hereterodimer partner for KRT9 in palmplantar epidermis in a native endogenous environment by using co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis, etc. The proteomics analysis shows that KRT6C/KRT9 keratin pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating intermediate filament-based cytoskeleton organization and keratinization processes. What are the implications of this work? The new understanding of probable KRT6C/KRT9 pairwise correlation may help re-classify the genetic cutaneous disorders EPPK and PC-K6c as a group of hereditary defects at a molecular-based level, and lay foundation for pathogenic mechanism research in EPPK and PC-K6c. The densely related network components derived from the proteomic data using Metascape in the study and pairwise regulation fashion of specific keratin pairs should attract more attention in the further explorations when investigators concern the physiological functions of keratins and the pathogenesis of related skin diseases.
2022-01-17 | Highly branched poly(β-amino ester)s for gene delivery in hereditary skin diseases.
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
2018-10-11 | Keratin 17 in disease pathogenesis: from cancer to dermatoses
Abstract 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.
2003-12-01 | In vivo alteration of the keratin 17 gene in hair follicles by oligonucleotide-directed gene targeting.
Abstract: Using intradermal injection of a chimeric RNA–DNA oligonucleotide (RDO) or a single‐stranded oligonucleotide (ssODN) into murine skin, we attempted to make a dominant mutation (R94P) in the conserved α‐helical domain of keratin 17 (K17), the same mutation found in pachyonychia congenichia type 2 (PC‐2) patients with phenotypes ranging from twisted hair to multiple pilosebaceous cysts. Both K17A‐RDO and K17‐ssODN contained a single base mismatch (C G C to C C C) to alter the normal K17 sequence to cause an amino acid substitution (R94P). The complexes consisting of oligonucleotides and cationic liposomes were injected to C57Bl/6 murine skin at 2 and 5 day after birth. Histological examination of skin biopsies at postnatal day 8 from several mice showed consistent twisted hair shafts or broken hair follicles at the sebaceous gland level and occasional rupture of the hair bulb or epidermal cyst‐like changes. In the injected area, the number of full anagen hair follicles decreased by 50%. Injection of the control oligonucleotide, identical to K17A‐RDO but containing no mismatch to the normal sequence, did not result in any detectable abnormality. The frequency of gene alteration was lower than 3%, according to the restriction fragment length polymorphism (RFLP) analysis of the genomic DNA isolated by dissection of hair follicles from slides. Although intradermal injection of K17A‐RDO or K17‐ssODN caused a dominant mutation in K17 affecting hair growth and morphology, these phenotypic changes were transient either due to the compensation of K17 by other keratins or the replacement of the mutated cells by normal surrounding cells during hair growth.
proteins
2026-07-21 | Autosomal Recessive Palmoplantar Epidermal Differentiation Disorder Caused by Homozygous Stop-Gain Variant in KRT16 Gene.
Palmoplantar epidermal differentiation disorders (pEDDs) comprise a heterogeneous group of disorders characterized by hyperkeratotic thickening of the palms and soles due to pathogenic variants in genes that regulate palmoplantar epidermal differentiation and keratinization. Among these, KRT16-pEDD is caused by heterozygous mutations in the KRT16 gene and may present clinically either as isolated palmoplantar keratoderma (PPK) or as part of the broader phenotype of pachyonychia congenita. This report describes a rare bi-allelic pattern of inheritance involving a presumed loss-of-function variant in KRT16, thereby extending the clinical and genetic spectrum of KRT16-related disorders, and highlighting important implications for variant interpretation and genetic counseling.
2023-04-17 | 894 Towards a genetically- and phenotypically-relevant mouse model for pachyonychia congenita
Pachyonychia congenita(PC) is a rare disorder that features palmoplantar keratoderma(PPK) as its most significant symptom. PPK are thick calluses arising in palmar and plantar skin that are painful to the point of debilitation in PC and related disorders. PC is caused by dominantly-acting small mutations that affect the coding sequence of KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Unlike the case for many other keratinopathies, cell fragility is not a key driver of the genesis of PPK lesions in PC. There currently is no effective treatment for this disorder. We previously generated a mouse strain, Krt16 null, that develops PC-like PPK in footpad skin (J. Invest. Dermatol. 132:1384-91, 2012). The study of these mice has yielded novel insight into the pathophysiology of PC. However, given that most cases of PC involve dominantly-acting missense alleles in KRT16 and other PC genes, Krt16null mice are not genetically relevant to PC nor are they amenable to developing or testing mutant allele-specific therapies. To address this deficiency, we used CRISPR-Cas9 to introduce a R123C point mutation in the Krt16 gene of mice. This allele accounts for >20% of the KRT16-based cases of PC (33/157) and is associated with a classic PC presentation. The Krt16 R123C allele shows Mendelian inheritance and does not compromise viability in mouse offspring. At 5 months of age, mice homozygous for the Krt16 R123C allele show raised footpads but do not feature obvious hyperkeratosis or acanthosis upon histological examination of footpad skin. These findings contrast with Krt16 null mice, which frequently die pre-weaning (66% penetrance) and develop striking PPK-like lesions in footpad skin by two months of age (100% penetrance). Further analysis of Krt16 R123C mice will shed new light into the enigmatic disorder that PC represents.
2019-09-23 | The non-neuronal and nonmuscular effects of botulinum toxin: an opportunity for a deadly molecule to treat disease in the skin and beyond.
There is growing evidence that botulinum neurotoxins (BoNTs) exhibit biological effects on various human cell types with a host of associated clinical implications. This review aims to provide an update on the non-neuronal and nonmuscular effects of botulinum toxin. We critically analysed recent reports on the structure and function of cellular signalling systems subserving biological effects of BoNTs. The BoNT receptors and intracellular targets are not unique for neurotransmission. They have been found in both neuronal and non-neuronal cells, but there are differences in how BoNT binds to, and acts on, neuronal vs. non-neuronal cells. The non-neuronal cells that express one or more BoNT/A-binding proteins, and/or cleavage target synaptosomal-associated protein 25, include: epidermal keratinocytes; mesenchymal stem cells from subcutaneous adipose; nasal mucosal cells; urothelial cells; intestinal, prostate and alveolar epithelial cells; breast cell lines; neutrophils; and macrophages. Serotype BoNT/A can also elicit specific biological effects in dermal fibroblasts, sebocytes and vascular endothelial cells. Nontraditional applications of BoNT have been reported for the treatment of the following dermatological conditions: hyperhidrosis, Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita, multiple eccrine hydrocystomas, eccrine angiomatous hamartoma, eccrine sweat gland naevi, congenital eccrine naevus, Raynaud phenomenon and cutaneous leiomyomas. Experimental studies have demonstrated the ability of BoNT/A to protect skin flaps, facilitate wound healing, decrease thickness of hypertrophic scars, produce an anti-ageing effect, improve a mouse model of psoriasiform dermatitis, and have also revealed extracutaneous effects of BoNT arising from its anti-inflammatory and anticancer properties. BoNTs have a much wider range of applications than originally understood, and the individual cellular responses to the cholinergic impacts of BoNTs could provide fertile ground for future studies.
2019-05-25 | A treatment protocol for botulinum toxin injections in the treatment of pachyonychia congenita‐associated keratoderma
Severely debilitating plantar keratoderma pain is the most distressing clinical feature of pachyonychia congenita (PC). Several earlier publications have reported therapeutic success with plantar injections of botulinum toxin (Btx). To describe our 4-year experience during which we administered a total of 30 plantar Btx injections to five patients with PC following an optimized protocol. Five patients with PC (age 21-54 years) who were treated at our medical centre from April 2015 to June 2018 were included in the study. After an ultrasound-guided nerve block performed by an anaesthesiologist, the patients received plantar intradermal injections of Btx A. To ascertain the effect of the treatment, we used a dedicated quality-of-life questionnaire for patients with PC (PCQoL) and asked the patients to evaluate the intensity of eight parameters pertaining to their symptoms at baseline and before every treatment session. At study closure, patients were asked to evaluate the maximal improvement in the same eight parameters throughout the study period. All patients demonstrated a decrease in PCQoL scores during the follow-up period. All patients showed a significant improvement in PCQoL after the first treatment session and at the last evaluation (P = 0·043). The scores with the best improvement concerned morning feet burning and long-distance walking (> 500 m). The scores were significantly lower if the intervals between Btx injections were <100 days. Btx treatment of PC-associated keratoderma following an optimized protocol leads to a major change in patients' quality of life. What's already known about this topic? Plantar pain is considered by patients to be the most severe and debilitating manifestation of pachyonychia congenita (PC). Over the past few years, a number of reports have shown that plantar injections of botulinum toxin (Btx) reduce or even eliminate pain, blistering and callosities in patients with PC. However, the injection technique, doses of Btx and methods of anaesthesia varied between reports and patients. What does this study add? Here we report our 4-year experience in providing 30 treatments to five patients following an optimized protocol. Btx was found to provide a quantifiable improvement in all patients treated. What is the translational message? Btx treatment of PC-associated keratoderma using a structured approach, which includes the use of a sufficient dose of Btx (200-400 U of onabotulinumtoxinA or 500-1000 U of abobotulinumtoxinA), and regular intervals between treatment sessions (of < 100 days), leads to a major change in patients' quality of life.
2018-12-19 | Neuroendocrine Controls of Keratin Expression in Human Skin
The human skin serves as a source for a large number of neurohormones and neuropeptides, which affect skin biology on multiple different levels. Intriguingly, this includes the control of keratin expression by neurohormones such as thyrotropin-releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1-ligands. While this neuroendocrine regulation of human keratin biology in situ is likely to be involved in the maintenance of skin and hair follicle homeostasis and may participate in skin pathology, this regulation remains to be appreciated and explored by mainstream keratin research. Here, we review recent progress in this frontier of neuroendocrine and keratin skin research, define the many open questions in the field, and elaborate how neurohormones may be harnessed to treat selected genodermatoses and other skin disorders accompanied by abnormal keratin expression.
small molecules
2026-07-21 | Keratin 16 puts the brakes on type I interferon signalling.
A recent study by Cohen et al. identified stress-induced keratin 16 (KRT16) as an active regulator of skin innate immunity. By sequestering 14-3-3ε, KRT16 suppresses retinoic acid-inducible gene I-mediated type I interferon (IFN) signalling. KRT16 loss in pachyonychia congenita amplifies inflammatory IFN signalling, highlighting the KRT16-IFN signalling axis as a potential therapeutic target.
2026-07-02 | Case Report: Successful topical simvastatin therapy in a 2-year-old girl with keratin 16-associated palmoplantar epidermal differentiation disorder
Palmoplantar epidermal differentiation disorder associated with pachyonychia congenita is a rare autosomal dominant genodermatosis characterized by painful palmoplantar hyperkeratosis and nail dystrophy. Treatment options remain limited, particularly in young children, in whom systemic therapies carry safety concerns. Herein, we report a 2-year-old girl who presented with palmoplantar hyperkeratosis since 1 month of age, with progressive nail dystrophy involving all 20 nails. Whole-exome sequencing identified a hemizygous multi-exon deletion in keratin 16 (ClinVar: SUB16259296; OMIM: #167200), and orthogonal validation using amplicon-based high-throughput sequencing confirmed a 437-nucleotide deletion predicted to result in a frameshift with premature termination codon (PTC). American College of Medical Genetics and Genomics classification supported likely pathogenicity. Twice-daily application of topical 2.5% simvastatin/cholesterol cream for 11 weeks produced substantial improvement in plantar hyperkeratosis, resolution of painful fissures, and visibly improved morphology of nascent nail growth. No local or systemic adverse effects were observed. This case provides preliminary evidence that topical simvastatin may be an effective and well-tolerated therapy for keratin 16-associated palmoplantar epidermal differentiation disorder in young children, and highlights the potential importance of topical drug delivery in achieving therapeutic efficacy for this genetic subtype.
2026-04-08 | Keratin 16 inhibits type I interferon responses in differentiating keratinocytes of stressed and diseased skin.
The stress-induced keratin 16 intermediate filament gene, KRT16, and K16 protein are spatially restricted to the suprabasal layers of the epidermis and widely used as biomarkers in psoriasis, hidradenitis suppurativa, atopic dermatitis, and other inflammatory disorders. Pathogenic variants in KRT16 cause pachyonychia congenita (PC), a rare genetic condition in which tissue homeostasis is disrupted in palmoplantar epidermis, nail, oral mucosa, and other KRT16-expressing epithelial appendages. How K16 may regulate the molecular mechanisms underlying these conditions is poorly understood. Here, we show that K16 negatively regulates type I interferon (IFN) signaling and innate immune responses in skin. Clinically, the signature palmoplantar keratoderma lesions in individuals with PC showed enhanced type I IFN signaling. In mouse skin in vivo, loss of Krt16 led to exacerbation of imiquimod-induced psoriasiform disease and heightened recruitment of neutrophils in a phorbol ester-induced model of acute sterile inflammation. In KRT16-null human keratinocytes, loss of K16 amplified IFN signaling including phosphorylated interferon regulatory factor 7 (IRF7) and interferon-stimulated gene 15 (ISG15) after treatment with synthetic dsRNA poly(I:C). Mechanistically, K16 interacted with effectors of the RIG-I-like receptor (RLR) pathway, including 14-3-3ɛ, and inhibited the 14-3-3ɛ:RIG-I interaction upstream of IFN activation in mouse and immortalized human keratinocytes ex vivo. Topical application of the Janus kinase inhibitor cream ruxolitinib to palmoplantar keratoderma lesions of Krt16-null mice reduced lesion severity. These findings uncover a previously unrecognized paradigm for keratin-dependent regulation of innate immunity, with implications for our understanding of inflammatory skin diseases and potential treatments for PC.
2026-04-01 | Miliaria Crystallina in a Case of Pachyonychia Congenita: An Unusual and Underreported Association
Abstract Pachyonychia congenita (PC) is a rare genodermatosis characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, and oral leukokeratosis. We report the case of a 5-year-old boy with classical features of PC along with the rare co-occurrence of extensive miliaria crystallina, a combination reported only once previously. The patient presented with thickened nails from infancy, widespread follicular hyperkeratosis, recurrent summer-onset vesicular lesions, and oral leukokeratosis. Histopathology confirmed features of both PC and miliaria. Based on clinical, dermoscopic, and histopathological findings, a diagnosis of PC was established. The patient responded well to a combination of oral isotretinoin, urea-based keratolytics, and topical steroid-antibiotic therapy. This case highlights a rare and unusual presentation of PC and underscores the importance of recognizing such associations for accurate diagnosis and management.
2026-02-26 | KRT6A Variant Underlies Pachyonychia Congenita: Insights Into Protein Aggregation and PPAR Signaling.
Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to identify the causative mutation in a PC family and investigate the underlying pathogenic mechanism. We performed exome sequencing on this PC pedigree and validated candidate variations using Sanger sequencing. In silico predictions and in vitro experiments showed that the heterozygous missense variant c.512A>G in KRT6A was pathogenic, inducing protein aggregation and disrupting filamentous network structures. Enrichment analysis suggested that the PPAR signaling pathway played a crucial role in PC, with decreased expression of PPARβ/δ in HeLa cells. Comparative analysis of PC patients carrying the p.Asn171 variant revealed marked heterogeneity in clinical manifestations. Notably, oral leukokeratosis, a common phenotype in KRT6A mutation carriers, was not observed in the patients in this study. Interestingly, one patient presented with small papules around the lips and nasal bridge. We conclude that the c.512A>G variant in KRT6A is the genetic cause of this PC family, diagnosed as PC-K6a subtype. This study expands the phenotypic spectrum of congenital PC and suggests the PPAR signaling pathway as a potential therapeutic target.
gene therapies
2023-09-28 | Pachyonychia Congenita: Clinical Features and Future Treatments.
Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.
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Drug Discovery Landscape
9 orphan drug designations for Pachyonychia congenita.
9 orphan drug designations for Pachyonychia congenita.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
erlotinib | small molecules | FDA | Alembic Pharmaceuticals Inc. | |
(R)-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl) pyrrolidin-1-yl)(5-fluoropyridin-2-yl)methanone | small molecules | FDA | Orvida Pharma Ltd. | |
(R)-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl) pyrrolidin-1-yl)(5-fluoropyridin-2-yl)methanone | small molecules | EMA | — | Granzer Regulatory Consulting & Services GmbH |
Erlotinib | small molecules | EMA | Imagine Institut Des Maladies Genetiques Necker Enfants Malades | |
Sirolimus | small molecules | EMA | Raremoon Consulting Esp S.L. | |
Synthetic double-stranded siRNA oligonucleotide directed against the keratin 6a N171K mutation | RNAs | EMA | Alan Irvine | |
sdTD-K6a.513a.12; small interfering RNA composed of 2 strands of hybridized RNAs | RNAs | FDA | — | TransDerm, Inc. |
sirolimus | small molecules | FDA | Palvella Therapeutics, Inc. | |
TD-K6a.513a.12 | RNAs | FDA | — | TransDerm, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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