Pachyonychia congenita: A father and son with a novel variant in the KRT16 gene.

This study underscores the significance of identifying the clinical manifestations of pachyonychia congenita (PC) and emphasizes the patterns of genetic inheritance. A 12-month-old boy presented with a "white hairy tongue" and, following a comprehensive evaluation, was diagnosed with PC. His father exhibited similar symptoms. Genetic testing revealed a KRT16 pathogenic variant (c.616 T > G) in both the patient and his father, marking it as a novel variant in the PC literature. This case contributes to a broader understanding of PC's genetic diversity and its clinical presentations.

Scrutinising the role of simvastatin in a patient of Pachyonychia Congenita with KRT6A gene mutation.

A 25-year-old male patient presented with palmoplantar keratoderma, dystrophic nails, severe plantar pain and oral leukokeratosis since birth. On genetic analysis, a heterozygous KRT6A gene missense mutation (c.1381G > A, p.Glu461Lys in exon 7) was identified by next-generation sequencing technology, consistent with pachyonychia congenita 6a. Oral simvastatin 40 mg was started once daily, and after 16 weeks of therapy, excellent improvement was noted in palmoplantar keratoderma and plantar pain. The maximum thickness of his foot callosity reduced by 4 mm on ultrasonography, and the Dermatology Life Quality Index score dropped significantly by eight points. These benefits may be attributed to inhibition of KRT6A gene expression, modulation of autophagy and mitophagy and Keap1-Nrf2 signalling activation; the latter two mechanisms of statins previously undiscussed in the context of pachyonychia congenita. Simvastatin and other statins are pathogenesis-targeted, disease-modifying therapy in pachyonychia congenita, therefore qualifying as a promising treatment avenue and warranting further clinical trials.

Keratin 17 in disease pathogenesis: from cancer to dermatoses.

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-ß) 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.

The histopathological features of the nail plate in pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant disorder of keratinization mediated by genetic mutations in KRT6A, KRT6B, KRT6C, KRT16, or KRT17. While nail dystrophy in PC has a significant impact on quality of life, the histopathological features of the nail plate in PC have not been previously reported. We report the histopathological features of nail plates provided by 19 patients with genetically confirmed PC. METHODS: Nineteen patients with genetically confirmed PC provided a total of 56 nail plates for histopathologic examination. The nail plates were examined for the presence of hyphae, yeast, bacteria, neutrophils, parakeratosis, plasma globules, and hemorrhage. Specimens with onychomycosis (three patients) were excluded from the analysis. RESULTS: No specific histopathological feature was identified in PC nails. Parakeratosis and plasma globules were the most prominent features in both clinically affected and unaffected PC nails. There was a significant association between clinical dystrophy of all 20 nails and KRT6A mutations, and a lack of dystrophy of all 20 nails in KRT6B mutations. CONCLUSIONS: Parakeratosis and plasma globules in the absence of other inflammatory disorders should raise PC in the histopathologic differential diagnosis. The presence of onychomycosis in a nail plate does not exclude a diagnosis of PC.

Generalized bullae in a young girl with KRT6A-related pachyonychia congenita.

Pachyonychia congenita (PC) is a rare genodermatosis showing heterogeneity with five causative keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). Clinically, PC is characterized by hypertrophic onychodystrophy, painful palmoplantar keratoderma, oral leukokeratosis, and follicular hyperkeratosis. We describe an atypical case of PC in a young Chinese girl presenting with generalized bullae and identified a recurrent heterozygous missense mutation c.1406T > C (p.Leu469Pro) in KRT6A. This suggests that bullae may represent an important feature of KRT6A-related PC.

Pachyonychia congenita responding favorably to a combination of surgical and medical therapies.

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.

Nociceptin/orphanin FQ opioid peptide-receptor expression in pachyonychia congenita.

Nociceptin/orphanin FQ opioid peptide (NOP)-receptor (NOP-R) is a member of the opioid receptor family. NOP-R activation has demonstrated analgesic effects in preclinical pain models without the addiction risks associated with other opiate targets. Pachyonychia congenita (PC) is a palmoplantar keratoderma characterized by neuropathic pain in affected skin. A cohort of KRT6A gene mutation PC patients with no other explanation for their neuropathic pain offered a unique opportunity to assess potential of NOP-R as a therapeutic target. Plantar biopsies from 10 PC patients and 10 age/gender matched controls were performed at the ball (PC-affected) and the arch (PC-unaffected) of the foot. NOP-R expression was assessed by immunohistochemistry. Localization of NOP-R in subsets of epidermal nerve fibers was investigated using the pan-neuronal marker PGP9.5, markers for unmyelinated peptidergic fibers (calcitonin gene-related peptide [CGRP] and substance P [SP]), as well as for myelinated Aδ and Aß fibers (neurofilament H [NFH]). Robust NOP-R expression was detected in epidermal keratinocytes and in a subset of PGP9.5+ fibers in both epidermis and dermis, confirmed by western blot and absorption experiments with NOP-R peptide. NOP-R expression in keratinocytes was significantly reduced in PC-affected plantar skin compared with PC-unaffected skin. In addition, NOP-R expression occurred in dermal NFH+ myelinated fibers in all groups, although few CGRP+ fibers co-expressed NOP-R. Furthermore, most SP+ fibers also co-expressed NOP-R. These findings indicate that NOP-R is expressed on epidermal keratinocytes, as well as on epidermal and dermal nerve fibers and has potential as a promising target to treat neuropathic pain in PC.

Efficacy of botulinum toxin in pachyonychia congenita type 1: report of two new cases.

Pachyonychia congenita (PC) is a rare genodermatosis caused by a mutation in keratin genes, which can lead to hypertrophic nail dystrophy and focal palmoplantar keratoderma (predominantly plantar), amongst other manifestations. Painful blisters and callosities, sometimes exacerbated by hyperhidrosis, are major issues that can have a significant impact on patient quality of life. Many alternative treatments for this condition have been applied with variable and partial clinical response, but a definitive cure for this disease has yet to be discovered. After obtaining informed consent, two patients with genetically confirmed PC type 1 were treated with plantar injections of botulinum toxin type A. Both patients showed a marked improvement in pain and blistering with an average response time of one week, a six-month mean duration of effectiveness, and a lack of any side effects or tachyphylaxis.

First case of pachyonychia congenita in the Czech Republic.

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by hypertrophic nail dystrophy, oral leukokeratosis, and painful palmoplantar keratoderma. It is associated with a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The International PC Research Registry (IPCRR) confirms that as of January 2014 there have been 547 cases of PC genetically confirmed. It is estimated that there are between 2000 and 10,000 cases of PC in the world. However, the exact prevalence of PC is not yet established. We report a case of PC-K6a, p.Arg164Pro, in a 40-year-old man. Initially he was diagnosed with onychomycosis and was treated with systemic antifungals. This is the first genetically confirmed case of PC in the Czech Republic.

Mutation p.Arg127Pro in the 1A Domain of KRT16 Causes Pachyonychia Congenita in Chinese Patient: A Case Report of PC Associated with Acral Melanoma.

Pachyonychia congenita (PC) is a group of rare hereditary disorders, characterised by hypertrophic nails and palmoplantar keratoderma (PPK), particularly localised to the pressure areas of the feet. At a molecular level, it is caused by mutations in genes encoding KRT6A, KRT6B, KRT6C, KRT16, or KRT17. To identify the underlying gene mutation in a Chinese family with PC presenting with disabling palmoplantar keratoderma and subsequent associated acral melanoma. Genomic DNA was extracted from peripheral blood samples of three available individuals in the Chinese family, which included the patient and his two unaffected sisters. The index patient presented with severe palmoplantar keratoderma as well as a newly diagnosed acral malignant melanoma (MM). Whole-exome sequencing (WES) was carried out with amplification of exon 1 of KRT16 by polymerase chain reaction (PCR). PCR products were then sequenced to identify potential mutations. We identified the proline substitution mutation p.Arg127Pro (c.380G>C) in our patient's 1A domain of KRT16. The same mutation was not found in his sisters or unrelated healthy controls. The mutation (p.Arg127Pro (c.380G>C)) in KRT16 has been reported in Dutch patients with PC. However, it is the first such report of a patient with a PC of Chinese origin. In addition, the acral MM occurred under the background of genetic PPK caused by KRT16 mutation in this patient.

A novel heterozygous frameshift mutation in the KRT6A gene responsible for an uncommon phenotype of pachyonychia congenita: One case report and review of literature.

Pachyonychia congenita is an uncommon autosomal dominant skin disorder characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and cutaneous cysts. And fissured tongue is rarely reported in patients with pachyonychia congenita. The disease is primarily associated with mutations in five keratin genes, namely KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Herein we report a 9-year-old Chinese girl who has thickened nails, keratinized plaques, and fissured tongue since birth. To investigate the underlying genetic cause, whole-exome sequencing and Sanger sequencing were performed in this patient and her family members. We identified a candidate variant c.1460-2_1460del (p.S487Lfs*21) in the KRT6A gene (NM_005554.4) by whole-exome sequencing. Sanger sequencing revealed the absence of the mutation in both parents, indicating that it is a de novo variant. Thus, the novel heterozygous frameshift mutation c.1460-2_1460del (p.S487Lfs*21) within exon 9 of KRT6A was identified as the genetic cause of the patient. Our study identified a rare de novo heterozygous frameshift mutation in the KRT6A gene in a patient with pachyonychia congenita presenting fissured tongue. Our findings expand the KRT6A gene mutation spectrum of Pachyonychia congenita, and will contribute to the future genetic counseling and gene therapy for this disease.

Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.

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.

Pachyonychia Congenita Project: Advancing Research and Drug Development through Collaboration.

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.

Phenotype and genotype features of Vietnamese children with pachyonychia congenita.

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.

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.

Walking a day in a pachyonychia congenita patient's shoes: Impact on plantar pain and activity levels measured with wristband activity trackers.

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.

Surgical Management of Pachyonychia Congenita in a 3-Year-Old.

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.