Pachyonychiacongenita - pathogenesis of pain and approaches to treatment. Pachyonychiacongenita 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 pachyonychiacongenita and provides a summary of the current and future therapeutic options.
Prevalence and Patient Characteristics of PachyonychiaCongenita. This cross-sectional study estimates the prevalence of genetically confirmed cases of pachyonychiacongenita in Denmark.
PachyonychiaCongenita: A Research Agenda Leading to New Therapeutic Approaches. Pachyonychiacongenita (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 PachyonychiaCongenita 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.
EGFR signaling is overactive in Pachyonychiacongenita: effective treatment with oral erlotinib. Pachyonychiacongenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma (PPK) for which there is no standard current treatment. PC is caused by dominant mutations in keratin 6A, 6B, 6C, 16, and 17 genes involved in stress, wound healing, and epidermal barrier
Scrutinising the role of simvastatin in a patient of PachyonychiaCongenita 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 pachyonychiacongenita 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
KERATIN 17-related recessive atypical pachyonychiacongenita with variable hair and tooth anomalies. We present the first pachyonychiacongenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma
Coexistence of pachyonychiacongenita and hidradenitis suppurativa: more than a coincidence. The coexistence of pachyonychiacongenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. To determine the genetic defect underlying the coexistence of PC and HS in a large kindred , to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International PachyonychiaCongenita Research Registry
Revisiting pachyonychiacongenita: a case-cohort study of 815 patients. Pachyonychiacongenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. To harness the same resource to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. In total, 815 individuals with confirmed keratin mutations registered in the International PachyonychiaCongenita Research Registry were surveyed for clinical findings associated with PC. Data were
Symptomatic mucosal involvement in pachyonychiacongenita: challenges in infants and young children. Pachyonychiacongenita (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 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? Pachyonychiacongenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement
A treatment protocol for botulinum toxin injections in the treatment of pachyonychiacongenita-associated keratoderma. Severely debilitating plantar keratoderma pain is the most distressing clinical feature of pachyonychiacongenita (PC). Several earlier publications have reported therapeutic success with plantar injections of botulinum toxin (Btx). To describe our 4-year experience during which 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 pachyonychiacongenita (PC). Over the past few years, a number of reports have shown that plantar injections of botulinum toxin (Btx) reduce or even
Pathophysiology of pachyonychiacongenita-associated palmoplantar keratoderma: New insight into skin epithelial homeostasis and avenues for treatment. Pachyonychiacongenita (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 of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychiacongenita (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
Follicular occlusion tetrad in a male patient with pachyonychiacongenita: clinical and genetic analysis. The case of a 24-year-old male patient affected by follicular occlusion tetrad (acne conglobata, hidradenitis suppurativa, pilonidal cyst and dissecting cellulitis of the scalp) associated with clinical signs of pachyonychiacongenita (PC)-2 (focal palmoplantar keratoderma, plantar pain
Pachyonychiacongenita: A case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation. Pachyonychiacongenita (PC) is a rare autosomal dominant disorder characterized by nail dystrophy and palmoplantar keratoderma with severe plantar pain affecting quality of life. There is no effective treatment. Heterozygous mutations in the keratin genes KRT6A, KRT6B, KRT6C was demonstrated by sonography. Our patient also experienced significant pain relief that allowed her to increase physical activity (Children's Dermatology Life Quality Index score dropped nine points following treatment). Collectively, these improvements suggest that rosuvastatin may offer a promising treatment for PC. What's already known about this topic? Pachyonychiacongenita (PC) is an autosomal dominant
Sex Matters: Interfering with the Oxidative Stress Response in PachyonychiaCongenita. Pachyonychiacongenita is an incurable and often debilitating genodermatosis. Topical application of the antioxidative response inducer sulforaphane, however, alleviates disease symptoms in a murine pachyonychiacongenita model, forecasting clinical benefits. The Coulombe laboratory now reports sex-dependent differences in sulforaphane responsiveness of pachyonychiacongenita mice, thereby dampening treatment expectations but also unveiling novel aspects of sex-specific oxidative stress reactivity in the epidermis.
Genetic variants in pachyonychiacongenita-associated keratins increase susceptibility to tooth decay Pachyonychiacongenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychiacongenita.
Chronic pain in PachyonychiaCongenita: evidence for neuropathic origin. Pachyonychiacongenita (PC) is a rare autosomal dominant skin disease, with chronic pain being the most prominent complaint. Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy. Here, for the first time, we
Sexual dimorphism in response to a NRF2 inducer in a model for pachyonychiacongenita. Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychiacongenita is caused by mutations in keratin genes and typified by dystrophic lesions affecting nails, glands, oral mucosa, and palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK ) severely impairs mobility in pachyonychiacongenita. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in pachyonychiacongenita, develop pachyonychiacongenita-like PPK. In male Krt16 mice, oxidative stress associated with impaired glutathione synthesis and nuclear factor erythroid-derived 2 related factor 2 (NRF2)-dependent gene expression precedes PPK onset, which can be prevented
Report of the 13th Annual International PachyonychiaCongenita Consortium Symposium. The International PachyonychiaCongenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for pachyonychiacongenita, a rare autosomal dominant skin disorder. The research presented at the 13th Annual Research Symposium of the IPCC, held on 10-11