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Journal of the European Academy of... Sep 2020
Topics: Humans; Pachyonychia Congenita; Rosuvastatin Calcium
PubMed: 32236980
DOI: 10.1111/jdv.16393 -
Journal of the European Academy of... Apr 2024
Topics: Humans; Pachyonychia Congenita; Simvastatin
PubMed: 37994233
DOI: 10.1111/jdv.19630 -
European Journal of Dermatology : EJD Dec 2023
Topics: Humans; Human Papillomavirus Viruses; Epidermal Cyst; Steatocystoma Multiplex; Warts
PubMed: 38465555
DOI: 10.1684/ejd.2023.4550 -
JAAD Case Reports Nov 2022
PubMed: 36275875
DOI: 10.1016/j.jdcr.2022.09.011 -
Clinical and Experimental Dermatology Aug 2019Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous... (Comparative Study)
Comparative Study
Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenita tarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.
Topics: Adolescent; Adult; Child; Diagnostic Errors; Ectodermal Dysplasia; Female; Humans; Keratoderma, Palmoplantar; Male; Middle Aged; Nail Diseases; Nails, Malformed; Pachyonychia Congenita; Polymorphism, Genetic; Young Adult
PubMed: 31074523
DOI: 10.1111/ced.13980 -
Clinical and Experimental Dermatology Jul 2021Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current...
BACKGROUND
Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants.
AIMS
We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity.
METHODS
We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ and Kruskal-Wallis tests.
RESULTS
We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation.
CONCLUSIONS
We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.
Topics: Age of Onset; Case-Control Studies; Child, Preschool; Cohort Studies; Genetic Variation; Heterozygote; Humans; Infant; Keratin-16; Keratin-17; Keratin-6; Keratins; Keratoderma, Palmoplantar; Keratosis; Leukoplakia, Oral; Mutation; Nail Diseases; Nails, Malformed; Pachyonychia Congenita; Phenotype; Predictive Value of Tests; Registries; Severity of Illness Index
PubMed: 33486795
DOI: 10.1111/ced.14569 -
BMC Medical Genomics Nov 2021Pachyonychia congenita (PC, OMIM #167200, #167210, #615726, #615728, and #615735) is a rare autosomal dominant disorder caused by keratin gene mutations in...
BACKGROUND
Pachyonychia congenita (PC, OMIM #167200, #167210, #615726, #615728, and #615735) is a rare autosomal dominant disorder caused by keratin gene mutations in KRT6A,KRT6B,KRT6C,KRT16 or KRT17. It is characterized with nail dystrophy and palmoplantar keratoderma (PPK). The most prominent manifestation is plantar pain. This is a further unusual case of parental mosaicism in PC. Although very rare, germ cell mosaicism should be considered when providing genetic counselling for unaffected parents of a child with PC.
CASE PRESENTATION
We report the case of a 5-year-old boy with thickening nails and oral leukokeratosis at birth. He began to develop palmoplantar keratoderma at 2 years old and his sister has similar clinical manifestation characterized with nail discoloration and thickening. A previously reported heterozygous mutation, p.Ile462Asn, was identified in KRT6A in the proband and his affected sister. SNaPshot sequencing revealed mosaicism at a level of 2.5% and 4.7% in DNA from blood and hair bulbs from the unaffected mother. HiSeq deep sequencing demonstrated low-grade mosaicism in the patient's younger sister and parents.
CONCLUSION
These findings indicate the ability of WES and SNaPshot sequencing to detect low-frequency mosaic mutations. Although very rare, germinal mosaicism should be considered when genetic counseling is given to families with presumed spontaneous cases of PC.
Topics: Child, Preschool; China; Female; Genomic Imprinting; Humans; Keratin-6; Male; Mosaicism; Mutation; Pachyonychia Congenita
PubMed: 34724947
DOI: 10.1186/s12920-021-01109-4 -
The British Journal of Dermatology Mar 2020Epidermal differentiation is a multilevel process in which keratinocytes need to lose their organelles, including their mitochondria, by autophagy. Disturbed autophagy...
BACKGROUND
Epidermal differentiation is a multilevel process in which keratinocytes need to lose their organelles, including their mitochondria, by autophagy. Disturbed autophagy leads to thickening of the epidermis as seen in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17.
OBJECTIVES
To ask if mitophagy, the selective degradation of mitochondria by autophagy, is disturbed in PC and, if so, at which stage.
METHODS
Immortalized keratinocytes derived from patients with PC were used in fluorescence-based and biochemical assays to dissect the different steps of mitophagy.
RESULTS
PC keratinocytes accumulated old mitochondria and displayed disturbed clearance of mitochondria after mitochondrial uncoupling. However, early mitophagy steps and autophagosome formation were not affected. We observed that autolysosomes accumulate in PC and are not sufficiently recycled.
CONCLUSIONS
We propose an influence of keratins on autolysosomal degradation and recycling. What's already known about this topic? Terminal epidermal differentiation is a multistep process that includes the elimination of cellular components by autophagy. Autophagy-impaired keratinocytes have been shown to result in thickening of epidermal layers. Hyperkeratosis also occurs in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17. What does this study add? Keratins contribute to mitochondrial quality control as well as maintenance of mitochondria-endoplasmic reticulum contact sites. Keratins influence autolysosomal maturation or reformation. What is the translational message? Overaged mitochondria and autolysosomes accumulate in PC. Mutations in keratin 6a lead to severely impaired mitophagy, which might contribute to PC pathogenesis.
Topics: Humans; Keratin-6; Keratins; Mitochondria; Mutation; Pachyonychia Congenita
PubMed: 31004504
DOI: 10.1111/bjd.18014 -
American Family Physician May 2020
Topics: Adult; Callosities; Diagnosis, Differential; Foot; Hand; Humans; Male; Pachyonychia Congenita
PubMed: 32412219
DOI: No ID Found -
The British Journal of Dermatology Nov 2022
Topics: Humans; Pachyonychia Congenita; Hidradenitis Suppurativa; Keratins; Pedigree; Cytoskeletal Proteins; Keratin-6; Keratin-17; Keratin-16
PubMed: 35996837
DOI: 10.1111/bjd.21807