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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 -
Pharmaceutics Oct 2021Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold... (Review)
Review
Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.
PubMed: 34684016
DOI: 10.3390/pharmaceutics13101722 -
Indian Journal of Dermatology 2015Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis,...
Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis, and cystic lesions. It is classically subdivided into two major variants, PC-1 (Jadassohn-Lewandowski syndrome) and PC-2 (Jackson-Lawler syndrome), according to the localization of the mutations in the KRT6A/KRT16 or KRT6B/KRT17 genes, respectively. We report a 9-year-old male patient with a history of thickened, discolored nails, raised spiny skin lesions all over the body since birth with focal plantar keratoderma and absence of natal teeth.
PubMed: 26538744
DOI: 10.4103/0019-5154.159665 -
Advanced Drug Delivery Reviews Sep 2021Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the... (Review)
Review
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.
Topics: Animals; Epidermolysis Bullosa Dystrophica; Gene Transfer Techniques; Genetic Therapy; Humans; Polymers; Skin Diseases, Genetic; Translational Research, Biomedical
PubMed: 34293384
DOI: 10.1016/j.addr.2021.113842 -
Experimental Dermatology Jul 2012Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily... (Review)
Review
Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy.
Topics: Animals; Botulinum Toxins, Type A; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Inflammation; Keratins; MAP Kinase Signaling System; Molecular Chaperones; Mutation; Nanoparticles; Proteasome Endopeptidase Complex; Retinoids; Skin Diseases, Genetic; Ubiquitin
PubMed: 22716242
DOI: 10.1111/j.1600-0625.2012.01534.x -
Acta Medica Iranica 2014Pachyonychia congenital (PC) is a rare autosomal dominant genodermatosis characterized hyperkeratosis affecting the nails and palmoplantar areas, oral leukokeratosis,...
Pachyonychia congenital (PC) is a rare autosomal dominant genodermatosis characterized hyperkeratosis affecting the nails and palmoplantar areas, oral leukokeratosis, and cystic lesions. A 39-year-old woman with PC type 1 (Jadassohn-Lewandowsky syndrome) and B-cell lymphoma is described. No similar disorders or parental consanguinity were found in her family. Typical features of PC developed since her early childhood and the diagnosis of B-cell lymphoma was established seven years ago, without a clear causal relation between these entities. Despite inherent limitations of a single case, this report may contribute to PC understanding.
Topics: Adult; Diagnosis, Differential; Female; Humans; Lymphoma, B-Cell; Magnetic Resonance Imaging; Pachyonychia Congenita; Tomography, X-Ray Computed
PubMed: 25135271
DOI: No ID Found -
The Journal of Investigative... Oct 2005The similarities between the human and mouse genomes often allow researchers to make accurate predictions about the roles of their human counterparts. Because of the... (Review)
Review
The similarities between the human and mouse genomes often allow researchers to make accurate predictions about the roles of their human counterparts. Because of the similar physiology between these two mammals, mice are used extensively in the laboratory to investigate the mechanisms of human diseases. Furthermore, mice provide us with the option of testing the toxicity of drugs and the safety of therapeutic approaches prior to human application. Here, we review the existing mouse models involving the keratin genes (K6a, K6b, K16, and K17) that cause the human genetic disorder pachyonychia congenita (PC). We also suggest methods to more accurately model this autosomal dominant skin condition in the mouse in order to better understand the pathophysiological processes underlying PC and importantly, provide a test-bed for testing emerging therapies in vivo.
Topics: Animals; Darier Disease; Disease Models, Animal; Ectodermal Dysplasia; Genetic Techniques; Humans; Keratins; Keratoderma, Palmoplantar; Mice; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Mutation; Nails, Malformed; Phenotype
PubMed: 16250208
DOI: 10.1111/j.1087-0024.2005.10206.x -
Indian Journal of Dermatology 2016The case of an 8-year-old boy is hereby reported, who presented with nail dystrophy, subungual hyperkeratosis, oral leukokeratosis, and numerous follicular papules all...
The case of an 8-year-old boy is hereby reported, who presented with nail dystrophy, subungual hyperkeratosis, oral leukokeratosis, and numerous follicular papules all over the body. The features were consistent with a diagnosis of pachyonychia congenita type 1. The case is being reported for its rarity. We also discuss in a nutshell, the literature till date.
PubMed: 27057022
DOI: 10.4103/0019-5154.177761 -
International Journal of General... 2021Pachyonychia congenita (PC) is a rare, autosomal dominant genodermatosis characterized by palmoplantar keratoderma, nail dystrophy, cystic lesions, follicular...
BACKGROUND
Pachyonychia congenita (PC) is a rare, autosomal dominant genodermatosis characterized by palmoplantar keratoderma, nail dystrophy, cystic lesions, follicular hyperkeratosis, mucosal leukokeratoses, hyperhidrosis, hoarseness, and, rarely, natal teeth. Five keratin genes, and , have been found to be associated with PC.
METHODS
Using polymerase chain reaction and Sanger sequencing techniques, the purpose of the present study was to investigate the clinical features associated with PC and discover disease-associated variants. The , and exonic and flanking region sequences were amplified and directly sequenced to detect mutations.
RESULTS
Across two independent instances of PC, we identified a previously reported c.1393T>C (p.Tyr465His) mutation in exon 7 of , and a novel c.1237G>C (p.Glu413Gln) heterozygous missense mutation in exon 6 of the gene.
CONCLUSION
Through phenotype-genotype analysis among PC pedigrees, confirmed diagnoses of PC-K6a and PC-K16 were made in the two patients who presented with symptoms of PC. A new pathogenic mutation site in PC-K16 was potentially discovered.
PubMed: 33762842
DOI: 10.2147/IJGM.S280160 -
The Pan African Medical Journal 2016Pachyonychia congenita (PC) is a rare hereditary disease, mainly characterized by a painful palmoplantar keratoderma, thickened nails, cysts and white lesions of the...
Pachyonychia congenita (PC) is a rare hereditary disease, mainly characterized by a painful palmoplantar keratoderma, thickened nails, cysts and white lesions of the oral mucosa. Its clinical manifestations are very variable, it may appear from birth to adulthood. This study report the case of a child with pachyonychia congenita associated with bronchiectasis and renal artery stenosis. The diagnosis of pachyonychia congenita was retained based on clinical and histological data. However the presence of renal artery stenosis and bronchiectasis suggests a possible association as part of a particular syndromic group.
Topics: Bronchiectasis; Child; Female; Humans; Pachyonychia Congenita; Renal Artery Obstruction; Syndrome
PubMed: 27795780
DOI: 10.11604/pamj.2016.24.183.9284