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The Journal of Investigative... Oct 2005Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes... (Review)
Review
Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes that are differentially expressed in specific epithelial structures of the body, many of which involve the epidermis and its appendages. Pachyonychia congenita (PC) is a group of autosomal dominant genodermatoses affecting the nails, thick skin and other ectodermal structures, according to specific sub-type. The major clinical variants of the disorder (PC-1 and PC-2) are known to be caused by dominant-negative mutations in one of four differentiation-specific keratins: K6a, K6b, K16, and K17. A total of 20 human keratin genes are currently linked to single-gene disorders or are predisposing factors in complex traits. In addition, a further six intermediate filament genes have been linked to other non-epithelial genetic disorders. We have established a comprehensive mutation database that catalogs all published independent occurrences of intermediate filament mutations (http://www.interfil.org), with details of phenotypes, published papers, patient support groups and other information. Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved.
Topics: Age of Onset; Darier Disease; Databases, Genetic; Ectodermal Dysplasia; Epidermolysis Bullosa Simplex; Female; Genotype; Humans; Keratins; Keratoderma, Palmoplantar; Male; Mutation; Nails, Malformed; Phenotype; Polymorphism, Genetic
PubMed: 16250207
DOI: 10.1111/j.1087-0024.2005.10205.x -
The Journal of Investigative Dermatology May 2018Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita is caused by mutations in keratin genes and...
Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita 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 pachyonychia congenita. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in pachyonychia congenita, develop pachyonychia congenita-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 by topical sulforaphane-mediated activation of NRF2. We report here that sulforaphane treatment fails to activate NRF2 and prevent PPK in female Krt16 mice despite a similar set of molecular circumstances. Follow-up studies reveal a temporal shift in PPK onset in Krt16 females, coinciding with sex-specific fluctuations in footpad skin glutathione levels. Dual treatment with sulforaphane and diarylpropionitrile, an estrogen receptor beta selective agonist, results in NRF2 activation, normalization of glutathione levels, and prevention of PPK in female Krt16 mice. These findings point to a sex difference in NRF2 responsiveness that needs be considered when exploring NRF2 as a therapeutic target in skin disorders.
Topics: Animals; Disease Models, Animal; Estrogen Receptor alpha; Female; Glutathione; Humans; Isothiocyanates; Keratin-16; Keratoderma, Palmoplantar; Male; Mice; NF-E2-Related Factor 2; Nitriles; Pachyonychia Congenita; Propionates; Sex Characteristics; Sulfoxides
PubMed: 29277538
DOI: 10.1016/j.jid.2017.09.054 -
Indian Dermatology Online Journal 2016Pachyonychia congenita is a rare type of ectodermal dysplasia further classified into 4 types. Cutaneous manifestations seen in most of the cases of Pachyonychia...
Pachyonychia congenita is a rare type of ectodermal dysplasia further classified into 4 types. Cutaneous manifestations seen in most of the cases of Pachyonychia congenita include palmoplantar keratoderma, follicular hyperkeratosis, wedge shaped nails, oral leukokeratosis and woolly hair. A 25-year-old male presented to us with thickened nails and scanty scalp hair. On examination, we noticed hyperkeratotic plaques over both the soles, palmoplantar hyperhidrosis and yellowish discoloration, wedging with subungual hyperkeratosis of all the nails. Follicular hyperkeratotic papules and steatocystoma multiplex were also observed over the scalp and face. The patient had history of natal teeth and on dental examination, lower central incisors were absent. All cutaneous changes in our case had manifested first in the 2(nd) decade except for natal teeth. All the above features suggested the diagnosis of pachyonychia congenita with late onset (PC tarda), which is an infrequently reported rare variant.
PubMed: 27559502
DOI: 10.4103/2229-5178.185463 -
The Journal of Investigative Dermatology May 2012Palmoplantar keratoderma is a hallmark of pachyonychia congenita (PC) and focal non-epidermolytic palmoplantar keratoderma (FNEPPK). By generating keratin 16...
Palmoplantar keratoderma is a hallmark of pachyonychia congenita (PC) and focal non-epidermolytic palmoplantar keratoderma (FNEPPK). By generating keratin 16 (Krt16)-deficient mice, Lessard and Coulombe, as described in this issue, have generated a mouse model to replicate these palmoplantar lesions. Studies using this model may provide novel insights into the molecular mechanisms responsible for the formation of palmoplantar lesions in PC and FNEPPK patients.
Topics: Animals; Female; Keratin-16; Keratoderma, Palmoplantar; Male; RNA, Messenger; Tongue
PubMed: 22499036
DOI: 10.1038/jid.2012.58 -
Canadian Family Physician Medecin de... Dec 2018To provide family physicians with the information needed to recognize, diagnose, and discuss available treatment options for steatocystoma multiplex (SM). (Review)
Review
OBJECTIVE
To provide family physicians with the information needed to recognize, diagnose, and discuss available treatment options for steatocystoma multiplex (SM).
SOURCES OF INFORMATION
A comprehensive PubMed search using as either a text word or a MeSH term was conducted, and articles reporting on treatment outcomes were included.
MAIN MESSAGE
Steatocystoma multiplex is a benign disorder often characterized by numerous asymptomatic dermal cysts on the trunk, arms, axillae, face, thighs, and scalp. Psychological distress due to these undesirable lesions is not uncommon for this condition. A literature review identified the following SM treatments, all of which were associated with limitations: carbon dioxide laser, modified surgical techniques, cryotherapy, and medical management. Steatocystoma multiplex is challenging to treat and, at this time, effective management is most often achieved through patient education.
CONCLUSION
Family physicians play a critical role in the early diagnosis and management of SM. Education about treatment options and managing patient expectations might greatly alleviate the psychosocial implications of this disease.
Topics: Disease Management; Early Diagnosis; Epidermal Cyst; Female; Humans; Physicians, Family; Steatocystoma Multiplex; Young Adult
PubMed: 30541803
DOI: No ID Found -
Heliyon Mar 2024Pachyonychia congenita is an uncommon autosomal dominant skin disorder characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and...
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 , , , or . 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 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 was identified as the genetic cause of the patient. Our study identified a rare de novo heterozygous frameshift mutation in the gene in a patient with pachyonychia congenita presenting fissured tongue. Our findings expand the gene mutation spectrum of Pachyonychia congenita, and will contribute to the future genetic counseling and gene therapy for this disease.
PubMed: 38468954
DOI: 10.1016/j.heliyon.2024.e27195 -
Annals of Dermatology Dec 2022
PubMed: 36478435
DOI: 10.5021/ad.20.248 -
Indian Dermatology Online Journal Jul 2013Pachyonychia congenita (PC) is a rare genodermatosis with only 450 cases reported since 1906. It is of two types, type I due to mutation in genes 6a and 16, and 6b and...
Pachyonychia congenita (PC) is a rare genodermatosis with only 450 cases reported since 1906. It is of two types, type I due to mutation in genes 6a and 16, and 6b and 17 in type II with an autosomal dominant inheritance in both types. A 22 yr old female patient presented in our OPD with hypertrophy of finger and toe nails, palmoplantar keratoderma, oral punctuate leukokeratosis, hyperhidrosis in palms and soles with maceration and malodour since childhood. She had a positive family history with father and grandfather affected but less severely. Microscopy and culture of nail clippings and scrapping were done to rule out fungal infection. On biopsy acanthotic epidermis, parakeratosis, orthokeratosis were seen. No evidence of any associated malignancy was found after thorough workup. She was diagnosed as PC Type 1. She was put on topical steroids and orally on acetretin 25 mg OD. Paring of the nails was done too reduce the thickness of nails & to provide symptomatic relief. She was on a regular treatment for 3-4 months and showed some improvement in the form of reduced palmoplantar hyperkeratosis and reduced oral punctate keratosis but was later lost on followup. She showed no adverse effect to therapy during this period. This case is being reported because of its rarity.
PubMed: 23984242
DOI: 10.4103/2229-5178.115527 -
Gaceta Medica de Mexico 2015Pachyonychia congenita is a group of autosomal dominant inheritance pattern disorders characterized by hypertrophic nail dystrophy There are two main clinical subtypes:...
Pachyonychia congenita is a group of autosomal dominant inheritance pattern disorders characterized by hypertrophic nail dystrophy There are two main clinical subtypes: type 1 and 2. Pachyonychia congenita type 2 is readily differentiated from type 1 by multiple steatocysts and/or presence of natal teeth and can be confirmed by mutations of KRT6B and KRT17. We report the case of a 33-year-o/d female patient with the missense mutation in KRT17 gene (c.280C> T, p.Arg94Cys) and discuss the several clinical features found with this mutation in the literature.
Topics: Adult; Female; Humans; Pachyonychia Congenita
PubMed: 25946540
DOI: No ID Found -
The Journal of Investigative Dermatology May 2012Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis...
Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis upon wounding and other stressors. Mutations altering the coding sequence of KRT16 cause pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, oral leukokeratosis, and palmoplantar keratoderma (PPK). PPK associated with PC is extremely painful and compromises patient mobility, making it the most debilitating PC symptom. In this study, we show that, although inherited in a recessive manner, the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk. Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms.
Topics: Animals; Epithelium; Female; Keratin-16; Keratin-17; Keratin-6; Keratoderma, Palmoplantar; Locomotion; Male; Mice; Mice, Knockout; Mutation; Pachyonychia Congenita; RNA, Messenger; Tongue
PubMed: 22336941
DOI: 10.1038/jid.2012.6