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The British Journal of Dermatology Mar 2020Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy... (Review)
Review
BACKGROUND
Pachyonychia congenita (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 quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound-repair-associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature.
OBJECTIVES
This review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms.
METHODS
We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK.
RESULTS
There are three main stages of progression of PPK-like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1-Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis.
CONCLUSIONS
The progress made suggests new avenues to explore for the treatment of PC-based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (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 keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.
Topics: Animals; Homeostasis; Kelch-Like ECH-Associated Protein 1; Keratin-16; Keratoderma, Palmoplantar; Mice; Mutation; NF-E2-Related Factor 2; Pachyonychia Congenita; Quality of Life
PubMed: 31021398
DOI: 10.1111/bjd.18033 -
The British Journal of Dermatology Mar 2020
Topics: Humans; Pachyonychia Congenita; Rare Diseases; Skin; Skin Diseases
PubMed: 32107781
DOI: 10.1111/bjd.18817 -
Actas Dermo-sifiliograficas Apr 2024Nail disorders in newborns can show independently or as components of systemic illnesses or genodermatoses. The examination of these abnormalities is complex and... (Review)
Review
Nail disorders in newborns can show independently or as components of systemic illnesses or genodermatoses. The examination of these abnormalities is complex and sometimes challenging. However, familiarity with these disorders can significantly contribute to uncovering potential underlying conditions. This review includes the physiological nail changes seen within the first few months of life, such as Beau's lines, onychoschizia, koilonychia, congenital nail fold hypertrophy of the first digit, and onychocryptosis. This review also focuses on the most relevant congenital disorders reported and how to perform differential diagnosis. Finally, this review highlights those hereditary diseases in which nail involvement is crucial for diagnosis, such as nail-patella syndrome, congenital pachyonychia, or congenital dyskeratosis, among others.
PubMed: 38663727
DOI: 10.1016/j.ad.2024.04.002 -
JAMA Dermatology Nov 2021This survey study examines the prevalence and characteristics of itch in pachyonychia congenita.
This survey study examines the prevalence and characteristics of itch in pachyonychia congenita.
Topics: Humans; Pachyonychia Congenita; Prevalence; Pruritus
PubMed: 34468688
DOI: 10.1001/jamadermatol.2021.3335 -
Postepy Dermatologii I Alergologii Feb 2021Keratinization means cytodifferentiation of keratinocytes turning into corneocytes in the stratum corneum. Disorders of keratinization (hyperkeratosis, parakeratosis and... (Review)
Review
Keratinization means cytodifferentiation of keratinocytes turning into corneocytes in the stratum corneum. Disorders of keratinization (hyperkeratosis, parakeratosis and dyskeratosis) are causing many dermatological diseases, including various types of ichthyoses, pachyonychia congenita, pityriasis rubra pilaris, all subtypes of psoriasis, pityriasis lichenoides, dyskeratosis congenita, leukoplakia and keratosis follicularis, which apart from skin lesions may affect the eye's adnexae causing ectropion, entropion, blepharitis, madarosis, and trichiasis, the ocular surface causing keratitis, conjunctivitis, corneal ulceration and episcleritis, which in turn cause uveitis and various fundoscopic changes (proliferative retinopathy, retinal vasculopathy, macular oedema and birdshot chorioretinopathy). Knowledge of ocular symtoms associated with pathological keratinization is crucial, preventing sight-threatening complications such as corneal perforation, lagophthalmus, phthisis bulbi, retinal neovascularization, retinal vasculopathy and optic nerve atrophy. This review encourages dermatologists to monitor patients for ocular symptoms and encourage ophthalmologists to monitor patients for dermatological symptoms.
PubMed: 34408561
DOI: 10.5114/ada.2021.104272 -
Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.The British Journal of Dermatology Mar 2020Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17)....
BACKGROUND
Pachyonychia congenita (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 and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction.
OBJECTIVES
To characterize patients with PC with symptomatic mucosal involvement.
METHODS
We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction.
CONCLUSIONS
It is important for dermatologists and otolaryngologists 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? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.
Topics: Child; Child, Preschool; Humans; Infant; Keratin-6; Keratins; Keratoderma, Palmoplantar; Mutation; Pachyonychia Congenita
PubMed: 31777952
DOI: 10.1111/bjd.18742 -
The Journal of Investigative Dermatology Apr 2024Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been... (Review)
Review
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.
Topics: Humans; Pachyonychia Congenita; Keratoderma, Palmoplantar; Administration, Cutaneous; Apoptosis; Cell Differentiation; Mutation
PubMed: 38099888
DOI: 10.1016/j.jid.2023.10.030 -
The Journal of Investigative Dermatology Feb 2023Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is...
Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is caused by dominant mutations in keratin (K) K6A, K6B, K6C, K16, or K17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive. In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. Abnormal late terminal keratinization was associated with elevated TGM1 activity. In addition, the calcium ion permeable channel TRPV3 was significantly increased in PC-lesional skin, suggesting a predominant role of the TRPV3/EGFR signaling complex in PC. We hypothesized that this complex contributes to promoting TGM1 activity and induces the expression and shedding of EGFR ligands. To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL. Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC.
Topics: Humans; ErbB Receptors; Erlotinib Hydrochloride; Keratoderma, Palmoplantar; Mutation; Pachyonychia Congenita; Pain; Quality of Life
PubMed: 36116508
DOI: 10.1016/j.jid.2022.08.045 -
Clinical and Experimental Dermatology May 2024Pachyonychia congenita is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma, and hypertrophic...
Pachyonychia congenita 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 pachyonychia congenita and provides a summary of the current and future therapeutic options.
PubMed: 38805703
DOI: 10.1093/ced/llae199 -
Archives of Plastic Surgery Nov 2023Pachyonychia congenita is a rare genetic disorder characterized by hypertrophic nail plates, hyperkeratotic nail beds, and thickened hyponychium of the fingers and toes,...
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.
PubMed: 38143838
DOI: 10.1055/s-0043-1771520