RARE DISEASE
Punctate palmoplantar keratoderma type 1
Punctate palmoplantar keratoderma type 1
Punctate palmoplantar keratoderma type 1
Synonyms: Buschke-Fischer-Brauer syndrome, Keratodermia palmoplantaris papulosa, Buschke-Fischer-Brauer type, PPKP1
Synonyms: Buschke-Fischer-Brauer syndrome, Keratodermia palmoplantaris papulosa, Buschke-Fischer-Brauer type, PPKP1
Synonyms: Buschke-Fischer-Brauer syndrome, Keratodermia palmoplantaris papulosa, Buschke-Fischer-Brauer type, PPKP1
Drug discovery
0
drugs
With orphan designations
Overview
Punctate palmoplantar keratoderma type 1 (PPKP1), also termed Buschke-Fischer-Brauer disease, is an autosomal dominant disorder characterized by hyperkeratotic papules ("raindrop keratosis") on pressure-bearing palmoplantar surfaces. Mutations in AAGAB (15q22.33-q23) drive keratinocyte proliferation via disrupted clathrin-mediated receptor tyrosine kinase regulation, while COL14A1 mutations are less established [1][9][14]. Lesions typically emerge in adolescence, with variable penetrance and asymptomatic-to-painful presentations. Diagnosis combines clinical features, family history, and genetic testing [5][9].
Categories: rare genetic diseases, rare skin diseases
Research Papers
12 drug discovery papers about Punctate palmoplantar keratoderma type 1, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
12 drug discovery papers about Punctate palmoplantar keratoderma type 1, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2021-03-26 | A novel AAGAB mutation in a Peruvian family with punctate palmoplantar keratoderma
Buschke-Fischer-Brauer (BFB) disease is a rare keratoderma characterized by multiple hyperkeratotic lesions on the palms and soles, with an autosomal dominant pattern.In several countries, some genetic alterations have been associated with this clinical entity.A 68-year-old Peruvian woman presenting with hyperkeratotic lesions on both her palms and soles was diagnosed with BFB keratoderma.After sequencing of the genes that had previously been related to this disease, a mutation (c.249C>G) that was predicted to generate a termination codon (Tyr83*) was found in the alpha and gamma adaptin binding protein P34 gene (AAGAB).After treatment with 30% urea plus 10% salicylic acid, the patient experienced an improvement in her condition.Here we report a novel mutation in the AAGAB gene of a patient diagnosed with BFB keratoderma and a treatment that improved her symptoms.
2019-03-19 | Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma
The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.
2018-03-03 | Case of punctate palmoplantar keratoderma type I treated with combination of low‐dose oral acitretin and topical salicylic acid and steroid
Abstract Palmoplantar keratodermas ( PPK ) are heterogeneous disorders characterized by abnormal keratinization. Especially, punctate PPK ( PPPK ), one of the subtypes of hereditary PPK , is a rare punctate keratoderma characterized by tiny “raindrop” keratoses having a tendency to coalesce on the edge of soles, which are exposed to sustained pressure. If typical punctate lesions are confined to the palms and soles and the patient has a family history and late onset, it can be considered as PPPK type I ( PPKP 1), also called Buschke–Fisher–Brauer disease. The exact etiology of PPPK has not been fully understood. Furthermore, no standardized treatment for PPPK has been established and treatment options are limited. Above all, traditional systemic retinoids have been used in several cases, but dose‐related adverse effects are common. Therefore, combination of low‐dose systemic retinoids and adjuvant topical therapy can be an alternative treatment option for PPPK . Herein, we report a case of PPKP 1 treated with combination of low‐dose oral acitretin (10 mg/day) and topical salicylic acid and steroid. Despite low capacity, low‐dose acitretin showed excellent regression of the lesions by combined use of topical ointments. The supplementary topical therapy may be useful in reducing the dose of systemic retinoids and preventing potential toxicity.
2017-04-01 | Hereditary punctate keratoderma: clinical, pathology, treatment and follow-up
GIORnaLE ITaLIanO DI DERmaTOLOGIa E VEnEREOLOGIa 323 dyskeratosis, vacuolar degeneration or exaggerated clumping of tonofilaments, that contrariwise have been highlighted in PP. 5 In acquired PK, the incidence of malignancies, as well as other internal disease, remains inexplicably high.However, based on the long follow-up (14 years), both patients did not show any internal disorders or malignancies associated to PK.On the one hand, topical treatments of PK, including urea, salicylic acid, vitamin a, retinoids, and tacalcitol, usually show poor results. 2 On the other hand, systemic therapy with oral retinoids could lead to a good improvement of lesions. 2 However, recurrence after stopping therapy is common, 2 as reported in our case.
2015-04-28 | Low‐dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work
Abstract Punctate palmoplantar keratoderma type 1 ( PPKP 1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss‐of‐function mutations in AAGAB have recently been reported as a cause of PPKP 1. Despite the discovery of the genetic cause of PPKP 1, pathogenesis‐based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP 1. In this study, we analyzed a Japanese woman with PPKP 1 and identified a novel frame‐shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB . Moreover, low‐dose etretinate was effective in improving the PPKP 1 lesions in our patient. Our published work review identified only eight cases of PPKP 1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP 1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP 1.
small molecules
2021-03-26 | A novel AAGAB mutation in a Peruvian family with punctate palmoplantar keratoderma
Buschke-Fischer-Brauer (BFB) disease is a rare keratoderma characterized by multiple hyperkeratotic lesions on the palms and soles, with an autosomal dominant pattern.In several countries, some genetic alterations have been associated with this clinical entity.A 68-year-old Peruvian woman presenting with hyperkeratotic lesions on both her palms and soles was diagnosed with BFB keratoderma.After sequencing of the genes that had previously been related to this disease, a mutation (c.249C>G) that was predicted to generate a termination codon (Tyr83*) was found in the alpha and gamma adaptin binding protein P34 gene (AAGAB).After treatment with 30% urea plus 10% salicylic acid, the patient experienced an improvement in her condition.Here we report a novel mutation in the AAGAB gene of a patient diagnosed with BFB keratoderma and a treatment that improved her symptoms.
2019-03-19 | Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma
The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.
2018-03-03 | Case of punctate palmoplantar keratoderma type I treated with combination of low‐dose oral acitretin and topical salicylic acid and steroid
Abstract Palmoplantar keratodermas ( PPK ) are heterogeneous disorders characterized by abnormal keratinization. Especially, punctate PPK ( PPPK ), one of the subtypes of hereditary PPK , is a rare punctate keratoderma characterized by tiny “raindrop” keratoses having a tendency to coalesce on the edge of soles, which are exposed to sustained pressure. If typical punctate lesions are confined to the palms and soles and the patient has a family history and late onset, it can be considered as PPPK type I ( PPKP 1), also called Buschke–Fisher–Brauer disease. The exact etiology of PPPK has not been fully understood. Furthermore, no standardized treatment for PPPK has been established and treatment options are limited. Above all, traditional systemic retinoids have been used in several cases, but dose‐related adverse effects are common. Therefore, combination of low‐dose systemic retinoids and adjuvant topical therapy can be an alternative treatment option for PPPK . Herein, we report a case of PPKP 1 treated with combination of low‐dose oral acitretin (10 mg/day) and topical salicylic acid and steroid. Despite low capacity, low‐dose acitretin showed excellent regression of the lesions by combined use of topical ointments. The supplementary topical therapy may be useful in reducing the dose of systemic retinoids and preventing potential toxicity.
2017-04-01 | Hereditary punctate keratoderma: clinical, pathology, treatment and follow-up
GIORnaLE ITaLIanO DI DERmaTOLOGIa E VEnEREOLOGIa 323 dyskeratosis, vacuolar degeneration or exaggerated clumping of tonofilaments, that contrariwise have been highlighted in PP. 5 In acquired PK, the incidence of malignancies, as well as other internal disease, remains inexplicably high.However, based on the long follow-up (14 years), both patients did not show any internal disorders or malignancies associated to PK.On the one hand, topical treatments of PK, including urea, salicylic acid, vitamin a, retinoids, and tacalcitol, usually show poor results. 2 On the other hand, systemic therapy with oral retinoids could lead to a good improvement of lesions. 2 However, recurrence after stopping therapy is common, 2 as reported in our case.
2015-04-28 | Low‐dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work
Abstract Punctate palmoplantar keratoderma type 1 ( PPKP 1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss‐of‐function mutations in AAGAB have recently been reported as a cause of PPKP 1. Despite the discovery of the genetic cause of PPKP 1, pathogenesis‐based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP 1. In this study, we analyzed a Japanese woman with PPKP 1 and identified a novel frame‐shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB . Moreover, low‐dose etretinate was effective in improving the PPKP 1 lesions in our patient. Our published work review identified only eight cases of PPKP 1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP 1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP 1.
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