Palmoplantar Keratoderma Research Articles

A KRT6A mutation p.Ile462Asn in a Chinese family with pachyonychia congenita, and identification of maternal mosaicism: a case report

BackgroundPachyonychia 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 presentationWe 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.ConclusionThese 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.

Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients.

Functional skin barrier requires sphingolipid homeostasis; 3-ketodihydrosphingosine reductase or KDSR is a key enzyme of sphingolipid anabolism catalyzing the reduction of 3-ketodihydrosphingosine to sphinganine. Biallelic mutations in the KDSR gene may cause erythrokeratoderma variabilis et progressive-4, later specified as PERIOPTER syndrome, emphasizing a characteristic periorifical and ptychotropic erythrokeratoderma. We report another patient with compound heterozygous mutations in KDSR, born with generalized harlequin ichthyosis, which progressed into palmoplantar keratoderma. To determine whether patient-associated KDSR mutations lead to KDSR substrate accumulation and/or unrecognized sphingolipid downstream products in stratum corneum (SC), we analyzed lipids of this and previously published patients with non-identical biallelic mutations in KDSR. In SC of both patients, we identified 'hitherto' unobserved skin ceramides with an unusual keto-type sphingoid base in lesional and non-lesional areas, which accounted for up to 10% of the measured ceramide species. Furthermore, an overall shorter mean chain length of free and bound sphingoid bases was observed-shorter mean chain length of free sphingoid bases was also observed in lesional psoriasis vulgaris SC, but not generally in lesional atopic dermatitis SC. Formation of keto-type ceramides is probably due to a bottle neck in metabolic flux through KDSR and a bypass by ceramide synthases, which highlights the importance of tight intermediate regulation during sphingolipid anabolism and reveals substrate deprivation as potential therapy.

A multicenter study on quality of life of the \u201cgreater patient\u201d in congenital ichthyoses

BackgroundAutosomal recessive congenital ichthyoses (ARCI) are a genetically heterogeneous group of rare and chronic disorders characterized by generalized skin scaling and hyperkeratosis, erythroderma, and palmoplantar keratoderma. Additional features include ectropion, eclabium, ear deformities, foul-smell, joints contractures and walking problems, recurrent infections, as well as pruritus and pain. No curative therapy is available and disease care mainly relies on daily application of topical emollients and keratolytics to the whole-body surface. Altogether, disease signs and symptoms and treatment modalities have a major impact on quality of life of patients and their caregivers. However, very few studies have evaluated the family disease burden in ARCI.MethodsWe have performed an Italian multicenter cross-sectional study to assess the secondary disease impact on family members of pediatric and adult patients with ARCI, using a validated dermatology-specific questionnaire, the family dermatology life quality index (FDLQI). Disease severity was assessed by the dermatologist in each center.ResultsSeventy-eight out of 82 patients who were accompanied by at least one family member filled the FDLQI. Forty-eight (61.5%) patients were aged less than 18 years. The mean FDLQI score was 10.3 (median 10), and the most affected dimensions were (1) time needed for care, (2) extra-housework, and (3) household expenditure. Higher total FDLQI score significantly correlated with more severe disease score (P = 0.003). Features associated with greater family burden included recurrent infections (P = 0.004), foul-smell (P = 0.009), palmoplantar keratoderma (P = 0.041), but also presence of scales on the face (P = 0.039) and ear deformities (P = 0.016).ConclusionsOur findings highlight the major socio-economic and psychological burden imposed by ARCI on the QoL of family caregivers. In addition, they show that global evaluation of disease impact also on family members is an essential part of patient-reported outcomes. Finally, our data underline the need to develop specific measures for family support.

Woolly hair nevus caused by somatic mutation and Costello syndrome caused by germline mutation in HRAS: Consider parental mosaicism in prenatal counseling

Germline mutations in HRAS cause Costello syndrome (CS), while mosaic mutations in HRAS show a variability of phenotypes, ranging from mild features such as keratinocytic epidermal nevus (KEN), sebaceous nevus (SN), woolly hair nevus (WHN) with KEN, to severe manifestations of CS with cutis laxa. We report two individuals. The first was a 2-year-old boy with woolly hair nevus (WHN) without any other cutaneous involvement, in whom somatic HRAS mutation (c.34G>A; p.Gly12Ser) was identified in his affected scalp and hair follicle specimens. This is the first reported WHN type 1 (no cutaneous involvement) patient caused by somatic HRAS mutation. The other individual was a 12-year-old girl with CS caused by germline HRAS mutation (c.34G>A), that manifested with coarse face, palmoplantar keratoderma, deep palmar and plantar creases, hyperpigmented patches, asymmetry and deformity of lower limbs, atopic dermatitis, as well as mental retardation. Of note, a linear hyperpigmented plaque was observed in her father's lumbosacral region. Although the father refused to provide semen and skin tissue for further examination, this reminds us of possible mosaicism in parents of individuals with germline de novo HRAS mutation and underlines the importance of parental evaluation for prenatal counseling.

063 A new case series of Olmsted syndrome subjects confirms EGFR activation and shows remarkable efficacy of targeted systemic EGFR inhibition with acceptable side effects

Olmsted syndrome (OS) is a rare, painful, and severe form of palmoplantar keratoderma (PPK). It is most often caused by dominant mutations in the transient receptor potential vanilloid-3 (TRPV3) gene, resulting in the constitutive activation of this thermosensitive calcium channel. TRPV3 signaling leads to epidermal growth factor receptor (EGFR) activation and subsequent abnormal proliferation and differentiation of keratinocytes in mice and cell lines. We previously reported that blocking EGFR transactivation with oral Erlotinib treatment resulted in remarkable improvement in 4 young patients.

162 Loss-of-function variants in SERPINA12 underlie autosomal recessive palmoplantar keratoderma

Inherited palmoplantar keratodermas (PPKs) refer to a large and heterogeneous group of conditions resulting from abnormal epidermal differentiation and featuring thickening of the skin of the palms and soles. Here, we aimed at delineating the genetic basis of an autosomal recessive form of PPK manifesting with erythematous hyperkeratotic plaques over the palms and soles, extending to non- palmoplantar areas and associated with peripheral peeling of the skin. Whole exome sequencing revealed homozygous nonsense variants in the SERPINA12 gene in affected individuals.

159 CRISPR/Cas9 nickase mediated gene therapy in primary keratinocytes derived from patients with EPPK

Epidermolytic palmoplantar keratoderma (EPPK) is a rare, autosomal dominantly inherited skin disorder. The disease is often caused by heterozygous point mutations in the keratin 9 gene (KRT9) coding for the type I intermediate filament (IF) protein keratin 9 (K9), whose expression is confined to the suprabasal layers of palmoplantar epidermis. Integration of mutant K9 into the IF cytoskeleton has a dominant negative effect resulting in massive thickening and making it prone to develop fissures, infections, and severely impairing the flexibility of hands and feet. The aim of this project is to correct the IF fragility in EPPK patient-derived primary keratinocyte (KC) cultures by establishing a CRISPR/Cas9 D10A double-nicking approach to induce non-homologous end joining (NHEJ) mediated silencing of the mutant disease-causing allele while leaving the wild-type (WT) allele intact. To avoid the risk of integrations into the genome, we used ribonucleoproteins to transfect KCs. We show that mutant K9 massively reduces cytoskeleton stability, resulting in IF clumping upon stress. Moreover, we demonstrate successful targeting and NHEJ of KRT9 using a pair of gRNAs, one of which targets the mutation in an allele specific manner. Using sequencing, we identified single cell clones with a premature STOP-codon on the mutated allele. These clones show a stable K9 IF structure after stress application, similar to the WT controls. Taken together, these results demonstrate CRISPR/Cas9 nickase-mediated rescue of IF fragility due to mutant K9 in primary cultured KCs.

172 Discovery of small molecule compounds with readthrough potency at premature termination codon

Nagashima-type palmoplantar keratosis (NPPK) is the most common palmoplantar keratoderma in the East Asian populations. NPPK is caused by biallelic loss-of-function mutations in SERPINB7. Notably, almost all NPPK patients carry the TGAA nonsense mutation c.796C>T (p.Arg266Ter) in SERPINB7, which creates a premature termination codon (PTC) and leads to highly reduced production of full-length, functional SERPINB7 polypeptides. The suppression of a PTC, also known as ‘readthrough’, is able to restore the full-length protein. As the currently available drugs, including topical vitamin D3 and topical keratolytic, yield very limited improvement of NPPK skin phenotypes, we sought to tackle the disease by the readthrough therapy. We first performed a high- throughput screening of 19,992 small molecule compounds for readthrough activity using firefly luciferase assay. A total of 64 compounds survived retest screening and were shortlisted as potential readthrough candidates. Next, we generated a FLAG-tagged mutant SERPINB7 cDNA vector which contains the nonsense mutation c.796C>T and perform single and multiple concentrations screening using this vector for the selected 64 compounds. 2 hit compounds were identified with readthrough efficiency at their optimal concentration. Additional small molecule compounds with similar chemical structures of the 2 hit compounds were purchased for hit expansion; the process in which derivatives with similar chemical structure are selected from databases. Along with the hit expansion compounds, they have shown to induce a higher readthrough potency than the currently available drugs such as gentamicin and ataluren (Translarna®). As approximately 10% of all described gene lesions in genetic diseases are caused by nonsense mutations, the discovery of potent hit compounds can benefit not only NPPK patients but also patients who suffer from diseases caused by nonsense mutations.

Punctate Palmoplantar Keratoderma

A 5-year-old caucasian boy, born of non-consanguineous parents, was referred to the dermatology department due to palmar hiperlinearity and multiple 2-3 mm hyperkeratotic circular lesions in the soles (Fig. 1). The remaining physical examination was unremarkable. There was a family history of palmoplantar hyperkeratosis in the mother and maternal grandfather. To spare the child, a punch skin biopsy was taken from his mother. Pathology revealed an epidermis with irregular acanthosis and orthokeratotic hyperkeratosis, without other morphologic alterations (Fig. 2). Clinical aspect of the lesions associated with a positive family history and histologic findings allowed the diagnosis of punctate palmoplantar keratoderma. Satisfactory results were achieved with urea 20% cream and emollient applied to the soles. [...]

Identification of a Rare Case With Nagashima-Type Palmoplantar Keratoderma and 18q Deletion Syndrome via Exome Sequencing and Low-Coverage Whole-Genome Sequencing.

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

Papillon-lefevere syndrome-Consanguity as a risk factor in siblings (Case series)

Papillon-Lefevere syndrome is a very rare autosomal recessive trait characterized by palmoplantar hyperkeratosis and severe generalized early-onset periodontitis leading to premature loss of primary and permanent dentitions. Various etiopathogenesis factors are associated with syndrome. The palmoplantar keratoderma typically has its onset between the ages of 1 and 4 years and severe periodontitis starts at age of 3-4 years. A dentist plays an important role in early diagnosing and preserving remaining teeth in oral cavity. This case series describes three cases of PLS in siblings with consanguineously married parents. All siblings in the family were affected which makes this a rare case.

English

BACKGROUND Erythroderma is a clinical entity that may cause severe systemic manifestations. The difficulty with erythroderma lies in finding the underlying aetiology. It is imperative to demonstrate precise aetiology whenever possible so that distinct therapy may be initiated. At times, despite finding the aetiology, relapses constitute a great menace. The purpose of our study was to assess the clinical profile and aetiology of erythroderma. Besides, the study also illustrated factors leading to relapses; such studies are rare in literature. METHODS This hospital-based, cross-sectional study included 88 patients of erythroderma of either sex and age more than 18 years; their clinical, laboratory, histopathological findings, treatment and outcome were studied. RESULTS The mean age of onset was 47.3 ± 12.35 years with the male to female ratio being 2.38:1. The most common cause of erythroderma was pre-existing dermatoses (67 %) followed by drugs (10.2 %), infections (3.4 %), malignancies (4.54 %), and idiopathic (14.7 %). Psoriasis was the predominant aetiology (45.4 %) among the pre-existing dermatoses with a maximum number of relapses (P = 0.02). Psoriasis was significantly associated with pruritus (P = 0.001), subungual hyperkeratosis (P = 0.0001), palmoplantar keratoderma (P = 0.001). Clinicohistological association was found in 64.6 % of cases. Mortality was seen in 6.8 % of cases. CONCLUSIONS As in previous studies, pre-existing dermatoses were the most common causes in our study; albeit, a special emphasis on factors leading to relapses was given to prevent further episodes. The most common factor of relapse was uncontrolled comorbid disorders (diabetes and hypertension) followed by medication nonadherence. Hence, our study suggests a need for more effective comorbidity management and creating awareness regarding judicial use of drugs which can go far in preventing mortality and morbidity. KEY WORDS Erythroderma, Adults, Aetiology, Relapses, Comorbidities.

Ichthyosiform Erythroderma, a Multifaceted Syndromic Entity.

Ichthyosiform Erythroderma, a Multifaceted Syndromic Entity.

Recurrent Fevers in a Boy Toddler with Dysmorphic Features and Hypodontia.

Recurrent Fevers in a Boy Toddler with Dysmorphic Features and Hypodontia.

26726 A case of transient reactive papulotranslucent acrokeratoderma: Exploring the role of epidermal barrier dysfunction during the COVID-19 pandemic

Transient reactive papulotranslucent acrokeratoderma (TRPA) is characterized by an acquired transient induction of edematous translucent papules or ‘wrinkling’ on the palmar and/or plantar surfaces that occurs after a few minutes of water immersion and disappears with hand-drying. While this condition is likely more common than initially thought, the etiopathogenesis and the optimal treatment have yet to be elucidated. We present a case of TRPA appearing in a 21-year-old atopic female during a period of increased hand-washing amidst the COVID-19 pandemic. Diagnosis was made on a clinical basis, including review of patient photos and a water immersion test, which revealed characteristic edematous papules on the bilateral palmar surfaces that disappeared with hand-drying. The patient was initially treated with 20% ammonium lactate with significant, but not complete improvement after two weeks of treatment. A punch biopsy of the palmar surface obtained at this time was inconclusive. Topical calcipotriene was added to the patient’s treatment regimen with complete resolution of the dermatosis after 2 weeks of use. The authors feel TRPA could become a more frequent dermatologic office complaint given its proposed relationship with epidermal barrier dysfunction. We postulate that increases in hand washing and sanitizing during the pandemic may contribute to disease incidence in susceptible individuals. We also propose atopic dermatitis, a dermatosis in which epidermal barrier dysfunction plays a prominent role, could represent a factor for increased risk. In addition, atopic patients who develop TRPA may respond better to treatment with agents that target the epidermal barrier.

Acral Lentiginous melanoma arising in Brauer-Buschke-Fischer plantar keratoderma

Type I Punctuate palmoplantar keratoderma or Brauer-Buschke-Fischer keratoderma (BBFK) is a rare autosomal dominant keratinisation disorder with variable penetrance. \r\n The emergence of acral lentiginous melanoma on palmoplantar keratoderma is rarely reported. Herein, we present a case of a 53-year-old woman with a history of BBFK in both palms and soles, who developed an acral lentiginous melanoma. The clinical examination showed multiple tiny hyperkeratotic and translucent papules on both palms and soles. On the right sole, she developed an acral lentiginous melanoma over a hyperkeratoic area. This case presentation illustrates a rare association of malignant melanoma and BBFK and seeks to enhance further investigations to determine its pathophysiological mechanism.\r\n

Inhibition of temperature-sensitive TRPV3 channel by two natural isochlorogenic acid isomers for alleviation of dermatitis and chronic pruritus

Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoderma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC50 values of 2.7 ± 1.3 and 0.9 ± 0.3 μmol/L, respectively, and reduce the channel open probability to 3.7 ± 1.2% and 3.2 ± 1.1% from 26.9 ± 5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus.

Effectiveness of a cosmetic device containing a combination of alpha- and beta-hydroxy acids, urea, and thuja for the treatment of seborrheic keratoses.

Seborrheic keratosis is a benign epidermal tumor of cosmetic concern-as it progressively increases in size, thickness, and pigmentation-on which topical treatments are poorly effective. Considering its keratotic component, effective products may include active principles with keratolytic action. Evaluate the efficacy and tolerability of a topical cosmetic product with urea and hydroxy acids, in the treatment of seborrheic keratoses. Twenty patients were enrolled in an observational, prospective, open-label study. The topical device was applied on seborrheic keratoses twice daily for 30days. We evaluated the progression of the treatment by clinical examination-using Daily Life Quality Index-and epiluminescence microscopy at baseline and day 30. After 30days of treatment, we documented a significant reduction in seborrheic keratosis thickness and number, which was confirmed also by epiluminescence microscopy. On day 30, global Daily Life Quality Index improved by 99.95%. The tolerability of the cosmetic device was considered excellent, according to 19/20 subjects (95%). The results of our study showed the efficacy and tolerability of this cosmetic device. Its active compounds favor gradual removal of seborrheic keratoses, even in case of pigmented variants. This non-invasive treatment represents an alternative to surgical procedures, mainly for fragile patients and delicate skin areas. It is possible to speculate its usefulness in the topical treatment of circumscribed hyperkeratosis, palmoplantar keratoderma, and thick psoriatic plaques.

Differential Pathomechanisms of Desmoglein 1 Transmembrane Domain Mutations in Skin Disease

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.

Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy.

Desmoplakin (DSP), encoded by the DSP gene, is the main desmosome component and is abundant in the myocardial tissue. There are three DSP isoforms that assume the role of supporting structural stability through intercellular adhesion. It has been found that DSP regulates the transcription of adipogenic and fibrogenic genes, and maintains appropriate electrical conductivity by regulating gap junctions and ion channels. DSP is essential for normal myocardial development and the maintenance of its structural functions. Studies have suggested that DSP gene mutations are associated with a variety of hereditary cardiomyopathy, such as arrhythmia cardiomyopathy, dilated cardiomyopathy (DCM), left ventricular noncompaction, and is also closely associated with the Carvajal syndrome, Naxos disease, and erythro-keratodermia-cardiomyopathy syndrome with skin and heart damage. The structure and function of DSP, as well as the clinical manifestations of DSP-related cardiomyopathy were reviewed in this article.