Palmoplantar Keratoderma Research Articles

Unilateral focal palmoplantar keratoderma associated with a postzygotic variant in PIK3CA and activation of the PI3K/AKT/mTOR pathway.

Palmoplantar keratoderma (PPK) is a group of -disorders with genetic and phenotypic heterogeneity featuring skin thickening of the palms and soles. More than 60 genes involved in various biological processes are implicated in PPK. PIK3CA is an oncogene encoding p110α, and its somatic variants contribute to a spectrum of congenital overgrowth disorders, including epidermal nevi (EN). To identify the genetic basis and elucidate the pathogenesis of a patient with unilateral focal PPK. Whole-exome sequencing and Sanger sequencing combined with laser capture microdissection (LCM) were performed on genomic DNA extracted from the patient's peripheral blood and skin lesion. Skin biopsies were taken from the lesion of the patient and normal controls for immunofluorescence. Molecular docking was performed using Alphafold2-multimer. A three-year-old girl presented with unilateral focal PPK with an identified missense -variant (c.3140A>G, p.His1047Arg) in PIK3CA from affected tissue. This variant only existed in the lesional epidermis. Elevated PI3K/AKT/mTOR signalling in the affected epidermis and an increased number of Ki67-positive keratinocytes were demonstrated. Molecular docking indicated instability of the p110α-p85α dimer caused by the PIK3CA His1047Arg variant. We describe the first PPK case associated with a variant in PIK3CA, which expands the spectrum of PIK3CA-related disorders. Our study further underscores the importance of the PI3K/AKT/mTOR pathway in the homeostasis of skin keratinization.

SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for NPPK because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. Additionally, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a three-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a 'protease-substrate' manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor, and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in NPPK. These findings may lead to the development of therapeutic strategies for NPPK.

An antisense lncRNA mediated mechanism controls desmoplakin gene expression

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol (Italy). Background Desmosomal genes are established as definitive genes for Arrhythmogenic Cardiomyopathy (ACM). The desmoplakin encoding gene, DSP, is amongst the most frequently mutated genes in ACM patients. While rare genetic variants within desmosomal genes can cause ACM, common variants might also affect cardiac conduction traits in the general population. Purpose 1) To explore the association between common genetic variants in ACM desmosomal genes (DSC2, DSG2, PKP2, JUP, DSP) and cardiac conduction traits. 2) To investigate the effect of a lncRNA, identified from downstream analyses, on DSP gene expression. Methods P-wave, PR, QRS and QT intervals were measured using standard 12-lead electrocardiograms (ECG) in 4295 participants to the Cooperative Health Research in South Tyrol (CHRIS) study (data release 2). Samples were genotyped using the Illumina HumanOmniExpressExome array and imputed on the 1000 Genome Phase 1 panel. We conducted a genetic association study on 3458 variants within the linkage disequilibrium blocks that encompass desmosomal genes, assuming an additive genetic model, at 1.9x10-4 statistical significance. Mendelian Randomization (MR) analyses integrating ECG traits and Genotype-Tissue Expression (GTEx) database transcription levels were performed. A specific GapmeR was used to downregulate the antisense RP3-512B11.3 lncRNA expression in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). hiPSC-CMs lysates were analyzed by digital droplet PCR and Wes™ immunoassay system. Results The rs2744389 variant in DSP gene is associated with a shorter QRS interval (-1.10 ms per effect allele copy; p=3.5x10-6). In the GTEx database, rs2744389 is identified as an expression quantitative trait locus for the antisense lncRNA. MR results support a causal effect of the lncRNA on QRS. To assess the hypothesis that the lncRNA regulates DSP gene expression, we identified a Gapmer able to downregulate the lncRNA expression by approximately 60% in hiPSC-CMs. The lncRNA downregulation led to a significant increase of DSP expression, both at mRNA and protein level, compared to hiPSC-CMs treated with a negative control Gapmer (DSP/RPP30: 16.39±3.32 vs 11.84±1.79; p=0.0313), (Desmoplakin/total protein: 2.44±0.29 vs 1.66±0.11; p=0.0156). Conclusions Starting with the identification of an association between a common genetic variant in DSP gene and a significantly shorter QRS interval in a general population sample, we further unrevealed a new mechanism regulating DSP expression through an antisense lncRNA. While requiring further evidence, these findings might pave the way to a potentially novel therapeutic approach for DSP mutations carriers characterized by desmoplakin protein deficit, as for example patients affected by ACM, but also by dilated cardiomyopathy, cardiocutaneous diseases such as the Carvajal syndrome, and some cancer conditions.

Pachyonychia congenita - pathogenesis of pain and approaches to treatment.

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.

O22 Unravelling the pathophysiology of KLICK syndrome to identify therapeutically targetable pathways

Abstract Introduction and aims Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultrarare genodermatosis associated with a homozygous pathogenic variant, c.-95delC in POMP, which encodes for proteasome maturation protein. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. The pathophysiology of KLICK syndrome is poorly understood, resulting in nonspecific, limited treatment options. The aim of this work is to characterize KLICK syndrome at the cellular and molecular level, with the utilization of transcriptomic techniques for potential drug repurposing. Methods A lesional skin biopsy was obtained, following informed consent, from a 32-year-old female patient with KLICK syndrome. Histology and immunostaining were used to characterize the disrupted skin architecture. RNA sequencing was used to identify key dysregulated pathways and the L1000FWD reverse transcriptomics tool enabled the generation of a shortlist of potential therapeutics for KLICK syndrome. CRISPR editing techniques and induced pluripotent stem cell (iPSC) reprogramming Methods were used to generate cellular based models carrying the pathogenic POMP variant in order to support evaluation of the shortlisted therapeutic options. Results KLICK syndrome skin histology featured hyperkeratosis, hypergranulosis and delayed cellular flattening. Consistent with pathological features, pathway analysis of transcriptomic data revealed keratinocyte differentiation and epidermis development as key upregulated pathways in KLICK syndrome. Interestingly, the Panther pathway analysis tool suggested dysregulation in epidermal growth factor receptor (EGFR) signalling, and reverse transcriptomics identified erlotinib, an EGFR inhibitor, as a potential therapeutic treatment for KLICK syndrome. HaCaT keratinocytes were successfully edited using CRISPR-Cas9 to carry the KLICK patient POMP variant and a KLICK patient iPSC line was generated to support in vitro KLICK syndrome modelling. Conclusions KLICK syndrome is a hyperproliferative inflammatory skin disorder associated with a pathogenic variant in POMP. Reverse transcriptomics is a useful tool for shortlisting drugs with biologically relevant mechanisms of action with potential for treatment of rare genetic diseases such as KLICK syndrome.

Genetic analysis of seven patients with inherited ichthyosis and Nagashima‑type palmoplantar keratoderma.

Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole‑exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis‑like but distinct clinical manifestations. Genetic analysis identified diagnostic variations in the FLG, STS, KRT10 and SERPINB7 genes and clarified the carrying status of each variant in the respective family members. The two residues affected by the detected missense variants remained conserved across multiple species. Of note, the two variants, namely STS: c.452C>T(p.P151L) and c.647_650del(p.L216fs) are novel. In conclusion, a clear genetic differential diagnosis was made for the enrolled ichthyosis‑associated patients; the study findings also extended the mutation spectrum of ichthyosis and provided solid evidence for the counseling of the affected families.

A Cross-Sectional Study of Dermoscopy and Clinical and Histopathological Study of Acquired Palmoplantar Keratodermas: A Research Protocol.

Background Acquired palmoplantar keratodermas (PPKs) pose diagnostic and therapeutic challenges due to their varied clinical presentations and overlapping features. This study aims to elucidatediagnostic criteria; assess correlations between clinical, dermoscopic, and histopathological features;and evaluate treatment outcomes for acquired PPKs, particularly palmoplantar psoriasis. Methods A prospective, cross-sectional study will be conducted at the Department of Dermatology, Venereology, and Leprosy, Acharya Vinoba Bhave Rural Hospital (AVBRH), Wardha, Maharashtra. Patients with acquired PPKs will undergo comprehensive clinical, dermoscopic, and histopathological evaluations. Treatment outcomes for palmoplantar psoriasis will be assessed following standard therapy. Statistical analysis will include descriptive statistics, diagnostic accuracy assessments, correlation analyses, and treatment outcome evaluations. Results The study is anticipated to establish reliable diagnostic criteria for acquired PPKs, identify correlations between features, and demonstrate the effectiveness of standard therapies for palmoplantar psoriasis. The findings are expected to inform evidence-based guidelines and protocols for diagnosing and managing acquired PPKs. Conclusion This study aims to advance the understanding and management of acquired PPKs by providing insights into diagnostic accuracy, correlations between features, and treatment outcomes. The study seeks to enhance patient care and outcomes for individuals affected by acquired PPKs by improving diagnostic precision and guiding therapeutic interventions.

Cutaneous manifestations of hypothyroidism: An observational study in a tertiary care center of Eastern India

Cutaneous manifestations of hypothyroidism: An observational study in a tertiary care center of Eastern India

Collodion Baby Progressing to Camisa Syndrome: Case Report and Review of Literature in Asian Population

Palmoplantar keratoderma (PPK) is a broad entity comprising wide range of hereditary and acquired disorders. Herein, we present a case of 18-year-old female who presented with complaints of palmoplantar thickening since birth and progressive constriction bands around digits for 3 years. On examination, diffuse transgradient honeycomb type of PPK was present. Fibrous constriction bands (pseudoainhum) were present circumferentially around the distal interphalangeal joint of fifth finger and metatarsophalangeal joint of fifth toe bilaterally. Punch biopsy from palms revealed hyperkeratotic, stratified squamous epithelium with vacuolar degeneration and prominent keratohyaline granules. Audiogram was normal. On the basis of history, clinical examination and investigations, a diagnosis of Camisa syndrome was made and the patient was started on oral retinoids. We also discussed case findings of Camisa Syndrome reported in Asian population.

Case Study: Urgent Medical Care for Asylum-Seeking Infant at US-Mexico Border

A 22-month-old male presented at a triage facility within an immigration shelter with wounds, inflammation, and swelling across legs and arms; bloody and pus-filled discharge; skin discoloration, scaling, and swelling; and significant pain. His family had been released from immigration detention after migrating from Central America to the U.S. southern border. The attending triage nurse-midwife immediately transferred the patient to a local hospital for emergency care, in addition to signing the patient’s family into Specialty Care Action Network (SCAN), a pediatric component of Health Network, a virtual system for medical care coordination. After transfer to another hospital for higher level care, where he received a diagnosis of Carvajal syndrome, the patient was sufficiently stable for transport to a hospital in California, his family’s final destination. The resident physician in San Antonio, a SCAN case manager, a network of clinicians, and the medical director in California arranged for his extensive and diverse subspecialty care, through nonprofit funding and charity care in the absence of case management or care for migrants provided by federal immigration and/or health systems.

Typical Electrocardiographic Features in Arrhythmogenic Left Ventricular Cardiomyopathy

Since 2020 arrhythmogenic cardiomyopathy includes a right dominant form, a biventricular form and a left dominant form. Already in 2004 Carvajal syndrome was first described in Ecuador within families [1]. This syndrome includes a slighty dilated, poor contracting left ventricle and hair and skin abnormalities with curly hair and plantopalmar keratosis. The genetic background were mutations of the desmoplakin gene.

Paraneoplastic Eczematous Dermatitis With Palmoplantar Keratoderma as an Initial Manifestation of Acute Myeloid Leukemia

Paraneoplastic Eczematous Dermatitis With Palmoplantar Keratoderma as an Initial Manifestation of Acute Myeloid Leukemia

A Role for Aquaporin-5 Variants in Regulation of the Actin Cytoskeleton in Non-Epidermolytic Palmoplantar Keratoderma

A Role for Aquaporin-5 Variants in Regulation of the Actin Cytoskeleton in Non-Epidermolytic Palmoplantar Keratoderma

Wood's light as a noval diagnostic tool in aquagenic keratoderma

AbstractAquagenic keratoderma, also known as aquagenic wrinkling of the palms, transient reactive papulotranslucent acrokeratoderma, or transient aquagenic hyper‐wrinkling, is an uncommon disorder that affects the palms and occasionally the soles. It presents with translucent whitish to yellowish papules and increased wrinkling upon water exposure. The frequency of this condition is yet to be determined among the general population. However, it is frequently observed in patients among patients with cystic fibrosis or carriers of the cystic fibrosis gene, with frequency estimated to be up to 41%. In this paper, we report the utility and novelty of Wood's light as a bedside adjunct tool to aid in diagnosing aquagenic keratoderma. To our knowledge, this is the first case reporting the use of Wood's light in diagnosing aquagenic keratoderma.

Epidermal growth factor receptor inhibition leads to cellular phenotype correction of DSP-mutated keratinocytes.

Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4:c.3337C>T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of DSP mRNA and protein expression. Patient's keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.

Resolution of paraneoplastic palmoplantar keratoderma after treating mixed serous neuroendocrine tumor of the pancreas: a case report and literature review

Palmoplantar keratodermas (PPKs), also known as ‘keratosis palmaris et plantaris’, are a heterogeneous group of disorders characterized by abnormal thickening of the epidermal skin of the palms and soles leading to hyperkeratosis. It could be acquired or hereditary. Acquired PPK often occurs as a paraneoplastic syndrome as well as a stigma of other dermatoses. We report a rare case of paraneoplastic PPK secondary to mixed neuroendocrine tumor of the pancreas with complete remission after surgical excision of the cancer.

Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark.

Palmoplantar keratoderma (PPK) is a heterogeneous group of rare skin diseases characterized by hyperkeratosis on the palms or soles. The subtype isolated punctate PPK is caused by heterozygous variants in AAGAB. We investigated if the variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate PPK in the Region of Southern Denmark represented a founder variant and estimated the age to the most recent common ancestor. We performed haplotype analysis on samples from 20 patients diagnosed with punctate PPK and the AAGAB c.370C>T, p.Arg124Ter variant. Using the Gamma Method, we calculated the years to the most recent common ancestor. We also explored the presence of the variant in other populations through literature and databases (HGMD, ClinVar, and gnomAD). Our analysis revealed a shared haplotype of 3.0 Mb, suggesting shared ancestry. The ancestral haplogroup was estimated to an age of 12.1 generations (CI: 4.9-20.3) equivalent to approximately 339 years (CI: 137-568). This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant. We recommend testing for the variant as initial screening in our region and potentially for all Danish patients presenting with punctate PPK.

WOOLY HAIR PALMOPLANTAR KERATODERMA : A CASE REPORT

Wooly hair is a rare hair shaft abnormality characterized by extremely curly hair. It can occur in isolation or associated with palmoplantar keratoderma (PPK) and cardiac defects. We present the case of a 56-year-old female patient who initially presented with non-itchy, painful skin lesions over palms and soles since 5years and had abnormal scalp hair texture since childhood. She responded positively to treatment with topical application of 6%salicylic acid twice a day for 3 months on which the thickness and size of the plaques gradually reduced.

Autosomal recessive plantar keratoderma with ragged periungual hyperkeratosis caused by a homozygous missense variant inKRT16.

In the present study, we report a consanguineous Kuwaiti pedigree with pseudo-dominant inheritance of a recessive KRT16 variant in which homozygotes had focal nonepidermolytic palmoplantar keratoderma accompanied by ragged periungual hyperkeratosis. The key value of this submission is that we believe we have identified the first autosomal recessive inherited skin disorder resulting from pathogenic variants in the keratin 16 gene, KRT16. Our findings expand both the genetic basis and phenotypic expression of inherited KRT16-related disorders.

P21 Bi-allelic TUFT1 variants in two siblings with woolly hair and skin fragility

Abstract TUFT1 encodes tuftelin-1, a glycoprotein thought to play a major role in mineralization and structural organization of enamel, but it has not been implicated in any monogenic enamel disorders. Recently, Jackson et al. (2023) identified that tuftelin-1 has a role in desmosomal function. Pathology in desmosomal components causes disorders affecting the skin, hair, and heart. Newly described bi-allelic loss-of-function TUFT1 variants (OMIM600087) cause a novel skin fragility-woolly hair phenotype. We present two siblings from non-consanguineous parents of Irish and British ancestry. Both had normal skin at birth and developed widespread blisters on day two of life, on the limbs, buttocks area and inside the mouth. Although their skin fragility had improved with age, they still developed flare-ups with multiple small blisters, mainly on their limbs when viral illness. They had mild palmoplantar keratoderma and skin peeling. Their most characteristic phenotype was slow-­growing woolly hair that did not need cutting until the age of 5 years old in the older sibling. The eyebrows and eyelashes were unaffected. Recently, the older sibling has developed keratosis pilaris on her arms. The heart was unaffected with normal electrocardiogram and echocardiogram. Whole exome sequencing identified homozygous NM_020127:c.60+1G>A TUFT1 variants in both affected individuals. These two cases reflect a novel condition. The predominant clinical phenotype is woolly hair and early signs of skin fragility. Despite having a role in desmosomal integrity bi-­allelic loss-of-function TUFT1 variants do not appear to cause cardiac pathology.