RESUMEN

Symmetrical acral keratoderma (SAK) is a rare skin disorder with symmetric hyperkeratotic patches on the acral regions. Variants in the filaggrin gene (FLG) have been associated with SAK since 2020. To explore the clinical and genetic basis in six patients with SAK. Whole-exome sequencing, direct sequencing, and prediction of protein structure and function were performed. In this study, we identified two novel variants, c.3320del and c.4909del, and seven previously reported variants, c.3099C>G, c.4544C>A, c.6950_6957del, c.7264G>T, c.7945del, c.8117C>G, c.12064A>T. The findings of this study bolster the existing evidence implicating FLG variants in SAK, introducing two novel variants to the database of FLG variants associated with the condition.

Asunto(s)

Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Humanos , Proteínas de Filamentos Intermediarios/genética , Femenino , Masculino , Secuenciación del Exoma , Adulto , Queratodermia Palmoplantar/genética , Persona de Mediana Edad

RESUMEN

Introduction: Palmoplantar keratoderma is an abnormal thickening of the skin on the palms of the hands and soles of the feet. The classification of palmoplantar keratoderma depends on the clinical characteristics and whether it is hereditary or acquired. The traditional approach tries to soften and minimize skin thickness. The usual treatment choices include emollients, keratolytics like salicylic acid or urea, antifungal cream or pills, as well as topical retinoids/calcipotriol and systemic retinoids. However, the persistent use of such medications frequently exhausts the patients because the problem returns as soon as the local applications are discontinued. Methods: The case was recorded in the dermatological department of Dr DY Patil HMC & RC. A 27-year-old female patient prediagnosed with Palmoplantar Keratoderma was treated with individualized homeopathic medicine (iHOM) between 25th February 2021 to 22nd July 2021. During the follow-up visits outcome was assessed. To assess whether the changes were due to homeopathic medicine a modified Naranjo criteria was performed. Based on the totality of symptoms, individualized homeopathic medicine Petroleum 30C was given. Results: The patient was successfully treated for palmoplantar keratoderma with homeopathic Petroleum 30C over five months. Cracks and thickening of skin on the palms and soles resolved completely with no pain and itching. Conclusion: Individualized homeopathic treatment of palmoplantar keratoderma is possible and offers a gentle, non-invasive alternative to pharmaceutical use.

Asunto(s)

Queratodermia Palmoplantar , Humanos , Femenino , Queratodermia Palmoplantar/tratamiento farmacológico , Adulto , Homeopatía/métodos

RESUMEN

Palmoplantar keratoderma (PPK) is a multi-faceted skin disorder characterized by the thickening of the epidermis and abrasions on the palms and soles of the feet. Among the genetic causes, biallelic pathogenic variants in the FAM83G gene have been associated with PPK in dogs and humans. Here, a novel homozygous variant (c.794G>C, p.Arg265Pro) in the FAM83G gene, identified by whole exome sequencing in a 60-year-old female patient with PPK, is reported. The patient exhibited alterations in the skin of both hands and feet, dystrophic nails, thin, curly and sparse hair, long upper eyelid eyelashes, and poor dental enamel. FAM83G activates WNT signalling through association with ser/thr protein kinase CK1α. When expressed in FAM83G-/- DLD1 colorectal cancer cells, the FAM83GR265P variant displayed poor stability, a loss of interaction with CK1α and attenuated WNT signalling response. These defects persisted in skin fibroblast cells derived from the patient. Our findings imply that the loss of FAM83G-CK1α interaction and subsequent attenuation of WNT signalling underlie the pathogenesis of PPK caused by the FAM83GR265P variant.

Asunto(s)

Caseína Quinasa Ialfa , Queratodermia Palmoplantar , Vía de Señalización Wnt , Humanos , Femenino , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Persona de Mediana Edad , Caseína Quinasa Ialfa/metabolismo , Caseína Quinasa Ialfa/genética , Secuenciación del Exoma , Unión Proteica , Fibroblastos/metabolismo

RESUMEN

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.

Asunto(s)

Fosfatidilinositol 3-Quinasa Clase I , Queratodermia Palmoplantar , Mutación Missense , Transducción de Señal , Preescolar , Femenino , Humanos , Fosfatidilinositol 3-Quinasa Clase I/genética , Secuenciación del Exoma , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

BACKGROUND: Plantar keratoma are common hyperkeratinized, deep-seated lesions, often located on weightbearing areas of the foot. Such lesions are frequently associated with pain and disability. Intractable plantar keratomata (IPK) are highly recurrent and, in most patients, require regular, palliative treatment visits with a significant impact on patient time, cost, and quality of life. METHODS: We undertook a retrospective chart review of 9 patients (with a total of 21 lesions) who underwent a minimum of two treatments using microwave therapy to their IPK. Pain levels were assessed at each of their treatments using a 10-point scale and patients were invited for review for follow-up in the following year. A total of seven patients undertook four treatments and were included in the final analysis. RESULTS: Mean baseline pain scores significantly dropped with each subsequent treatment, equating to a 90.4% mean reduction in pain between the first and fourth visits, with 71.4% of patients reporting a zero-pain rating at their final treatment visit. CONCLUSIONS: The use of microwave therapy has been shown to be effective in producing significant and prolonged pain reduction in a cohort of patients with painful IPK.

Asunto(s)

Microondas , Humanos , Estudios Retrospectivos , Microondas/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Dimensión del Dolor , Adulto , Resultado del Tratamiento , Queratodermia Palmoplantar/terapia , Manejo del Dolor/métodos

RESUMEN

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.

Asunto(s)

Antígenos Ly , Queratodermia Palmoplantar , Ratones Noqueados , Activador de Plasminógeno de Tipo Uroquinasa , Animales , Femenino , Masculino , Ratones , Antígenos Ly/genética , Antígenos Ly/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Ratones Endogámicos C57BL , Umbral del Dolor/fisiología , Activador de Plasminógeno de Tipo Uroquinasa/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo

RESUMEN

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 whole­exome 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 ichthyosis­like 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 ichthyosis­associated patients; the study findings also extended the mutation spectrum of ichthyosis and provided solid evidence for the counseling of the affected families.

Asunto(s)

Secuenciación del Exoma , Proteínas Filagrina , Ictiosis , Queratodermia Palmoplantar , Linaje , Esteril-Sulfatasa , Humanos , Femenino , Masculino , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/diagnóstico , Queratodermia Palmoplantar/patología , Niño , Ictiosis/genética , Ictiosis/diagnóstico , Adulto , Pruebas Genéticas , Serpinas/genética , Queratina-10/genética , Adolescente , Preescolar , Mutación Missense , Mutación , Adulto Joven , Predisposición Genética a la Enfermedad

Asunto(s)

Anticuerpos Monoclonales Humanizados , Queratodermia Palmoplantar , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/diagnóstico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Queratodermia Palmoplantar/tratamiento farmacológico , Queratodermia Palmoplantar/diagnóstico , Femenino , Fármacos Dermatológicos/uso terapéutico , Diagnóstico Diferencial , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación

RESUMEN

BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

Asunto(s)

Síndrome de Costello , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Síndrome de Costello/genética , Síndrome de Costello/complicaciones , Estudios Prospectivos , Femenino , Masculino , Niño , Proteínas Proto-Oncogénicas p21(ras)/genética , Adolescente , Preescolar , Adulto , Adulto Joven , Displasia Ectodérmica/genética , Síndrome de Noonan/genética , Síndrome de Noonan/complicaciones , Acantosis Nigricans/genética , Diagnóstico Diferencial , Queratodermia Palmoplantar/genética , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/complicaciones , Fenotipo , Papiloma/genética , Papiloma/patología , Acitretina/uso terapéutico , Cejas/anomalías , Cejas/patología , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/etiología , Lactante , Queratolíticos/uso terapéutico , Facies

Asunto(s)

Queratodermia Palmoplantar , Leucemia Mieloide Aguda , Síndromes Paraneoplásicos , Humanos , Leucemia Mieloide Aguda/complicaciones , Queratodermia Palmoplantar/etiología , Queratodermia Palmoplantar/diagnóstico , Síndromes Paraneoplásicos/diagnóstico , Eccema/etiología , Eccema/diagnóstico , Masculino , Persona de Mediana Edad , Femenino

RESUMEN

ABSTRACT: Spiny keratoderma is a rare entity presenting with minute keratotic spines on the palms and soles. Spiny keratoderma can be inherited or acquired, and the acquired form may be associated with underlying malignancy or systemic disease. Clinically, the differential diagnosis includes other digitate keratoses on acral sites, most notably arsenical keratosis, filiform verruca, and punctate porokeratosis. Biopsy findings typically include a column of parakeratosis overlying a diminished granular cell layer. In this article, we present 3 cases of acquired spiny keratoderma in patients with various systemic diseases, but no underlying malignancy.

Asunto(s)

Queratodermia Palmoplantar , Humanos , Femenino , Masculino , Persona de Mediana Edad , Queratodermia Palmoplantar/patología , Queratodermia Palmoplantar/diagnóstico , Anciano , Biopsia , Adulto

RESUMEN

We present a case of a young patient with chest pain. Labs and cardiac imaging were suspicious for acute myocarditis. Genetic testing revealed a diagnosis of desmoplakin cardiomyopathy. Desmoplakin cardiomyopathy may be considered in patients with recurrent acute myocarditis or a family history of cardiac disease to avoid the potential for misdiagnosis.

Asunto(s)

Cardiomiopatías , Miocarditis , Valor Predictivo de las Pruebas , Humanos , Enfermedad Aguda , Biopsia , Cardiomiopatías/genética , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatía Dilatada , Desmoplaquinas/genética , Diagnóstico Diferencial , Electrocardiografía , Predisposición Genética a la Enfermedad , Enfermedades del Cabello , Queratodermia Palmoplantar , Mutación , Miocarditis/diagnóstico por imagen , Miocarditis/genética , Fenotipo , Femenino , Adolescente

RESUMEN

Acrokeratoelastoidosis (AKE) is a rare autosomal dominant hereditary skin disease characterized by small, round-oval, flat-topped keratotic papules on the palms, soles and dorsal aspect of hands or feet. The causative gene for AKE remains unidentified. This study aims to identify the causative gene of AKE and explore the underlying biological mechanisms. A large, three-generation Chinese family exhibiting classic AKE symptoms was identified. A genome-wide linkage analysis and whole-exome sequencing were employed to determine the causative gene. shRNA knockdown in human skin fibroblasts and CRISPR/Cas9 knockout in HEK293T cells were utilized to assess gene functions in the progression of elastic fiber biosynthesis. The linkage analysis identified a susceptibility region between rs7296765 to rs10784618 on chromosome 12. Whole-exome sequencing confirmed a splicing mutation of 1101 + 1 G > A in the CCDC91 gene, resulting in exon 11 skipping and a subsequent 59-amino-acid-residue loss (residues L309-Q367del). Further functional analysis revealed distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-HSF cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates. There are no significant changes in Fibrillin-1 microfibril assembly and lysyl oxidase activity. The findings strongly suggest that the protein product of the CCDC91 gene plays a crucial role in elastin transport. This discovery enhances our understanding of CCDC91's function and broadens the known pathogenic mechanisms of AKE.

Asunto(s)

Linaje , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Secuenciación del Exoma , Células HEK293 , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Queratodermia Palmoplantar/metabolismo , Mutación

Asunto(s)

Artritis Reumatoide , Queratodermia Palmoplantar , Serpinas , Humanos , Queratodermia Palmoplantar/complicaciones , Queratodermia Palmoplantar/genética , Mutación , Artritis Reumatoide/complicaciones , Serpinas/genética

Asunto(s)

Humanos , Femenino , Niño , Fibrosis Quística/complicaciones , Dermatoglifia , Queratodermia Palmoplantar , Glándulas Ecrinas , Resultado del Tratamiento , Pacientes Internos , Examen Físico , Evaluación de Síntomas , España , Pediatría , Fibrosis Quística/tratamiento farmacológico

Asunto(s)

Acuaporina 5 , Queratodermia Palmoplantar , Humanos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/genética , Actinas/metabolismo , Actinas/genética , Acuaporina 5/genética , Acuaporina 5/metabolismo , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología

Asunto(s)

Pueblo Asiatico , Queratodermia Palmoplantar , Serpinas , Humanos , Serpinas/genética , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/diagnóstico , Masculino , Femenino , Pueblo Asiatico/genética , Linaje , China , Mutación , Adulto , Pueblos del Este de Asia

Asunto(s)

Queratodermia Palmoplantar , Humanos , Queratodermia Palmoplantar/diagnóstico , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/etiología , Queratodermia Palmoplantar/patología , Femenino , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cabello/patología , Masculino , Enfermedades del Cabello/diagnóstico , Adulto , Persona de Mediana Edad

RESUMEN

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.

Asunto(s)

Desmoplaquinas , Receptores ErbB , Enfermedades del Cabello , Queratodermia Palmoplantar , Humanos , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Epidermis/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Enfermedades del Cabello/genética , Queratinocitos/metabolismo , Queratodermia Palmoplantar/genética , Fenotipo , Piel/metabolismo

RESUMEN

This case report describes diffuse waxy palmoplantar hyperkeratosis in a symmetrically well-demarcated "gloves and socks" distribution with nail dystrophy.

Asunto(s)

Queratodermia Palmoplantar , Humanos , Linaje