RESUMEN
The gene expression time-course of repeated challenge of contact allergy (CA) remains largely unknown. Therefore, using diphenylcyclopropenone (DPCP) as model allergen in healthy humans we set out to examine: (i) the monotonous and complex gene expression time-course trajectories following repeated DPCP challenges to find the predominant gene expression pattern, (ii) the time-course of cell infiltration following repeated DPCP challenges and (iii) the transcriptome of a repeated CA exposure model. We obtained punch biopsies from control and DPCP-exposed skin from ten DPCP sensitized individuals at 5-6 monthly elicitation challenges. Biopsies were used for microarray gene expression profiling, histopathology and immunohistochemical staining. Validation of microarray data by qRT-PCR was performed on 15 selected genes. Early gene expression time points were also validated in an independent data set. An increasing and decreasing trend in gene expression followed by a plateau was predominantly observed during repeated DPCP challenges. Immune responses reached a plateau after two challenges histopathologically, immunohistochemically and in the time-course gene expression analysis. Transcriptional responses over time revealed a Th1/Th17 polarization as three upstream regulators (IFN-γ, IL-1 and IL-17) activated most of the top upregulated genes. Of the latter genes, 9 of 10 were the same throughout the time course. Excellent correlations between array and PCR data were observed. The transcriptional responses to DPCP over time followed a monotonous pattern. This response pattern confirms and supports the newly reported clinical time-course observations in de novo-sensitized individuals showing a plateau response, and thus, there is concordance between clinical response, histopathology, immunohistochemistry and microarray gene expression in volunteers de novo-sensitized to DPCP.
Asunto(s)
Dermatitis Alérgica por Contacto/genética , Dermatitis Alérgica por Contacto/inmunología , Expresión Génica , Piel/metabolismo , Transcriptoma , Adulto , Biopsia , Ciclopropanos , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/patología , Femenino , Perfilación de la Expresión Génica , Voluntarios Sanos , Humanos , Interferón gamma/metabolismo , Interleucina-1/metabolismo , Interleucina-17/metabolismo , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Piel/patología , Células TH1/inmunología , Células Th17/inmunología , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Cetuximab inhibits the epidermal growth factor receptor (EGFR), and papulopustular eruptions is a frequent side effect. Vitamin K3 (menadione) has preclinically shown to be a potential activator of the EGFR by phosphorylating the receptor (pEGFR). The present randomised study investigated the effect of a vitamin K3 cream on cetuximab-induced rash. MATERIALS AND METHODS: Thirty patients were included in this double-blinded placebo-controlled trial. Patients receiving cetuximab 500 mg/m2 every second week plus chemotherapy for metastatic cancer were included. In each patient, vitamin K3 cream and placebo were applied twice daily on two separate areas of the skin of minimum 10 × 10 cm for up to 2 months. Papulopustular eruptions were evaluated clinically and monitored by clinical photos. Skin biopsies, from ten patients taken before and after 1 month of treatment from each treatment area, were stained for EGFR and pEGFR. RESULTS: Application of vitamin K3 cream twice daily during treatment with cetuximab did not reduce the number of papulopustular eruptions, and this was independent of the use of systemic tetracycline. No significant changes in the staining of EGFR or pEGFR were observed in the skin of the vitamin K3-treated area compared to the placebo area. CONCLUSION: The present data do not support any clinical or immunohistochemical benefit of using vitamin K3 cream for cetuximab-induced rash.
Asunto(s)
Cetuximab/efectos adversos , Exantema/inducido químicamente , Vitamina K 3/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vitamina K 3/administración & dosificación , Vitamina K 3/farmacologíaRESUMEN
BACKGROUND: Odonto-onycho-dermal dysplasia (OODD) is a rare form of ectodermal dysplasia characterized by severe oligodontia, onychodysplasia, palmoplantar hyperkeratosis, dry skin, hypotrichosis, and hyperhidrosis of the palms and soles. The ectodermal dysplasias resulting from biallelic mutations in the WNT10A gene result in highly variable phenotypes, ranging from isolated tooth agenesis to OODD and Schöpf-Schulz-Passarge syndrome (SSPS). CASE PRESENTATION: We identified a female patient, with consanguineous parents, who was clinically diagnosed with OODD. Genetic testing showed that she was homozygous for a previously reported pathogenic mutation in the WNT10A gene, c.321C > A, p.Cys107*. The skin and nail abnormalities were for many years interpreted as psoriasis and treated accordingly. A thorough clinical examination revealed hypotrichosis and hyperhidrosis of the soles and dental examination revealed agenesis of permanent teeth except the two maxillary central incisors. Skin biopsies from the hyperkeratotic palms and soles showed the characteristic changes of eccrine syringofibroadenomatosis, which has been described in patients with ectodermal dysplasias. Together with a family history of tooth anomalies, this lead to the clinical suspicion of a hereditary ectodermal dysplasia. CONCLUSION: This case illustrates the challenges of diagnosing ectodermal dysplasia like OODD and highlights the relevance of interdisciplinary cooperation in the diagnosis of rare conditions.
Asunto(s)
Codón sin Sentido , Displasia Ectodérmica/genética , Homocigoto , Odontodisplasia/genética , Proteínas Wnt/genética , Adulto , Femenino , HumanosRESUMEN
BACKGROUND: An autosomal dominant form of diffuse non-epidermolytic palmoplantar keratoderma, palmoplantar keratoderma of Bothnian type, is caused by mutations in the AQP5 gene encoding the cell-membrane water channel protein aquaporin 5 leading to defective epidermal-water-barrier function in the epidermis of the palms and soles. CASE PRESENTATION: We report the first Danish family diagnosed with diffuse non-epidermolytic palmoplantar keratoderma of Bothnian type in which fourteen individuals are potentially affected. The proband, a 36-year-old male had since childhood been affected by pronounced hyperhidrosis of the palms and soles along with palmoplantar keratoderma. He reported a very distinctive feature of the disorder, aquagenic wrinkling, as he developed pronounced maceration of the skin with translucent white papules and a spongy appearance following exposure to water. The patient presented recurrent fungal infections, a wellknown feature of the condition, but also periodic worsening with pitted keratolysis and malodour due to bacterial infections. CONCLUSIONS: Palmoplantar keratoderma of Bothnian type, which may be associated with hyperhidrosis, is frequently complicated by fungal infections and may be complicated by Corynebacterium infections.
Asunto(s)
Acuaporina 5/genética , Infecciones por Corynebacterium/etiología , Hiperhidrosis/genética , Queratodermia Palmoplantar/genética , Mutación , Adulto , Niño , Dinamarca , Humanos , MasculinoAsunto(s)
Padre , Herencia , Ictiosis Lamelar/genética , Ictiosis Lamelar/patología , Queratina-10/genética , Mosaicismo , Mutación , Piel/patología , Biopsia , Preescolar , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
BACKGROUND: Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated. CASE PRESENTATION: We report a female patient with a systemic keratinocytic nevus also involving the oral mucosa. Molecular genetic analysis revealed a mosaicism of the FGFR3 hotspot mutation R248C in the EN lesions of the skin and of the oral mucosa. The detection of the R248C mutation in a proportion of blood leukocytes and a slight scoliosis suggest an EN syndrome. CONCLUSIONS: Our results show that activating FGFR3 mutations can also affect the oral mucosa and that extracutaneous manifestations of EN syndrome can be subtle. We highlight the theoretical risk of the patient having an offspring with thanatophoric dysplasia as gonadal mosaicism for the R248C mutation cannot be excluded.
Asunto(s)
Epidermis/patología , Mucosa Bucal/patología , Mutación Missense/genética , Nevo/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Femenino , Humanos , MosaicismoRESUMEN
Heterozygous nonsense mutations in the CDSN gene encoding corneodesmosin (CDSN), an adhesive protein expressed in cornified epithelia and hair follicles, cause hypotrichosis simplex of the scalp (HSS), a nonsyndromic form of alopecia. Truncated mutants of CDSN ((mut)CDSN), which bear the N-terminal adhesive Gly/Ser-rich domain (GS domain) of the protein, abnormally accumulate as amorphous deposits at the periphery of hair follicles and in the papillary dermis of the patient skin. Here, we present evidence that the (mut)CDSN deposits display an affinity for amyloidophilic dyes, namely Congo red and thioflavin T. We also detected the serum amyloid protein component in the dermis of HSS patients. We demonstrated that recombinant forms of (mut)CDSN and of the GS domain assemble in vitro into ring-shaped oligomeric structures and fibrils. The amyloid-like nature of the fibrils was demonstrated by dye binding and Fourier transform infrared spectrometry measurements. We showed that the ring-shaped oligomers of (mut)CDSN, but not the fibrillar forms, are toxic to cultured keratinocytes. Finally, online algorithms predicted the GS domain to be a particularly disordered region of CDSN in agreement with circular dichroism measurements. This identifies HSS as a human amyloidosis related to the aggregation of natively unfolded (mut)CDSN polypeptides into amyloid fibrils.
Asunto(s)
Amiloidosis/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas/ultraestructura , Anciano , Amiloidosis/genética , Células Cultivadas , Dicroismo Circular , Glicoproteínas/genética , Humanos , Hipotricosis/metabolismo , Hipotricosis/patología , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Masculino , Microscopía Electrónica de Transmisión , Microscopía Inmunoelectrónica , Mutación , Pliegue de Proteína , Cuero Cabelludo/metabolismo , Cuero Cabelludo/patología , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
AIM: To present current and new knowledge on congenital self-healing reticulohistiocytosis, a benign variant of cutaneous Langerhans cell histiocytosis presenting with skin lesions in the neonatal period. METHODS: We describe and photo document two cases of this rare disease and review the literature. RESULTS: Only few newborns have acute access to a neonatal dermatologist, and we demonstrate how the spontaneous cutaneous involution may happen even prior to the first dermatological assessment. As no sole criterion can reliably distinguish the self-healing form from disseminated disease, multidisciplinary assessment and follow-up are essential. CONCLUSION: Our data document how easily the diagnosis congenital self-healing reticulocytosis may be missed and emphasize the importance and value of instant clinical photographing at the neonatal unit and the use of teledermatology whenever congenital self-healing reticulohistiocytosis is suspected.
Asunto(s)
Histiocitosis de Células de Langerhans/congénito , Diagnóstico Diferencial , Histiocitosis de Células de Langerhans/diagnóstico , Humanos , Recién Nacido , Masculino , Enfermedades de la Piel/etiologíaRESUMEN
To obtain a separation of the epidermal and dermal compartments to examine compartment specific biological mechanisms in the skin, we incubated 4 mm human skin punch biopsies in ammonium thiocyanate. We wanted to test (i) the histological quality of the dermo-epidermal separation obtained by different incubation times; (ii) the amount and quality of extractable epidermal RNA and (iii) its impact on sample RNA expression profiles assessed by large-scale gene expression microarray analysis in both normal and inflamed skin. At 30-min incubation, the split between dermis and epidermis was not always histologically well-defined (i.e. occurred partly intra-epidermally), but also varied between subjects. Consequently, curettage along the dermal surface of the biopsy was added to the procedure. This modified method resulted in an almost perfect separation of the epidermal and dermal compartments, and satisfactory amounts of high-quality RNA were obtained. Hybridization to Affymetrix HG_U133A 2.0 GeneChips showed that ammonium thiocyanate incubation had a minute effect on gene expression resulting in only one significantly downregulated gene (cystatin E/M). We conclude that epidermis can be reproducibly and almost completely separated from the dermis of 4 mm skin biopsies by 30 min incubation in 3.8% ammonium thiocyanate combined with curettage of the dermal surface, producing high-quality RNA suitable for transcriptional analysis. Our refined method of dermo-epidermal separation will undoubtedly prove valuable in the many different settings, where the epidermal and dermal compartments need to be evaluated separately.
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Biopsia/instrumentación , Biopsia/métodos , Dermis/efectos de los fármacos , Epidermis/efectos de los fármacos , ARN/aislamiento & purificación , Piel/patología , Tiocianatos/farmacología , Análisis por Conglomerados , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Transcripción GenéticaRESUMEN
We report the clinical and histopathological characteristics of two cases of signet ring cell carcinoma of the eye lids, and discuss the histogenesis of this neoplasm. Two 72-year-old Caucasian males both presented with slowly growing tumours of the eyelids. The tumours were excised and specimens were examined using light- and transmission electron microscopic techniques. Clinically, the tumours infiltrated both eyelids on one side of the face with swelling and periocular inflammation, creating a monocle-like appearance. Extensive clinical work-up excluded periocular metastases. Histopathologically, the tumours were composed of rather bland cells with mainly histiocytoid morphology. A minor proportion had a signet ring cell appearance. The cytoplasmic inclusions giving the signet ring morphology were PAS- and colloidal iron positive. The tumour cells reacted with antibodies against cytokeratins, carcinoembryonic antigen, epithelial membrane antigen, gross cystic disease fluid protein-15 and lysozyme. Transmission electron microscopy demonstrated tumour cells containing intracytoplasmic vacuoles lined by microvilli. The tumour cells aggregated in duct-like clusters. A diagnosis of primary signet ring cell carcinoma was made in both cases. Histopathological, immunohistological and ultrastructural findings indicated that the tumours were of sweat gland origin.
Asunto(s)
Carcinoma de Células en Anillo de Sello/metabolismo , Carcinoma de Células en Anillo de Sello/patología , Neoplasias de los Párpados/metabolismo , Neoplasias de los Párpados/patología , Neoplasias de las Glándulas Sudoríparas/metabolismo , Neoplasias de las Glándulas Sudoríparas/patología , Anciano , Ácido Aminosalicílico/metabolismo , Antígeno Carcinoembrionario/metabolismo , Proteínas Portadoras/metabolismo , Glicoproteínas/metabolismo , Histocitoquímica , Humanos , Inmunohistoquímica , Cuerpos de Inclusión Intranucleares/patología , Cuerpos de Inclusión Intranucleares/ultraestructura , Compuestos de Hierro/metabolismo , Queratinas/metabolismo , Masculino , Proteínas de Transporte de Membrana , Microvellosidades/ultraestructura , Mucina-1/metabolismo , Muramidasa/metabolismoRESUMEN
A change in clinical behavior of a disease should prompt search for differential diagnoses. Here, the appearance of ulcerated skin nodules in a preexisting cutaneous mastocytosis revealed a concurrent lymphomatoid papulosis - a CD30+ lymphoproliferative skin disease with histological features of a malignant lymphoma, but with a benign self-healing course.
Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Linfocitos/efectos de los fármacos , Metotrexato/uso terapéutico , Enfermedades Cutáneas Papuloescamosas/tratamiento farmacológico , Piel/efectos de los fármacos , Adulto , Biopsia , Mejilla , Femenino , Humanos , Linfocitos/patología , Piel/patología , Enfermedades Cutáneas Papuloescamosas/patología , Resultado del TratamientoRESUMEN
Loose anagen hair syndrome is an uncommon congenital disorder. It may occur in association with other syndromes and dysmorphic features. We report a girl who fulfilled the diagnostic criteria for this syndrome as proposed by Tosti (Arch Dermatol 2002, 138: 521-522). She also had several other anomalies including colobomas. We suggest that the combination of features in this patient may constitute a specific syndromic phenotype.
Asunto(s)
Alopecia/diagnóstico , Coloboma/diagnóstico , Anomalías Múltiples , Alopecia/patología , Niño , Coloboma/patología , Facies , Femenino , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/patología , Humanos , Fenotipo , SíndromeAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/efectos adversos , Linfocitos B/efectos de los fármacos , Colitis Ulcerosa/inducido químicamente , Enfermedad de Graves/tratamiento farmacológico , Linfopenia/inducido químicamente , Anticuerpos Monoclonales de Origen Murino , Femenino , Humanos , Persona de Mediana Edad , RituximabRESUMEN
Hydroa vacciniforme is one of the rarest forms of photosensitivity disorders of the skin. Effective treatment options are scarce and mainly constitute of strict sun protection. Lately, hydroa vacciniforme has been associated with Epstein-Barr virus infection. We present a patient with hydroa vacciniforme and concomitant previous/chronic Epstein-Barr virus infection. In this case, antiviral treatment was successful.
Asunto(s)
Aciclovir/análogos & derivados , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Hidroa Vacciniforme/virología , Valina/análogos & derivados , Niño , Enfermedad Crónica , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Humanos , Hidroa Vacciniforme/diagnóstico , Masculino , Valaciclovir , Valina/uso terapéuticoRESUMEN
Scurvy is a potentially lethal condition caused by inadequate vitamin C intake. Hypovitaminosis of vitamin C causes vessel fragility and follicular hyperkeratosis that can lead to palpable purpuric skin lesions. In this case report, we aim to remind readers that scurvy still occurs in Western countries and that the clinical presentation may resemble vasculitis.
RESUMEN
BRAF V600 mutation is an important biological marker for therapeutic guidance in melanoma, where mutation-positive cases are candidates for therapy targeting mutant B-Raf. Recent studies showing intratumor variation in BRAF mutation status have caused concern that sensitive mutation analysis can lead to mutation-positive results in patients with melanomas with small subsets of mutation-positive cells who may not benefit from therapy targeting mutant B-Raf. Mutation analysis with high analytical sensitivity is generally preferred, to reduce the risk of false-negative results. In this study, sensitive and quantitative BRAF V600E and V600K mutation-specific real-time quantitative PCR was used to study the occurrence of small subsets of mutation-positive cells in primary melanomas and melanoma metastases. The BRAF V600E mutation was detected in 39 of 82 melanoma patients. We observed a highly dichotomous pattern, with most samples either testing mutation positive in a high fraction of alleles (median, 51%) or negative with a high sensitivity (median, 0.06%). This finding demonstrates that the occurrence of small subsets of mutation-positive cells was rare in our study population and indicates that sensitive mutation analysis can generally be expected to produce clinically relevant results in melanoma patients.
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ADN de Neoplasias/genética , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Análisis Mutacional de ADN/métodos , Estudios de Evaluación como Asunto , Humanos , Melanoma/patología , Melanoma/secundario , Repeticiones de Microsatélite , Mutación , Metástasis de la Neoplasia , Sensibilidad y Especificidad , SuizaAsunto(s)
Anticuerpos Monoclonales/administración & dosificación , Linfocitos B/efectos de los fármacos , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/inmunología , Factores Inmunológicos/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Enfermedad de Graves/patología , Humanos , Depleción Linfocítica/métodos , Rituximab , Glándula Tiroides/inmunología , Glándula Tiroides/patologíaRESUMEN
AIM: Metastasis size in melanoma sentinel lymph nodes (SLNs) is an emerging prognostic factor. Two European melanoma treatment trials include SLN metastasis diameters as inclusion criteria. Whilst diameter estimates are sensitive to the number of sections examined, the level of this bias is largely unknown. We performed a prospective multicentre study to compare the European Organisation for Research and Treatment of Cancer (EORTC) recommended protocol with a protocol of complete step-sectioning. METHODS: One hundred and thirty-three consecutive SLNs from seven SLN centres were analysed by five central sections 50µm apart (EORTC Protocol) followed by complete 250µm step-sectioning. RESULTS: Overall, 29 patients (21.8%) were SLN-positive. The EORTC Protocol missed eight of these metastases (28%), one metastasis measuring less than 0.1mm in diameter, seven measuring between 0.1 and 1mm. Complete step-sectioning at 250µm intervals (Extensive Protocol) missed one metastasis (3%) that measured less than 0.1mm. Thirteen treatment courses (34%) performed if inclusion was based on the Combined Protocol would not be performed if assessed by the EORTC Protocol. Thus, 10 patients would be without completion lymph node dissection (EORTC MINITUB study), whilst three patients would not be eligible for anti-CTLA4 trial (EORTC protocol 18071). The corresponding number with the Extensive Protocol would be three; one patient for the MINITUB registration study and two patients for the anti-CTLA4 study. CONCLUSIONS: Examining SLNs by close central sectioning alone (EORTC Protocol) misses a substantial number of metastases and underestimates the maximum metastasis diameter, leading to important changes in patient eligibility for various treatment protocols.
Asunto(s)
Ganglios Linfáticos/patología , Melanoma/patología , Estadificación de Neoplasias/métodos , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos Clínicos , Femenino , Humanos , Metástasis Linfática , Masculino , Melanoma/secundario , Melanoma/terapia , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Cutáneas/terapia , Adulto JovenRESUMEN
The pathogenesis of irritant contact dermatitis (ICD) is poorly understood, and genes participating in the epidermal response to chemical irritants are only partly known. It is commonly accepted that different irritants have different mechanisms of action in the development of ICD. To define the differential molecular events induced in the epidermis by different irritants, we collected sequential biopsies ((1/2), 4, and 24 hours after a single exposure and at day 11 after repeated exposure) from human volunteers exposed to either sodium lauryl sulfate (SLS) or nonanoic acid (NON). Gene expression analysis using high-density oligonucleotide microarrays (representing 47,000 transcripts) revealed essentially different pathway responses (1/2)hours after exposure: NON transiently induced the IL-6 pathway as well as a number of mitogen-activated signaling cascades including extracellular signal-regulated kinase and growth factor receptor signaling, whereas SLS transiently downregulated cellular energy metabolism pathways. Differential expression of the cyclooxygenase-2 and matrix metalloproteinase 3 transcripts was confirmed immunohistochemically. After cumulative exposure, 883 genes were differentially expressed, whereas we identified 23 suggested common biomarkers for ICD. In conclusion, we bring new insights into two hitherto less well-elucidated phases of skin irritancy: the very initial as well as the late phase after single and cumulative mild exposures, respectively.