RESUMO
BACKGROUND: Moderate-to-severe atopic dermatitis (AD) can be difficult to manage in paediatric patients, with few licensed treatments in this age group. Dupilumab is approved for AD in children older than 6 months. OBJECTIVES: To assess the effectiveness and safety of dupilumab in a real-life cohort of paediatric AD patients in Spain. METHODS: A multicentre, retrospective real-life study on the effectiveness and safety of dupilumab in patients aged 2 to 18 years old with moderate-to-severe AD was conducted. Demographic and clinical characteristics were analysed, and effectiveness (EASI, IGA, DLQI, NRS itch), safety, and drug survival measures were assessed. A comparison of our results with other real-world outcomes and with clinical trials was made. RESULTS: Data from 243 patients from 19 centres was collected, with a mean follow-up of 85 weeks. Dupilumab exhibited significant effectiveness, with marked reductions in severity scores from week 4. By week 16, 79.4% of patients reached EASI75 and 40.5% reached EASI90. Mean percentage reduction in EASI was 79.7%. Increasing improvements were observed until week 52, with 85.8% and 49.6% achieving EASI75 and EASI90, respectively. Forty-three patients developed adverse events (AE) (43/243, 17.7%), being the most frequent ocular surface diseases (20/243, 8.2%), injection site reactions (8/243, 3.3%) and facial redness (7/243, 2.9%). Drug survival was high (96.9% and 93.1% after 1 and 2 years of follow-up, respectively), with only 19 (19/243, 7.8%) patients interrupting treatment: 7 (7/243, 2.9%) due to AE, 2 (2/243, 0.82%) due to secondary failure, 5 (5/243, 2.1%) were lost to follow-up and 5 (5/243, 2.1%) entered remission and stopped treatment. CONCLUSION: Real-life use of dupilumab in paediatric AD showcased sustained effectiveness, high drug survival, and acceptable safety profiles. Longer-term studies are crucial for AE surveillance and how to manage disease remission.
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Background: Keratinocytic epidermal naevi (KENs) are congenital benign skin mosaic lesions that share common mutations with some subsets of urothelial carcinomas. Moreover, several patients with extensive KEN who also developed urothelial carcinomas at young ages have been reported. Thus, patients with extensive KEN may harbour mosaic urothelial oncogenic mutations that would favour the early development of urothelial carcinomas. Methods: We selected five patients with extensive KEN involving the lower part of the back and performed a molecular characterisation of urothelial and cutaneous samples using a next-generation sequencing (NGS) custom panel targeting candidate oncogenic genes. Results: Mosaic pathogenic mutations were detected in KEN in all patients. In four out of five patients, mosaic pathogenic mutations in FGFR2 or HRAS were also detected in samples from the urothelial tract. Moreover, we report a patient who developed urothelial carcinomas at age 29 and harboured an HRAS G12S mutation both in skin and urothelial tumour samples. Conclusions: We conclude that patients with extensive KEN involving the lower part of the back frequently harbour oncogenic mutations in the urothelium that may induce the development of carcinomas. NGS panels can be considered as highly sensitive tools to identify this subgroup of patients, which might permit adoption of screening measures to detect malignant transformation at early stages.
Assuntos
Nevo/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Urotélio/metabolismo , Adulto , Carcinogênese/genética , Feminino , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nevo/complicações , Nevo/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Urotélio/patologia , Adulto JovemRESUMO
BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
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Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Capilares/anormalidades , Mutação em Linhagem Germinativa/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/genética , Receptor EphB4/genética , Proteína p120 Ativadora de GTPase/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , LinhagemAssuntos
COVID-19 , Pérnio , Humanos , Pérnio/epidemiologia , COVID-19/epidemiologia , Pandemias , SARS-CoV-2 , Surtos de DoençasRESUMO
Demodex mites are commensal organisms rarely found in healthy children. Human demodicosis can be classified as a primary or a secondary form. The secondary form in children usually affects severely immunodepressed children. To our knowledge, this is the first report of human demodicosis associated with Langerhans cell histiocytosis. These cases show that this skin disorder can occur months after completing chemotherapy, without recurrence of the systemic disease.
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Anti-Infecciosos/uso terapêutico , Antineoplásicos/efeitos adversos , Histiocitose de Células de Langerhans/complicações , Metronidazol/uso terapêutico , Infestações por Ácaros/diagnóstico , Animais , Antineoplásicos/uso terapêutico , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Lactente , Masculino , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/etiologia , ÁcarosRESUMO
Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB-PA is classified into Simplex form (EBS-PA: OMIM #612138) and Junctional form (JEB-PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB-PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non-lethal EB-PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of ß4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice-site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype-phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence-based therapeutic options for EB management.
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Displasia Ectodérmica/genética , Integrina beta4/genética , Deleção de Sequência , Biópsia , Pré-Escolar , Análise Mutacional de DNA , Displasia Ectodérmica/diagnóstico , Mapeamento de Epitopos , Epitopos/química , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Queratinócitos/citologia , Masculino , Repetições de Microssatélites/genética , Microscopia de Fluorescência , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Prognóstico , Análise de Sequência de DNA , Gêmeos DizigóticosRESUMO
We report the fifth case of epidermal choristoma of the oral cavity in a Caucasian newborn with a congenital melanotic macule on the dorsum of the tongue. Epidermal choristoma is an exceedingly rare and benign condition probably caused by a developmental abnormality. It is identified according to the presence of normal skin in an abnormal location. Histologically it is identified according to areas of stratified epithelium and hyperpigmentation of the basal layer along with cutaneous adnexal structures (hair follicles, sebaceous or sweat glands). The clinical presentation is variable, but most of the cases described presented with a congenital lingual pigmented macule. These lesions should be included within the differential diagnosis of congenital lingual macules and distinguished from other entities such as congenital lingual melanotic macules and melanocytic lesions. Surgical excision is the treatment of choice. Epidermal choristoma is a benign condition that probably is underdiagnosed because it is a new and rare entity, and dermatologists should be aware of it.
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Coristoma/diagnóstico , Glândulas Sebáceas , Doenças da Língua/diagnóstico , Biópsia , Diagnóstico Diferencial , Humanos , Recém-Nascido , Masculino , Melanose/diagnóstico , Doenças da Língua/patologiaRESUMO
BACKGROUND: Acquired hyperpigmented lesions in early childhood can be the presenting sign of serious diseases or benign conditions and often cause significant parental anxiety. OBJECTIVE: We sought to report a series of 25 young children with hyperpigmented macules on the forehead and temples without preceding erythema, edema, or desquamation. METHODS: We conducted a retrospective review of 25 children with similar clinical findings, seen from 2009 to 2013, from 5 medical centers in 3 countries. RESULTS: There were 13 boys and 12 girls of many races. Their ages ranged from 2 to 24 months (mean 12.2 months, median 6 months). The hyperpigmentation presented abruptly in the summer (12 cases), spring (5 cases), winter (5), and fall (2), and was not clearly specified in 1 case. Histopathologic analysis in 3 cases was consistent with postinflammatory hyperpigmentation. After a follow-up period ranging from 3 months to 4.5 years, the lesions persist to a variable degree in 19 cases in which follow-up was possible. LIMITATIONS: The age of our patients precluded patch testing and/or invasive diagnostic methods. CONCLUSIONS: The clinical features and prolonged clinical course over years do not correspond with any known or previously described cause of acquired facial hyperpigmented macules in young children.
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Dermatoses Faciais/diagnóstico , Hiperpigmentação/diagnóstico , Hiperpigmentação/epidemiologia , Fatores Etários , Biópsia por Agulha , Colúmbia Britânica , California , Pré-Escolar , Estudos de Coortes , Dermatoses Faciais/epidemiologia , Dermatoses Faciais/patologia , Feminino , Seguimentos , Humanos , Hiperpigmentação/patologia , Imuno-Histoquímica , Lactente , Masculino , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Espanha , Fatores de TempoRESUMO
Among nevus-associated melanomas, which overall account for 20%-30% of all melanomas, those arising specifically in congenital melanocytic nevi are infrequent, but can be disproportionately frequent in childhood and adolescence. Congenital melanocytic nevi (CMNi) are common benign melanocytic tumors that are present at birth or become apparent in early childhood. They are classified based on the projected adult size. Small and medium-sized CMNi are frequent, whereas large/giant CMNi (over 20â¯cm in diameter) are rare, but can be associated with high morbidity due to marked aesthetic impairment and the risk of neurocutaneous syndrome or melanoma development. In this setting, melanomas can appear in early childhood and are very aggressive, while the risk of small-medium CMNi of developing melanoma is low and similar to non-congenital melanocytic nevi. Histologically, most melanomas on CMNi initiate their growth at the epidermal-dermal junction, but in large/giant CMNi they can develop entirely in the dermis, in deeper tissues, or in extracutaneous sites (especially in the central nervous system). Most CMNi harbour an NRAS mutation, but other genes are rarely involved, and gene translocations have recently been described. However, no prognostic implications have been associated with the CMN genotype. Melanomas developed on CMNi harbour additional molecular alterations to which the aggressive clinical course of these tumors has been attributed. This review covers the distinctive clinical and pathological aspects of melanomas on CMNi, and includes the epidemiology, etiopathogenesis, clinical and dermoscopic presentation, histological and molecular characteristics, as well as tumour behaviour.
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Melanoma , Nevo de Células Epitelioides e Fusiformes , Nevo Pigmentado , Nitroimidazóis , Neoplasias Cutâneas , Adulto , Recém-Nascido , Adolescente , Humanos , Pré-Escolar , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Nevo Pigmentado/genéticaRESUMO
Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.
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Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Capilares/anormalidades , Mutação , Fenótipo , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/genética , Proteína p120 Ativadora de GTPase/genética , Substituição de Aminoácidos , Análise Mutacional de DNA , Feminino , Ordem dos Genes , Estudos de Associação Genética , Humanos , Masculino , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND: Activating RAS mutations in the germline cause rare developmental disorders such as Costello syndrome. Somatic RAS mutations are found in approximately 30% of human cancers. Keratinocytic epidermal nevi (KEN) represent benign congenital skin lesions arranged along Blaschko's lines. A subgroup of KEN is caused by hotspot oncogenic FGFR3 and PIK3CA mutations in mosaicism, but the majority lack these mutations. METHODS: This study screened 72 KEN for activating mutations in RAS genes and other oncogenes. RESULTS: Activating RAS mutations were identified in 28/72 (39%) of KEN. HRAS was the most commonly affected oncogene (86%), with the HRAS p.G13R substitution representing a new hotspot mutation. CONCLUSION: These results indicate that activating RAS somatic mutations leading to mosaicism result in benign KEN of the skin. Given the prevalence of KEN, mosaic HRAS mutations appear to be more common in patients than germline ones. These findings identify KEN as a mosaic RASopathy and lend further support to the notion that genetic mosaicism is an important contributor to disease.
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Epiderme/patologia , Genes ras , Queratinócitos/patologia , Mosaicismo , Mutação , Nevo/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fosfatidilinositol 3-Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Adulto JovemRESUMO
Bullous pemphigoid (BP) is an acquired autoimmune blistering disorder of unknown etiology uncommon in childhood. Unlike adult BP, infantile BP shows acral distribution and resolves rapidly with systemic steroids. We report three infants with infantile BP presenting shortly after vaccination for diphtheria, pertussis, tetanus, poliomyelitis, hepatitis B, Haemophilus influenzae B, and meningococcus C. Our cases further reinforce the causal association between childhood BP and vaccination.
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Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Vacinas contra Hepatite B/efeitos adversos , Penfigoide Bolhoso/etiologia , Penfigoide Bolhoso/patologia , Vacina Antipólio Oral/efeitos adversos , Feminino , Vacinas Anti-Haemophilus/efeitos adversos , Humanos , Lactente , Masculino , Vacinas Meningocócicas/efeitos adversosRESUMO
Epidermolysis bullosa simplex with mottled hyperpigmentation (EBS-MP) is an uncommon subtype of EBS. Its clinical features depend on the age of diagnosis, and clinical variations have been described even within family members. We present six cases from two unrelated Spanish families each with several affected members with EBS-MP and review the clinical and genetic findings in all reported patients. We highlight the changing clinical features of the disease throughout life.
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Epidermólise Bolhosa Simples/genética , Epidermólise Bolhosa Simples/patologia , Hiperpigmentação/genética , Hiperpigmentação/patologia , Queratina-5/genética , Adulto , Pré-Escolar , Saúde da Família , Feminino , Humanos , Lactente , Masculino , Linhagem , Pele/patologiaAssuntos
Alopecia/etiologia , Dermoscopia/métodos , Fluconazol/uso terapêutico , Cabelo/crescimento & desenvolvimento , Tinha do Couro Cabeludo/complicações , Alopecia/tratamento farmacológico , Alopecia/fisiopatologia , Feminino , Seguimentos , Cabelo/efeitos dos fármacos , Humanos , Lactente , Tinha do Couro Cabeludo/diagnóstico , Tinha do Couro Cabeludo/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Severe Combined Immunodeficiency (SCID) T-B-NK+ to Omenn syndrome (OS) through intermediate phenotypes, even for the same alteration. Nowadays, hematopoietic stem cell transplantation (HSCT) is the unique curative treatment available. METHODS: We describe three related patients from a Moroccan consanguineous family. Patient 1 developed at 1 month of age moderate eczematous dermatitis with eosinophilia, followed by infections and enteritis. He was transplanted and received reduced intensity conditioning regimen previous to HSCT. His brother, patient 2, was born preterm with a severe neonatal erythroderma, hepatosplenomegaly and lymphadenopathy. Patient 3, cousin of the two siblings, was also born preterm and fulfilled all criteria for classical OS. Immunological evaluation was performed and RAG genes were sequenced. RESULTS: Immunological data from all three patients were very diversed, from T lymphopenia to marked lymphocytosis, and different degrees of eosinophilia and IgE levels. Non-responder T cells and absent B cells were constant. All patients presented the same homozygous mutation in RAG1 gene (c.631delT). Patient 1 fully recovered both clinically and immunologically after HSCT. Two years later, he lost the accomplished lymphoid chimera and the disease relapsed as a classical OS, leading to patient's death. CONCLUSIONS: This is the first report of a RAG1 deficient patient with a changed clinical and immunological phenotype from SCID to OS after HSCT. The use of a myeloablative conditioning regimen that eliminates reminiscent T cells might have improved patient's outcome and it should be considered in similar cases.