Assuntos
Contratura , Doenças Musculares , Fibrose Pulmonar , Anormalidades da Pele , Biópsia , Proteínas de Ciclo Celular/genética , Contratura/genética , Fibrose , Humanos , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/genética , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/genética , Anormalidades da Pele/patologia , Tendões/patologiaRESUMO
Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in â¼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.
Assuntos
Acrocefalossindactilia/complicações , Proteínas Hedgehog/metabolismo , Mastocitose/complicações , Transdução de Sinais , Acrocefalossindactilia/metabolismo , Animais , Células Cultivadas , Criança , Humanos , Mastocitose/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , Células Tumorais CultivadasRESUMO
BACKGROUND: No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments. OBJECTIVES: To review the different treatments tried in patients with hPPK since 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treat hPPK. METHODS: We undertook a comprehensive review of the literature data published since 2008. RESULTS: Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance. New targeted treatments, according to the specific mechanisms of hPPK, appear promising for the future. CONCLUSIONS: More studies using robust methodology and involving larger cohorts of well-characterized patients (phenotype-genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN-Skin), with the aim of better management of patients with rare skin diseases.
Assuntos
Ceratodermia Palmar e Plantar , Qualidade de Vida , Humanos , Ceratodermia Palmar e Plantar/tratamento farmacológico , Ceratodermia Palmar e Plantar/genética , Ceratolíticos , Retinoides , PeleAssuntos
Linfangiectasia/epidemiologia , Vasos Linfáticos/anormalidades , Complicações Pós-Operatórias/epidemiologia , Malformações Vasculares/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Linfangiectasia/etiologia , Linfangiectasia/cirurgia , Vasos Linfáticos/cirurgia , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento , Malformações Vasculares/etiologia , Adulto JovemRESUMO
BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.
Assuntos
Granuloma/diagnóstico , Granuloma/patologia , Doenças da Imunodeficiência Primária/diagnóstico , Dermatopatias/diagnóstico , Dermatopatias/patologia , Anormalidades Múltiplas/diagnóstico , Ataxia Telangiectasia/etiologia , Criança , Pré-Escolar , Feminino , Granuloma/complicações , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Humanos , Hidrocolpos/complicações , Hidrocolpos/diagnóstico , Lactente , Masculino , Polidactilia/complicações , Polidactilia/diagnóstico , Doenças da Imunodeficiência Primária/complicações , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Dermatopatias/complicações , Úlcera Cutânea/etiologia , Doenças Uterinas/complicações , Doenças Uterinas/diagnósticoAssuntos
Hemangioma/complicações , Úlcera da Perna/etiologia , Propranolol/administração & dosagem , Adolescente , Bandagens , Biópsia , Feminino , Humanos , Úlcera da Perna/diagnóstico , Úlcera da Perna/patologia , Úlcera da Perna/terapia , Pele/irrigação sanguínea , Pele/patologia , Fatores de TempoRESUMO
BACKGROUND: Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes. OBJECTIVES: To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course. METHODS: This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and > 4 years of disease course were enrolled. The mean ± SD age at the final evaluation was 13·2 ± 4·8 years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics. RESULTS: Patients presented with maculopapular cutaneous mastocytosis (n = 44), diffuse cutaneous mastocytosis (n = 6) or mastocytoma (n = 3). The mean duration of disease was 12·1 years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2 years) is associated with worse evolution. CONCLUSIONS: PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.
Assuntos
Mastocitoma Cutâneo/genética , Proteínas Proto-Oncogênicas c-kit/genética , Urticaria Pigmentosa/genética , Adolescente , Idade de Início , Biópsia , Criança , Análise Mutacional de DNA , Progressão da Doença , Éxons/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Mastocitoma Cutâneo/diagnóstico , Mastocitoma Cutâneo/patologia , Mutação , Estudos Prospectivos , Índice de Gravidade de Doença , Pele/patologia , Urticaria Pigmentosa/diagnóstico , Urticaria Pigmentosa/patologiaRESUMO
BACKGROUND: Most cases of paediatric cutaneous mastocytosis (CM) occur before the age of 2 years, and regression occurs in only 67% of children. Given the absence of any specific therapy, CM is usually treated symptomatically. A few publications have reported the beneficial effect of calcineurin inhibitors for CM. AIM: We sought to evaluate the clinical effectiveness and safety profile of topical pimecrolimus cream for the treatment of CM. METHODS: We performed a retrospective study of all diagnosed cases of CM treated with topical pimecrolimus 1% cream between 2013 and 2015. All patients were evaluated in a paediatric dermatology unit of a tertiary medical centre. Epidemiological, clinical and treatment data, including effectiveness and safety, were reviewed. RESULTS: In total, 18 children (11 male, 7 female; age range 3-42 months) with CM were evaluated. Of the 146 treated lesions, 39 (26.7%) disappeared and 98 (67%) faded or developed postinflammatory hyperpigmentation. Of the 119 papular lesions, 24 (16.4%) showed partial flattening and 56 (47%) became macular. Darier sign became negative in 14 (82%) of 17 patients. No topical or systemic complications were observed. CONCLUSIONS: Topical therapy with pimecrolimus 1% cream should be considered in the treatment of CM.
Assuntos
Inibidores de Calcineurina/uso terapêutico , Mastocitose Cutânea/tratamento farmacológico , Tacrolimo/análogos & derivados , Administração Cutânea , Inibidores de Calcineurina/administração & dosagem , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Resultado do TratamentoAssuntos
Transtornos da Coagulação Sanguínea/tratamento farmacológico , Fármacos Hematológicos/administração & dosagem , Síndrome de Kasabach-Merritt/tratamento farmacológico , Sirolimo/administração & dosagem , Administração Oral , Estudos de Casos e Controles , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Contagem de Plaquetas , Resultado do TratamentoRESUMO
Hereditary epidermolysis bullosa (EB) is a heterogeneous group of rare genetic diseases characterized by fragile skin and/or mucous membrane, and it may be either local or generalized. It is caused by mutations in genes encoding different proteins involved mainly in the structure and function of the dermal-epidermal junction. Nineteen genes have so far been identified. They are classified by level of skin cleavage (from top to bottom) into four groups: EB simplex, junctional EB, dystrophic EB and Kindler syndrome. Clinically suspected diagnosis is confirmed by immunohistochemical examination of a skin biopsy at specialized centres in order to determine the level of cleavage and the deficient protein. This first step may be followed by genetic analysis. The severity of the disease is highly variable, ranging from localized forms with little effect on quality of life to rapidly lethal forms. In generalized severe forms, the extent and chronicity of lesions, as well as mucosal involvement, can lead to systemic complications: malnutrition, pain, joint contractures, chronic inflammation, amyloidosis, cutaneous squamous cell carcinoma. Some specific forms are associated with other cutaneous signs (nail involvement, alopecia, hyperpigmentation, palmoplantar keratoderma) or extracutaneous involvement (muscular dystrophy or pyloric atresia). No curative treatment of EB is available today. EB requires multidisciplinary medical care, nursing, psychological and social management. This is best provided by a specialized network, involving reference centres, centres of expertise and daily caregivers. The goal of treatment is the prevention and treatment of lesions with specific non-adherent dressings and the prevention, detection and treatment of complications. It is essential not to traumatize the skin (bandaging, friction, etc.). Protein, gene or cell replacement therapy, and allogeneic bone marrow, cord blood or pluripotent stem-cell transplantation are currently being assessed. The aim of these French recommendations (national diagnostic and treatment protocol [PNDS]) is to provide healthcare professionals with guidance on the course of EB and on optimal patient management.
Assuntos
Epidermólise Bolhosa/patologia , Epidermólise Bolhosa/terapia , Pele/patologia , Diagnóstico Diferencial , Epidermólise Bolhosa/classificação , Epidermólise Bolhosa/diagnóstico , França , Humanos , Guias de Prática Clínica como Assunto , Índice de Gravidade de DoençaAssuntos
Hemangioendotelioma , Síndrome de Kasabach-Merritt , Humanos , Linfedema , Sarcoma de KaposiRESUMO
BACKGROUND: Identification of patient at risk of subglottic infantile hemangioma (IH) is challenging because subglottic IH can grow fast and cause airway obstruction with a fatal course. OBJECTIVE: To refine the cutaneous IH pattern at risk of subglottic IH. METHODS: Prospective and retrospective review of patients with cutaneous IH involving the beard area. IHs were classified in the bilateral pattern group (BH) or in the unilateral pattern group (UH). Infantile hemangioma topography, subtype (telangiectatic or tuberous), ear, nose and throat (ENT) manifestations and subglottic involvement were recorded. RESULTS: Thirty-one patients (21 BH and 10 UH) were included during a 20-year span. Nineteen patients (16 BH and 3 UH) had subglottic hemangioma. BH and UH group overlap on the median pattern (tongue, gum, lips, chin and neck). Median pattern, particularly the neck area and telangiectatic subtype of IH were significantly associated with subglottic involvement. CONCLUSION: Patients presenting with telangiectatic beard IH localized on the median area need early ENT exploration. They should be treated before respiratory symptoms occur.
Assuntos
Glote/patologia , Hemangioma/patologia , Telangiectasia/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi-Goutières syndrome. To date, seven genes related to Aicardi-Goutières syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Goutières syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi-Goutières syndrome and Singleton-Merten syndrome.
Assuntos
Doenças da Aorta/genética , Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Hipoplasia do Esmalte Dentário/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Mutação/genética , Malformações do Sistema Nervoso/genética , Odontodisplasia/genética , Osteoporose/genética , Dermatopatias Genéticas/genética , Calcificação Vascular/genética , Adulto , Doenças da Aorta/patologia , Doenças Autoimunes do Sistema Nervoso/patologia , Pérnio/genética , Pré-Escolar , Hipoplasia do Esmalte Dentário/patologia , Heterozigoto , Humanos , Lactente , Helicase IFIH1 Induzida por Interferon , Lúpus Eritematoso Cutâneo/genética , Masculino , Metacarpo/patologia , Doenças Musculares/patologia , Doenças do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Odontodisplasia/patologia , Osteoporose/patologia , Fenótipo , Dermatopatias Genéticas/patologia , Perda de Dente/genética , Calcificação Vascular/patologiaAssuntos
Condrodisplasia Punctata/patologia , Doença de Darier/patologia , Calcinose/genética , Calcinose/patologia , Criança , Pré-Escolar , Condrodisplasia Punctata/genética , Doença de Darier/genética , Éxons/genética , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Testes Genéticos , Humanos , Recém-Nascido , Mutação/genética , Estudos Prospectivos , Estudos Retrospectivos , Esteroide Isomerases/genética , Adulto JovemRESUMO
Paediatric mastocytosis was previously considered to be a benign and spontaneously regressing disease. However, this evolution is impossible to predict. To clarify the characteristics and course of paediatric mastocytosis, we performed a literature review of 1747 cases published between 1950 and April 2014. Lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75% of cases), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1·4. KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2·9% of patients.
Assuntos
Mastocitose Cutânea/patologia , Idade de Início , Biópsia/métodos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mastocitose Cutânea/genética , Mutação/genética , Gravidez , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Urticaria Pigmentosa/etiologiaRESUMO
BACKGROUND: Lymphomatoid papulosis (LyP) is an uncommon cutaneous T-cell lymphoproliferative disorder (CTLPD) rarely encountered in children. OBJECTIVES: To specify characteristics of paediatric LyP and to describe both diagnostic difficulties and the course of the disease with the experience of 10 years' follow-up. METHODS: This was a retrospective, single-centre study of 25 children diagnosed with LyP according to the 2008 World Health Organization guidelines, and a clinical and pathological correlation by two experts. RESULTS: The mean age at onset was 7·5 years. The lesions were mostly papulonodular with frequent pruritus (40%). Mucosal involvement was sometimes observed. A single ulcerative nodule was initially suggestive of a primary cutaneous anaplastic large-cell lymphoma (C-ALCL). Pityriasis lichenoides was associated in 36% of cases, atopic dermatitis in 28% and nonspecific infections in 28%. Complete remission was observed in 44% of cases. Through the mean follow-up of 10 years, none of our patients have experienced lymphoma occurrence. Histopathological subtype A clearly predominated (82%). A marked eosinophilic infiltrate was present in 44% of cases and a cutaneous T-gamma clone in 40%. No correlation was observed between histopathological subtype, cutaneous clone or LyP clinical course. CONCLUSIONS: Paediatric LyP belongs to the group of CD30-positive CTLPDs including C-ALCL. Children have to be carefully followed up lifelong, even if the prognosis appears good. The high frequencies of an associated viral infection, atopic dermatitis, marked eosinophilic infiltrate and a good outcome suggest that paediatric LyP could be considered a reactional disease rather than a malignant disorder.