RESUMEN
Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.
Asunto(s)
Osteogénesis/genética , Factor de Transcripción STAT3/metabolismo , Animales , Desarrollo Óseo/genética , Remodelación Ósea/genética , Diferenciación Celular/efectos de los fármacos , Proteínas de Homeodominio/genética , Homeostasis/efectos de los fármacos , Homeostasis/genética , Factor de Transcripción MSX1/genética , Factor de Transcripción MSX1/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Anomalías Musculoesqueléticas/tratamiento farmacológico , Anomalías Musculoesqueléticas/genética , Anomalías Musculoesqueléticas/metabolismo , Osteoblastos/citología , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Transducción de Señal , Transcripción GenéticaRESUMEN
CLOVES syndrome is a rare, nonheritable sporadic overgrowth disorder. In the world 130-200 cases have been reported. This is the first case of CLOVES described in Portugal, which had been not been diagnosed for the last 36 years. With this paper, the authors look to highlight the clinical features of this syndrome so that it does not go unrecognized in daily practice. The authors also underline the efficacy and safety of sirolimus, and that this treatment should not be denied, even in adult patients.
Asunto(s)
Lipoma/diagnóstico , Lipoma/tratamiento farmacológico , Inhibidores mTOR/uso terapéutico , Anomalías Musculoesqueléticas/diagnóstico , Anomalías Musculoesqueléticas/tratamiento farmacológico , Nevo/diagnóstico , Nevo/tratamiento farmacológico , Sirolimus/uso terapéutico , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/tratamiento farmacológico , Adulto , Femenino , Humanos , Resultado del TratamientoRESUMEN
PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Descubrimiento de Drogas , Factores de Transcripción del Choque Térmico/antagonistas & inhibidores , Lipoma/metabolismo , Anomalías Musculoesqueléticas/metabolismo , Nevo/metabolismo , Malformaciones Vasculares/metabolismo , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Factores de Transcripción del Choque Térmico/metabolismo , Humanos , Lipoma/tratamiento farmacológico , Lipoma/genética , Lipoma/patología , Terapia Molecular Dirigida , Anomalías Musculoesqueléticas/tratamiento farmacológico , Anomalías Musculoesqueléticas/genética , Anomalías Musculoesqueléticas/patología , Mutación , Nevo/tratamiento farmacológico , Nevo/genética , Nevo/patología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/genética , Malformaciones Vasculares/patologíaRESUMEN
INTRODUCCIÓN: El síndrome de CLOVES se caracteriza por sobrecrecimiento lipomatoso asociado a malformaciones vasculares, representando un desafío diagnóstico y terapéutico. La rapamicina, un inhibidor de la vía mTOR, ha demostrado ser una buena alternativa terapéutica en un grupo de anomalías vasculares. Reportamos dos casos de síndrome de CLOVES con buena respuesta al tratamiento con rapamicina oral. OBJETIVO: Reportar la experiencia del uso de rapamicina oral en el tratamiento de dos pacientes con síndrome de CLOVES. CASOS CLÍNICOS: Caso 1: preescolar femenino de tres años de edad con sín drome de CLOVES e historia de hospitalizaciones reiteradas por infección severa de malformaciones linfáticas macroquísticas y episodios trombóticos. Evoluciona con mala calidad de vida, múltiples hospitalizaciones, riesgo quirúrgico y progresión de las lesiones, por lo que se indicó rapamicina oral. A los 6 meses de tratamiento se evidenció reducción clínica y radiológica del tamaño de las masas lipomatosas y linfáticas, ausencia de linforrea cutánea y mejoría significativa de la calidad de vida, sin requerir nuevas hospitalizaciones. Caso 2: escolar femenino de diez años de edad, portadora de síndrome de CLOVES, que desarrolló escoliosis y deterioro de su capacidad motora, haciéndose dependiente del uso de silla de ruedas. Se indicó rapamicina oral, evidenciándose a los cuatro meses de tratamiento mejoría en su capacidad física, independencia y autovalencia, con desaparición de la linforrea. CONCLUSIÓN: Proponemos la rapamicina oral para el tratamiento de pacientes con sín drome de CLOVES que presenten complicaciones y deterioro de la calidad de vida producto de su enfermedad.
INTRODUCTION: CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.
Asunto(s)
Humanos , Femenino , Preescolar , Niño , Sirolimus/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Lipoma/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Anomalías Musculoesqueléticas/tratamiento farmacológico , Nevo/tratamiento farmacológico , Administración Oral , Sirolimus/administración & dosificación , Antibióticos Antineoplásicos/administración & dosificaciónRESUMEN
PURPOSE OF REVIEW: To provide an update of vascular malformation syndromes by reviewing the most recent articles on the topic and following the new International Society for the Study of Vascular Anomalies (ISSVA) 2018 classification. RECENT FINDINGS: This review discusses the main features and diagnostic approaches of the vascular malformation syndromes, the new genetic findings and the new therapeutic strategies developed in recent months. SUMMARY: Some vascular malformations can be associated with other anomalies, such as tissue overgrowth. PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth. CLOVES syndrome and Klippel-Trénaunay syndrome are PROS disease. Proteus syndrome is an overgrowth syndrome caused by a somatic activating mutation in AKT1. CLOVES, Klippel-Trénaunay and Proteus syndromes are associated with high risk of thrombosis and pulmonary embolism. Hereditary hemorrhagic telangiectasia is an autosomic dominant disorder characterized by the presence of arteriovenous malformations. New therapeutic strategies with bevacizumab and thalidomide have been employed with promising results.
Asunto(s)
Bevacizumab/uso terapéutico , Trastornos del Crecimiento/genética , Anomalías Musculoesqueléticas/diagnóstico , Anomalías Musculoesqueléticas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/genética , Talidomida/uso terapéutico , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/tratamiento farmacológico , Anomalías Múltiples , Fosfatidilinositol 3-Quinasa Clase I , Trastornos del Crecimiento/complicaciones , Humanos , Anomalías Musculoesqueléticas/genética , Mutación , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Síndrome , Serina-Treonina Quinasas TOR , Malformaciones Vasculares/genéticaRESUMEN
BACKGROUND: Most patients with phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA)-related overgrowth spectrum become symptomatic early in life and need treatment before puberty. Recently, the specific inhibition of PIK3CA pathways has been proposed as a therapeutic option for these patients improving their surgical options and quality of life. Alpelisib, a specific alpha fraction inhibitor, has shown promising results. CASE: A 17-year-old girl presented with severe involvement of her external genitalia with a combined vascular malformation in the context of congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi and spinal/skeletal anomalies and/or scoliosis syndrome, needing frequent blood transfusions for anemia due to vaginal bleeding and use of a crutch for walking. After failure of treatment with rapamycin, compassionate treatment with alpelisib was started with excellent response. SUMMARY AND CONCLUSION: PIK3CA inhibitors might become a new option of treatment for PIK3CA-related overgrowth spectrum patients.
Asunto(s)
Genitales Femeninos/irrigación sanguínea , Lipoma/tratamiento farmacológico , Anomalías Musculoesqueléticas/tratamiento farmacológico , Nevo/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tiazoles/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Adolescente , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Femenino , HumanosRESUMEN
INTRODUCTION: CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Lipoma/tratamiento farmacológico , Anomalías Musculoesqueléticas/tratamiento farmacológico , Nevo/tratamiento farmacológico , Sirolimus/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Administración Oral , Antibióticos Antineoplásicos/administración & dosificación , Niño , Preescolar , Femenino , Humanos , Sirolimus/administración & dosificaciónRESUMEN
CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Lipoma/tratamiento farmacológico , Lipoma/enzimología , Terapia Molecular Dirigida , Anomalías Musculoesqueléticas/tratamiento farmacológico , Anomalías Musculoesqueléticas/enzimología , Nevo/tratamiento farmacológico , Nevo/enzimología , Tiazoles/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/enzimología , Adulto , Animales , Niño , Modelos Animales de Enfermedad , Femenino , Células HeLa , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Ratones , Fenotipo , Escoliosis/complicaciones , Escoliosis/tratamiento farmacológico , Sirolimus/uso terapéutico , Síndrome , Neoplasias Vasculares/complicaciones , Neoplasias Vasculares/tratamiento farmacológicoAsunto(s)
Distinciones y Premios , Toxinas Botulínicas/administración & dosificación , Parálisis Cerebral/terapia , Anomalías Musculoesqueléticas/terapia , Ortopedia/historia , Transferencia Tendinosa , Extremidad Superior/cirugía , Parálisis Cerebral/complicaciones , Parálisis Cerebral/tratamiento farmacológico , Parálisis Cerebral/cirugía , Historia del Siglo XXI , Inyecciones , Anomalías Musculoesqueléticas/tratamiento farmacológico , Anomalías Musculoesqueléticas/etiología , Anomalías Musculoesqueléticas/cirugía , Estudios Prospectivos , Estados UnidosRESUMEN
Symptomatic accessory soleus muscle (ASM) can cause exercise-induced leg pain due to local nerve/vascular compression, muscle spasm, or local compartment syndrome. As intramuscular injections of botulinum toxin type A (BTX-A) can reduce muscle tone and mass, we investigated whether local BTX-A injections relieve the pain associated with symptomatic ASM. We describe five patients presenting peri/retromalleolar exertional pain and a contractile muscle mass in the painful region. Com-pression neuropathy was ruled out by electromyo-graphic analysis of the lower limb muscles. Doppler ultrasonography was normal, excluding a local vascular compression. ASM was confirmed by magnetic resonance imaging. After a treadmill stress test, abnormal intramuscular pressure values in the ASM, confirmed the diagnosis of compartment syndrome only in one patient. All five patients received BTX-A injections in two points of the ASM. The treatment efficacy was evaluated based on the disappearance of exercise-induced pain and the resumption of normal physical and sports activities. After BTX-A injection, exertional pain disappeared and all five patients resumed their normal level of physical and sports performances. Neither side effects nor motor deficits were observed. BTX-A is well tolerated in patients with ASM and could be used as a new conservative therapeutic strategy for the treatment of symptomatic ASM before surgery.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Músculo Esquelético/anomalías , Anomalías Musculoesqueléticas/tratamiento farmacológico , Fármacos Neuromusculares/uso terapéutico , Dolor/tratamiento farmacológico , Adolescente , Adulto , Femenino , Humanos , Inyecciones Intramusculares , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/diagnóstico por imagen , Anomalías Musculoesqueléticas/complicaciones , Anomalías Musculoesqueléticas/diagnóstico por imagen , Dolor/etiología , Dimensión del Dolor , Resultado del Tratamiento , Adulto JovenRESUMEN
Vitamin D deficiency is a global public health problem and has been associated with an increased incidence and severity of many diseases including diseases of the respiratory system. These associations have largely been demonstrated epidemiologically and have formed the basis of the justification for a large number of clinical supplementation trials with a view to improving disease outcomes. However, the trials that have been completed to date and the ongoing experimental studies that have attempted to demonstrate a mechanistic link between vitamin D deficiency and lung disease have been disappointing. This observation raises many questions regarding whether vitamin D deficiency is truly associated with disease pathogenesis, is only important in the exacerbation of disease or is simply an indirect biomarker of other disease mechanisms? In this review, we will briefly summarize our current understanding of the role of vitamin D in these processes with a focus on lung disease.