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1.
Pediatrics ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511312

RESUMO

Hepatic hemangioma (HH) is a common asymptomatic, self-limiting benign vascular tumor of the liver in neonates. Although complicated HHs are rare, they have significant risks of morbidity and mortality, especially during the perinatal period. Because of the high risks of complications from surgical interventions, there is an unmet need for effective medical therapy. We report 2 neonates with life-threatening HH who were evaluated for a liver transplant before being treated successfully with combined medical therapy, which included sirolimus, corticosteroids, and propranolol.

2.
J Clin Invest ; 130: 3545-3561, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185000

RESUMO

Combined germline and somatic second hit inactivating mutations of the RASA1 gene, which encodes a negative regulator of the Ras signaling pathway, cause blood and lymphatic vascular lesions in the human autosomal dominant vascular disorder capillary malformation-arteriovenous malformation (CM-AVM). How RASA1 mutations in endothelial cells (EC) result in vascular lesions in CM-AVM is unknown. Here, using different murine models of RASA1-deficiency, we found that RASA1 was essential for the survival of EC during developmental angiogenesis in which primitive vascular plexuses are remodeled into hierarchical vascular networks. RASA1 was required for EC survival during developmental angiogenesis because it was necessary for export of collagen IV from EC and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras mitogen-activated protein kinase (MAPK) signal transduction in EC resulted in impaired folding of collagen IV and its retention in the endoplasmic reticulum (ER) leading to EC death. Remarkably, the chemical chaperone, 4-phenylbutyric acid, and small molecule inhibitors of MAPK and 2-oxoglutarate dependent collagen IV modifying enzymes rescued ER retention of collagen IV and EC apoptosis and resulted in normal developmental angiogenesis. These findings have important implications with regards an understanding of the molecular pathogenesis of CM-AVM and possible means of treatment.

3.
Curr Opin Pediatr ; 31(4): 498-508, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31246627

RESUMO

PURPOSE OF REVIEW: Vascular malformations (VaMs) are a consequence of disrupted morphogenesis that may involve arterial, capillary, venous, or lymphatic endothelium alone or in a combination. VaMs can have serious health impacts, leading to life-threatening conditions sometimes. Genetic mutations affecting proliferation, migration, adhesion, differentiation, and survival of endothelial cells, as well as integrity of extracellular matrix are believed to be the pathogenesis of these disorders. Here, we present an updated review of genetic mutations and potential therapeutic targets for VaMs. RECENT FINDINGS: Increased number of genetic mutations have been discovered in vascular anomalies via targeted deep sequencing. When a genetic defect is identified, it often presents in only a small percentage of cells within the malformation. In addition, mutations within the same gene may result in different clinical phenotypes. Management of VaMs can be challenging depending on the severity and functional impairment associated. There are no standard treatment algorithms available to date for VaMs, therefore the disorder has significant unmet clinical needs. Currently, the focus of therapeutic development is to target constitutively activated intracellular signaling pathways resulted from genetic mutations. SUMMARY: Knowledge about the genetic mutations and altered signaling pathways related to VaMs have improved our understanding about the pathogenesis of vascular anomalies and provided insights to the development of new targeted therapies.

4.
Dermatol Ther ; 32(3): e12919, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977938

RESUMO

Maffucci syndrome is a rare genetic disease due to somatic mutation of IDH1 gene. Currently there is no medical treatment available for spindle cell hemangioma associated with this disorder. Here we report successful management of these hemangiomas using sirolimus in combination with surgery.

5.
Am J Med Genet A ; 179(6): 966-977, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30920161

RESUMO

Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p = .0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

8.
JAMA Dermatol ; 154(11): 1316-1319, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30326494

RESUMO

Importance: Current therapeutic options for patients with extracranial head and neck arteriovenous malformations are limited. Surgical intervention, such as sclerotherapy or resection, often result in rapid recurrence and progression of disease. Objective: To assess the efficacy and tolerability of sirolimus as an adjuvant therapy for endovascular embolization in the management of complicated extracranial head and neck arteriovenous malformations. Design, Setting, and Participants: This case series examined 6 patients with extracranial head and neck arteriovenous malformations treated from January 1, 2013, to December 31, 2017, at a multidisciplinary vascular anomalies clinic within Stanford Hospital and Clinics. Intervention: Initiation of sirolimus at least 1 month prior to endovascular embolization, targeting a trough level of 10 to 15 ng/mL throughout the course of the endovascular embolization series and continued for at least 1 month after the series. Main Outcomes and Measures: Clinical manifestations; disease progression and overall response to treatment were assessed via clinical evaluation and radiographic imaging. Results: All 6 patients (4 male and 2 female patients; mean age, 24.5 years [range, 9-44 years]) responded favorably to the combination of sirolimus therapy followed by endovascular embolization, and 4 patients exhibited a near-complete response. The median duration of follow-up was 19 months (range, 6-40 months). One patient discontinued sirolimus soon after embolization and experienced regrowth of the arteriovenous malformation after 1 year. Sirolimus was resumed, which has stabilized his disease for more than 2 years. Mild adverse effects were noted in 4 patients. The combination therapy was well tolerated in all patients. One patient developed skin ulceration after embolization and required surgical debridement. Another patient developed pulmonary microthrombi after embolization with cyanoacrylate glue that resolved with a brief course of anti-inflammatory therapy. Conclusions and Relevance: Although further prospective trials are needed, this report suggests the benefit of a mammalian target of rapamycin inhibitor as an adjuvant therapy for surgical embolization of complex, extracranial head and neck arteriovenous malformations. The optimal dosing and therapeutic duration of sirolimus treatment before and after embolization remain to be determined.

10.
Pediatr Dermatol ; 35(4): e224-e227, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29786144

RESUMO

Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections. Cannabidiol, an active cannabinoid found in cannabis, is postulated to have antiinflammatory and analgesic effects. We report 3 cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study. One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use. Although these results demonstrate promise, further randomized, double-blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.


Assuntos
Canabidiol/administração & dosagem , Epidermólise Bolhosa/tratamento farmacológico , Administração Tópica , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Dor/tratamento farmacológico , Pele/patologia , Cicatrização/efeitos dos fármacos
11.
Curr Opin Pediatr ; 30(4): 505-513, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29771760

RESUMO

PURPOSE OF REVIEW: Childhood malnutrition is a major global health issue. It is often thought of as a developing world problem and therefore, underdiagnosed or misdiagnosed in developed countries. The delay in diagnosis and treatment can lead to increased morbidity and mortality. Cutaneous manifestations are often the initial presenting signs of nutritional deficiency. Early recognition is essential in timely initiation of the necessary interventions. This article will review pertinent cutaneous findings and systemic manifestations associated with common nutritional deficiencies. RECENT FINDINGS: Malnutrition has historically been associated with poverty in developing countries. However, recent literatures suggest that the incidence of nutritional deficiencies continuous to rise among infants from developed countries, as a result of dietary restrictions because of perceived food allergies or intolerance. It is also an emerging finding in children with complicated medical problems. SUMMARY: It is very important to raise awareness about cutaneous manifestations of nutritional deficiency as early and appropriate treatment results in excellent prognosis.

12.
Curr Opin Pediatr ; 30(4): 490-491, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29771762
13.
Pediatr Dermatol ; 34(5): 559-565, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28884903

RESUMO

BACKGROUND/OBJECTIVES: Lymphatic malformations (LMs) are challenging to treat. Reports on the benefits of sildenafil for LM management have been mixed. This study evaluated long-term clinical outcomes of pediatric LM patients after sildenafil treatment. METHODS: A retrospective chart review was performed on pediatric LM patients treated with sildenafil in the past 5 years. Patients were also contacted to complete a survey of comprehensive questions about their LM after sildenafil and subsequent interventions. RESULTS: Of 12 patients identified, 10 (83.3%) participated in the follow-up survey. The average age was 8 years (range 4-16 yrs), median treatment duration was 9 months, and the average time of follow-up after sildenafil was 4 years; one patient is still taking sildenafil. Ten patients surveyed (83.3%) reported positive therapeutic response, with improvement in the size and compressibility of their LM during posttreatment clinical visits. Six received additional interventions (four sirolimus, one sclerotherapy, one surgery) after sildenafil was discontinued, with all but one reporting a positive response to subsequent interventions. Minor side effects at the time of sildenafil treatment included mild flushing, dizziness, and transient nausea, but no adverse effects were reported at the long-term follow-up. CONCLUSION: This is the first report of long-term follow-up of pediatric LM patients treated with sildenafil. Our findings suggest that sildenafil is beneficial for the symptomatic treatment of LMs. Additional analysis on the role of sildenafil as adjuvant therapy is necessary to optimize the use of this medication in the management of complex LMs.


Assuntos
Anormalidades Linfáticas/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pesquisa Qualitativa , Estudos Retrospectivos , Citrato de Sildenafila/efeitos adversos , Resultado do Tratamento , Vasodilatadores/efeitos adversos
14.
Curr Opin Pediatr ; 29(4): 426-433, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28525403

RESUMO

PURPOSE OF REVIEW: Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals. RECENT FINDINGS: In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7). SUMMARY: Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.


Assuntos
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Síndromes Neoplásicas Hereditárias/genética , Dermatopatias Genéticas/genética , Neoplasias Cutâneas/genética , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Criança , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Melanoma , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Fatores de Risco , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia
15.
Pediatr Dermatol ; 34(4): 402-407, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28543716

RESUMO

BACKGROUND/OBJECTIVES: There is a lack of primary care provider (PCP) understanding of atopic dermatitis (AD) treatments and topical steroid use. We designed an AD management algorithm for pediatric PCPs. We hypothesized that the algorithm would improve pediatric PCPs' knowledge of AD diagnosis and management. METHODS: Pediatric primary care resident and attending physicians at three residency programs were invited to participate in an electronic AD algorithm survey that contained demographic and 19 knowledge-based questions. Participants were randomized to intervention and control groups, with the intervention group receiving a short lecture and copy of our algorithm to use in an inpatient or outpatient setting for 2 months. Changes in scores between preintervention and postintervention surveys were compared. RESULTS: Of the 54 participants, those in the intervention group (n = 26) performed significantly better than those in the control group (n = 28) after controlling for pretest scores (ß = 1.19 [95% confidence interval 0.07, 2.32], p = 0.04). The intervention group had a higher average score on the posttest knowledge questions (71% correct) than the control group (65% correct) (p = 0.06). The majority of physicians who received the algorithm agreed or strongly agreed that they liked using the algorithm. CONCLUSION: The use of a management algorithm improved physician knowledge about the diagnosis and treatment of AD and was well accepted by physicians. Use of this management algorithm may lead to better recognition and management of AD, particularly earlier recognition of and therapy for superinfection, improving treatment outcomes and quality of life for patients and families.


Assuntos
Competência Clínica/estatística & dados numéricos , Dermatite Atópica/tratamento farmacológico , Educação Médica/métodos , Médicos de Atenção Primária/educação , Algoritmos , Humanos , Internato e Residência , Projetos Piloto , Inquéritos e Questionários
16.
Dermatol Ther ; 30(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28133868

RESUMO

The management of trichoepitheliomas is challenging, especially in children. This challenge is exemplified in patients with multiple trichoepitheliomas who present with progression of lesion count and size despite treatment with current strategies, including CO2 laser and surgery. We present the novel use of topical 1% sirolimus cream in two siblings with multiple facial trichoepitheliomas; one was treated with a combination of CO2 laser ablation and topical sirolimus, and the other was treated with topical sirolimus alone. Both siblings had a reduction in the growth of new lesions with no reported side effects. This is the first report demonstrating that topical sirolimus, either in combination with CO2 laser or alone, can be a promising treatment for trichoepitheliomas.


Assuntos
Antineoplásicos/administração & dosagem , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Sirolimo/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Administração Tópica , Biópsia , Criança , Terapia Combinada , Feminino , Humanos , Terapia a Laser/instrumentação , Lasers de Gás/uso terapêutico , Masculino , Síndromes Neoplásicas Hereditárias/diagnóstico , Neoplasias Cutâneas/diagnóstico , Resultado do Tratamento
17.
J Neurointerv Surg ; 9(10): 1023-1026, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27707871

RESUMO

BACKGROUND: Sclerotherapy is one of the most commonly used minimally invasive interventions in the treatment of macrocystic lymphatic malformations (LMs). Several different sclerosing agents and injection protocols have been reported in the literature, each with varying degrees of success. The safety and efficacy of the treatments have not been evaluated comparatively in the pediatric population. METHODS: Chart review of pediatric patients with macrocystic/mixed head and neck LMs who underwent sclerotherapy using OK-432, doxycycline, or ethanolamine oleate at Lucile Packard Children's Hospital at Stanford during 2000-2014. Clinical evaluation and radiographic imaging were reviewed to assess lesion characteristics and response to sclerotherapy following each treatment session. The post-intervention clinical response was categorized as excellent, good, fair, or poor. RESULTS: Among the 41 pediatric cases reviewed, 10 patients were treated with OK-432, 19 patients received doxycycline, and 12 patients received ethanolamine. In univariate analysis, different sclerosants had similar effectiveness after the first injection and final clinical outcome (p=0.5317). In multivariate analysis controlling for disease severity stage as well as disease characteristics (macrocystic vs mixed subtypes), different sclerosants also had similar effectiveness after the first injection (p=0.1192). Radiologic analysis indicated an 84.5% average volume reduction, with similar effectiveness between the different sclerosants (p=0.9910). CONCLUSIONS: In this series of LM cases treated at Stanford, we found that doxycycline, OK-432, and ethanolamine oleate sclerotherapy appear to have a similar safety and efficacy profile in the treatment of macrocystic and mixed LMs of the head and neck in the pediatric population.


Assuntos
Cabeça/diagnóstico por imagem , Anormalidades Linfáticas/diagnóstico por imagem , Anormalidades Linfáticas/terapia , Pescoço/diagnóstico por imagem , Soluções Esclerosantes/uso terapêutico , Escleroterapia/métodos , Adolescente , Criança , Pré-Escolar , Doxiciclina/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Ácidos Oleicos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
18.
JAMA Dermatol ; 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27902821

RESUMO

Importance: Patients with basal cell nevus syndrome (BCNS) have a greater risk of developing numerous basal cell carcinomas (BCCs). Risk factors influencing the wide variation in tumor burden are poorly understood. Objective: To describe the burden of BCCs in patients with BCNS in the United States and identify potential risk factors for BCCs. Design, Setting, and Participants: Prospective clinical registry with data collected from September 2014 to March 2016. Participants were recruited from a mailing list of patients with BCNS at Children's Hospital Oakland Research Institute and Basal Cell Carcinoma Nevus Syndrome Life Support Network. Patients of all ages with a diagnosis of BCNS were eligible for enrollment. Participants completed a clinical questionnaire on their disease characteristics and risk factors. Main Outcomes and Measures: Number of BCCs in the past 2 years and over lifetime (disease burden), risk factors for BCCs. Results: A consecutive sample of the first 141 participants was included (34% [100 of 297] response rate from paper survey, 23% [41 of 179] from online survey; 85 [60%] female; mean age at start of study, 53 [range, 8-83] years; 131 [93%] white). In the previous 2 years, participants reported a mean of 25 BCCs (median, 11; range, 0-250). Over their lifetime, participants reported a mean of 257 BCCs (median, 160; range, 0-2200). Univariate analysis identified age (odds ratio [OR], 1.05; 95% CI, 1.03-1.07; P < .001), number of sunburns (OR, 1.05; 95% CI, 1.00-1.10; P = .047), and history of radiation exposure (OR, 2.26; 95% CI, 1.02-5.03; P = .046) as potential risk factors for lifetime BCC severity. On multivariate analysis, only age (OR, 1.04; 95% CI, 1.02-1.07; P < .001) and number of sunburns (OR, 1.06; 95% CI, 1.00-1.11; P = .04) were statistically significant. In our adjusted models, BCC burden increased by 4% per year of age and by 6% per number of sunburns. Conclusions and Relevance: Patients with BCNS have a high burden of BCCs. Age and number of sunburns were significantly associated with the severity of lifetime BCC. Further interventions to prevent and treat BCCs in patients with BCNS are needed.

20.
Curr Opin Pediatr ; 28(4): 507-16, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27386970

RESUMO

PURPOSE OF REVIEW: Epidermolysis bullosa is a hereditary skin disorder characterized by skin fragility. However, the disease can manifest in many different organ systems, therefore children born with epidermolysis bullosa may have life long, complex medical needs. In this review, we will use a system-based approach to highlight important aspects of disease management and recent advancements in each of the areas. In addition, we will overview some of the cutting edge therapeutic developments in epidermolysis bullosa. RECENT FINDINGS: Recent advancements in supportive care of epidermolysis bullosa with focus on wound, pain, pruritus and nutrition status were discussed. Clinical surveillance and complication prevention are critical to improve clinical outcomes. Generalized epidermolysis bullosa is a systemic disease with increased morbidity and mortality; therefore, complex care using a multidisciplinary approach will provide the greatest benefits for patients. Current targeted treatments for epidermolysis bullosa aim at restoring the skin integrity using protein, cell, and gene therapies. SUMMARY: Improvement in care of epidermolysis bullosa in recent years results from keen clinical observation, novel molecular targeting, and the embracement of translational research.


Assuntos
Epidermólise Bolhosa/terapia , Terapia de Alvo Molecular/tendências , Prurido/terapia , Infecção dos Ferimentos/prevenção & controle , Fatores Etários , Bandagens , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa/psicologia , Humanos , Estado Nutricional , Guias de Prática Clínica como Assunto , Qualidade de Vida , Pesquisa Médica Translacional/tendências , Cicatrização
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