RESUMO
Extracranial arteriovenous malformation (AVM) is a congenital vascular anomaly causing disfigurement, bleeding, ulceration, and pain. Most lesions are associated with somatic MAP2K1 activating mutations in endothelial cells (ECs). The purpose of this study was to determine if EC expression of mutant activated MAP2K1 is sufficient to produce vascular malformations in mice. We generated mice with a ROSA26 allele containing a lox-stop-lox gene trap (GT), Map2k1 cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (R26GT-Map2k1-GFP). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using Tg-Cdh5Cre or Tg-Cdh5CreER alleles. Tg-Cdh5Cre+/-;R26GT-Map2k1-GFP/+ animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. Tg-Cdh5CreER+/-;R26GT-Map2k1-GFP/+ animals in which mutant MAP2K1 expression was induced in ECs by tamoxifen at postnatal (P) day 1 developed vascular malformations in the brain, ear, and intestines by P23. The lesions consisted of abnormal networks of blood vessels containing recombined and non-recombined ECs. In conclusion, expression of MAP2K1 p.K57N is sufficient to cause vascular malformations in mice. This model can be used to study the malformation process and for pre-clinical pharmacologic studies.
Assuntos
Malformações Arteriovenosas , Malformações Vasculares , Animais , Camundongos , Células Endoteliais/metabolismo , DNA Complementar/metabolismo , Mutação/genética , Malformações Arteriovenosas/genética , Malformações Vasculares/patologiaRESUMO
BACKGROUND/OBJECTIVES: Patients with obesity and lipedema commonly are misdiagnosed as having lymphedema. The conditions share phenotypic overlap and can influence each other. The purpose of this study was to delineate obesity-induced lymphedema, obesity without lymphedema, and lipedema in order to improve their diagnosis and treatment. SUBJECTS/METHODS: Our Lymphedema Center database of 700 patients was searched for patients with obesity-induced lymphedema (OIL), obesity without lymphedema (OWL), and lipedema. Patient age, sex, diagnosis, cellulitis history, body mass index (BMI), and treatment were recorded. Only subjects with lymphoscintigraphic documentation of their lymphatic function were included. RESULTS: Ninety-eight patients met inclusion criteria. Subjects with abnormal lymphatic function (n = 46) had a greater BMI (65 ± 12) and cellulitis history (n = 30, 65%) compared to individuals with normal lymphatic function [(BMI 42 ± 10); (cellulitis n = 8, 15%)] (p < 0.001). Seventeen patients had a history of lipedema and two exhibited abnormal lymphatic function (BMI 45, 54). The risk of having lower extremity lymphedema was predicted by BMI: BMI < 40 (0%), 40-49 (17%), 50-59 (63%), 60-69 (86%), 70-79 (91%), ≥80 (100%). Five patients with OIL (11%) underwent resection of massive localized lymphedema (MLL) or suction-assisted lipectomy. Three individuals (18%) with lipedema were treated with suction-assisted lipectomy. CONCLUSIONS: The risk of lymphedema in patients with obesity and lipedema can be predicted by BMI; confirmation requires lymphoscintigraphy. Individuals with OIL are at risk for cellulitis and MLL. Patients with a BMI > 40 are first managed with weight loss. Excisional procedures can further reduce extremity size once BMI has been lowered.
Assuntos
Índice de Massa Corporal , Interpretação de Imagem Assistida por Computador/métodos , Lipedema , Vasos Linfáticos , Obesidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Lipedema/diagnóstico por imagem , Lipedema/fisiopatologia , Vasos Linfáticos/diagnóstico por imagem , Vasos Linfáticos/fisiopatologia , Linfocintigrafia , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/fisiopatologia , Estudos Retrospectivos , Adulto JovemRESUMO
Primary lymphedema results from the anomalous development of the lymphatic system and typically presents during infancy, childhood, or adolescence. Adult-onset primary lymphedema is rare and mutations associated with this condition have not been identified. The purpose of this investigation was to search for variants that cause adult-onset primary lymphedema. We discovered an autosomal dominant EPHB4 mutation in a patient who developed unilateral leg lymphedema at age 39 years; the same mutation affected his son who presented with the disease at 14 years of age.
Assuntos
Predisposição Genética para Doença , Linfedema/genética , Receptor EphB4/genética , Adolescente , Adulto , Feminino , Humanos , Linfedema/patologia , Masculino , Mutação/genéticaRESUMO
Lipoblastoma typically occurs in childhood and is associated with rearrangements of the PLAG1 gene. We present a patient with an isolated mass thought to be a lipoblastoma clinically, radiographically, and histologically. The lesion was diagnosed as a PIK3CA-adipose lesion after the tissue was negative for PLAG1 rearrangement and contained a somatic PIK3CA mutation (H1047R). Although PIK3CA variants are associated with PROS (PIK3CA-related overgrowth spectrum), this report illustrates a non-syndromic, lipoblastoma phenotype caused by a PIK3CA mutation.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Lipoblastoma , Classe I de Fosfatidilinositol 3-Quinases/genética , Humanos , Lipoblastoma/diagnóstico , Lipoblastoma/genética , Mutação , FenótipoRESUMO
Arteriovenous malformation (AVM) is a locally destructive congenital vascular anomaly caused by somatic mutations in MAP2K1. The mutation is isolated to endothelial cells (ECs). The purpose of this study was to determine the effects of mutant MAP2K1 on EC signaling and vascular network formation. Pathway effects were studied using both mutant MAP2K1 (K57N) human AVM tissue and human umbilical vein endothelial cells (HUVECs) engineered to overexpress the MAP2K1 (K57N) mutation. Western blot was used to determine cell signaling along the RAS/MAPK pathway. Geltrex tube formation assays were performed to assess EC vascular network formation. Cells were treated with a MAP2K1 inhibitor (Trametinib) to determine its effect on signaling and vascular tube formation. Human mutant MAP2K1-AVM ECs had similar baseline MEK1 and ERK1/2 expression with controls; however, mutant MAP2K1-AVM ECs produced significantly more phosphorylated ERK1/2 than wild-type ECs. Mutant MAP2K1 HUVECs demonstrated significantly more phosphorylated ERK1/2 than control HUVECs. Trametinib reduced the phosphorylation of ERK1/2 in mutant cells and prevented the ability of ECs to form vascular networks. AVM MAP2K1 mutations activate RAS/MAPK signaling in ECs. ERK activation and vascular network formation are reduced with Trametinib. Pharmacotherapy using MAP2K1 inhibitors may prevent the formation or progression of AVMs.
Assuntos
Malformações Arteriovenosas/genética , Células Endoteliais/metabolismo , MAP Quinase Quinase 1/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Proteínas ras/metabolismo , Malformações Arteriovenosas/metabolismo , Malformações Arteriovenosas/patologia , Células Cultivadas , Células Endoteliais/patologia , Ativação Enzimática , Células Endoteliais da Veia Umbilical Humana , Humanos , MAP Quinase Quinase 1/metabolismo , Sistema de Sinalização das MAP Quinases , Mutação PuntualRESUMO
Extracranial arteriovenous malformation (AVM) is most commonly caused by a somatic mutation in MAP2K1. We report two patients with vascular anomalies that had an unclear clinical diagnosis most consistent with either an AVM or congenital hemangioma. Lesions were cutaneous, reddish-purple with telangiectasias, present at birth, and had defined borders. Histopathology indicated AVM and both lesions contained somatic KRAS mutations. A rare AVM phenotype exists that shares clinical features with congenital hemangioma.
Assuntos
Malformações Arteriovenosas/genética , Anormalidades Congênitas/genética , Hemangioma/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/patologia , Pré-Escolar , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/patologia , Predisposição Genética para Doença , Hemangioma/diagnóstico , Hemangioma/patologia , Humanos , Masculino , Mutação/genética , FenótipoRESUMO
Diffuse capillary malformation with overgrowth (DCMO) is a clinical diagnosis describing patients with multiple, extensive capillary malformations (CMs) associated with overgrowth and foot anomalies. The purpose of the study was to identify somatic variants in DCMO. Skin containing CM and overgrown subcutaneous adipose tissue was collected from patients with DCMO. Exons from 447 cancer-related genes were sequenced using OncoPanel. Variant-specific droplet digital PCR (ddPCR) independently confirmed the variants and determined variant allele frequencies (VAF). One subject contained a somatic PIK3CA p.G106V variant. A second patient had a PIK3CA p.D350G variant. VAF was 27% to 29% in skin and 16% to 28% in subcutaneous adipose. Variants were enriched in endothelial cells (VAF 50%-51%) compared to nonendothelial cells (1%-8%). DCMO is associated with somatic PIK3CA variants and should be considered on the PIK3CA-related overgrowth spectrum (PROS). Variants are present in both skin and subcutaneous adipose and are enriched in endothelial cells.
Assuntos
Anormalidades Múltiplas/genética , Capilares/anormalidades , Classe I de Fosfatidilinositol 3-Quinases/genética , Predisposição Genética para Doença , Malformações Vasculares/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Capilares/metabolismo , Capilares/patologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Mutação/genética , Malformações Vasculares/patologia , Adulto JovemRESUMO
Autologous ear construction for microtia creates an auricle using a costal cartilage framework. To separate the construct from the mastoid, the most common methods incorporate the use of fascial flaps or skin grafting. The authors describe a V-Y skin and subcutaneous scalp advancement flap for ear elevation as part of autologous ear construction for microtia. The method is simple and reliable and offers advantages compared to other techniques.
Assuntos
Microtia Congênita/cirurgia , Cartilagem Costal/cirurgia , Pavilhão Auricular/cirurgia , Cartilagem da Orelha/cirurgia , Orelha Externa/cirurgia , Humanos , Processo Mastoide/cirurgia , Procedimentos de Cirurgia Plástica , Couro Cabeludo/cirurgia , Transplante de Pele , Tela Subcutânea/cirurgia , Retalhos Cirúrgicos/cirurgiaRESUMO
The majority of extracranial arteriovenous malformations (AVMs) are caused by somatic mutations in MAP2K1. We report a somatic HRAS mutation in a patient who has a facial AVM associated with subcutaneous adipose overgrowth. We performed whole exome sequencing on DNA from the affected tissue and found a HRAS mutation (p.Thr58_Ala59delinsValLeuAspVal). Mutant allelic frequency was 5% in whole tissue and 31% in isolated endothelial cells (ECs); the mutation was not present in blood DNA or non-ECs. Somatic mutations in HRAS can cause AVM.
Assuntos
Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Criança , Feminino , Humanos , PrognósticoRESUMO
BACKGROUND: Numerous thoracoscopic techniques have been used in the management of primary spontaneous pneumothorax (PSP), including wedge resection, pleurectomy, pleural abrasion, chemical pleurodesis, and staple line covering. The purpose of this systematic review was to compare outcomes for the most commonly reported techniques. MATERIALS AND METHODS: A systematic literature search looking at pneumothorax recurrence rate, length of stay, and chest tube duration after surgery was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed database. RESULTS: Fifty-one unique studies comprised of 6907 patients published between January 1988 and June 2015 were identified. Heterogeneity among effect sizes was significant for all outcomes. The lowest recurrence rates were observed in the wedge resection + chemical pleurodesis (1.7%; 95% confidence interval [CI], 1.0%-2.7%) and the wedge resection + pleural abrasion + chemical pleurodesis (2.8%; 95% CI, 1.7%-4.7%) groups. The shortest chest tube duration and length of stay were observed in the wedge resection + staple line covering ± other group (2.1 d; 95% CI, 1.4-2.9 and 3.3 d; 95% CI, 2.6-4.0, respectively). CONCLUSIONS: The variability in reported outcomes and the lack of published multicenter randomized controlled trials highlights a need for more robust investigations into the optimal surgical technique in the management of PSP. Based on the limited quality studies available, this systematic review favors wedge resection + chemical pleurodesis and wedge resection + pleural abrasion + chemical pleurodesis in terms of recurrence rate after surgery for PSP.
Assuntos
Pleurodese/métodos , Pneumonectomia/métodos , Pneumotórax/cirurgia , Grampeamento Cirúrgico , Toracoscopia/métodos , Humanos , Recidiva , Resultado do TratamentoRESUMO
Two of the most common types of congenital thoracic malformations are congenital pulmonary airway malformations (CPAMs) and bronchopulmonary sequestrations (BPS). Here we present the first known case of a hybrid lesion, with coexisting features of an extralobar sequestration (ELS) and CPAM type 2, with arterial inflow from the celiac trunk and venous outflow to the portal vein. The clinical presentation, investigative imaging and timing of surgery are discussed.
Assuntos
Anormalidades Múltiplas , Sequestro Broncopulmonar/diagnóstico , Pulmão/anormalidades , Veia Porta/anormalidades , Cirurgia Torácica Vídeoassistida/métodos , Sequestro Broncopulmonar/cirurgia , Humanos , Lactente , Pulmão/diagnóstico por imagem , Masculino , Veia Porta/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Cardiac metastasis caused by renal cell carcinoma (RCC) without vena caval involvement is rare. No mutation has been associated with this unique phenotype. A 77-year-old male presented to our clinic with a symptomatic right ventricular mass after nephrectomy for clear cell RCC (ccRCC). The mass was resected, and metastatic disease was confirmed. Targeted exon sequencing identified a VHL mutation (c.494T > G, p.V165G) in the resected specimen. While more than half of ccRCC cases are associated with VHL mutations, this case is the first to show the association between delayed, isolated cardiac metastasis and VHL V165G mutation. The phenotype presented 12 years after nephrectomy and localized to the right ventricular apex. Further genomic characterization of cases with cardiac metastases may provide clues regarding unique mutations noted. Patients exhibiting delayed spread of RCC to the heart must be screened for this mutation.
RESUMO
Somatic activating MAP2K1 mutations in endothelial cells (ECs) cause extracranial arteriovenous malformation (AVM). We previously reported the generation of a mouse line allowing inducible expression of constitutively active MAP2K1 (p.K57N) from the Rosa locus (R26GT-Map2k1-GFP/+) and showed, using Tg-Cdh5CreER, that EC expression of mutant MAP2K1 is sufficient for the development of vascular malformations in the brain, ear, and intestines. To gain further insight into the mechanism by which mutant MAP2K1 drives AVM development, we induced MAP2K1 (p.K57N) expression in ECs of postnatal-day-1 pups (P1) and investigated the changes in gene expression in P9 brain ECs by RNA-seq. We found that over-expression of MAP2K1 altered the transcript abundance of > 1600 genes. Several genes had > 20-fold changes between MAP2K1 expressing and wild-type ECs; the highest were Col15a1 (39-fold) and Itgb3 (24-fold). Increased expression of COL15A1 in R26GT-Map2k1-GFP/+; Tg-Cdh5CreER+/- brain ECs was validated by immunostaining. Ontology showed that differentially expressed genes were involved in processes important for vasculogenesis (e.g., cell migration, adhesion, extracellular matrix organization, tube formation, angiogenesis). Understanding how these genes and pathways contribute to AVM formation will help identify targets for therapeutic intervention.
Assuntos
Malformações Arteriovenosas , Malformações Vasculares , Animais , Camundongos , Malformações Arteriovenosas/genética , Células Endoteliais/metabolismo , Mutação , Malformações Vasculares/metabolismo , MAP Quinase Quinase 1/genéticaRESUMO
Lymphedema results from inadequate lymphatic function. Extreme obesity can cause lower extremity lymphedema, termed "obesity-induced lymphedema (OIL)." OIL is a form of secondary lymphedema that may occur once an individual's body mass index (BMI) exceeds 40. The risk of lymphatic dysfunction increases with elevated BMI and is almost universal once BMI exceeds 60. Obesity has a negative impact on lymphatic density in subcutaneous tissue, lymphatic endothelial cell proliferation, lymphatic leakiness, collecting-vessel pumping capacity, and clearance of macromolecules. Lymphatic fluid unable to be taken up by lymphatic vessels results in increased subcutaneous adipose deposition, fibrosis, and worsening obesity. Individuals with OIL are in an unfavorable cycle of weight gain and lymphatic injury. The fundamental treatment for OIL is weight loss.
Assuntos
Vasos Linfáticos , Linfedema , Tecido Adiposo , Células Endoteliais , Humanos , Linfedema/complicações , Obesidade/complicaçõesRESUMO
Background: Lymphedema is a chronic progressive condition without a cure. Although the disease can cause significant morbidity, it is not a contraindication to participating in sports. The purpose of this study was to illustrate patients who are able to perform vigorous athletic activities to encourage individuals newly diagnosed with lymphedema. Methods and Results: Our Lymphedema Program database was reviewed for patients who performed significant sports, outside of routine exercise and fitness. Inclusion criteria were a confirmed diagnosis of lymphedema, age >16 years, and body mass index (BMI) <30. Age, gender, type of lymphedema (i.e., primary or secondary), location of disease, BMI, and athletic activities were recorded. Fourteen patients met inclusion criteria: seven males and seven females. Average age was 34 years (range 17-77) and lymphedema was primary (n = 11) or secondary (n = 3). All subjects had lower extremity disease: right leg (n = 6), left leg (n = 5), bilateral (n = 3). The average BMI was 23 (range 18-27). Sports performed by the cohort included marathon running (n = 3), soccer team (n = 2), skiing (n = 2), basketball team, rugby, swimming team, college lacrosse team, hockey team, college tennis team, and surfing. Conclusions: Patients with lower extremity lymphedema are able to engage in competitive sports and a wide range of athletic activities. Individuals typically have a normal BMI and active lifestyle. Patients with lymphedema should be encouraged to participate in athletic pursuits that they enjoy and to maintain a normal BMI.
Assuntos
Basquetebol , Hóquei , Linfedema , Futebol , Masculino , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Linfedema/diagnóstico , Linfedema/etiologiaRESUMO
Significance: Obesity affects one-third of the U.S. population and lymphedema is a chronic disorder without a cure. The relationship between obesity and lymphedema has important implications for public health. Recent Advances: Extreme obesity can cause lower extremity lymphedema, termed "obesity-induced lymphedema (OIL)." OIL is a form of secondary lymphedema that may occur once an individual's body mass index (BMI) exceeds 40. The risk of lymphatic dysfunction increases with elevated BMI and is almost universal once BMI exceeds 60. Patients with OIL also may develop areas of massive localized lymphedema (MLL). Critical Issues: Individuals with OIL are in an unfavorable cycle of weight gain and lymphatic injury. As BMI increases lymphedema worsens, ambulation becomes more difficult, and BMI further rises. The fundamental treatment for OIL is weight loss. Resection of areas of MLL and lower extremity volume reduction are performed when the BMI is lowered to <40 to reduce complications and recurrence. Future Directions: The mechanisms by which obesity causes lymphedema are still being elucidated. Although lymphatic function can improve following weight loss, it is unclear whether lymphedema may be completely reversed.
Assuntos
Vasos Linfáticos , Linfedema , Índice de Massa Corporal , Humanos , Linfedema/etiologia , Linfedema/cirurgia , Obesidade/complicações , Redução de PesoRESUMO
Significance: Primary lymphedema is a chronic condition without a cure. The lower extremities are more commonly affected than the arms or genitalia. The disease can be syndromic. Morbidity includes decreased self-esteem, infections, and reduced function of the area. Recent Advances: Several mutations can cause lymphedema, and new variants continue to be elucidated. A critical determinant that predicts the natural history and morbidity of lymphedema is the patient's body mass index (BMI). Individuals who maintain an active lifestyle with a normal BMI generally have less severe disease compared to subjects who are obese. Because other causes of lower extremity enlargement can be confused with lymphedema, definitive diagnosis requires lymphoscintigraphy. Critical Issues: Most patients with primary lymphedema are satisfactorily managed with compression regimens, exercise, and maintenance of a normal body weight. Suction-assisted lipectomy is our preferred operative intervention for symptomatic patients who have failed conservative therapy. Suction-assisted lipectomy effectively removes excess subcutaneous fibro-adipose tissue and can improve underlying lymphatic function. Future Directions: Many patients with primary lymphedema do not have an identifiable mutation and thus novel variants will be identified. The mechanisms by which mutations cause lymphedema continue to be studied. In the future, drug therapy for the disease may be developed.
Assuntos
Lipectomia , Vasos Linfáticos , Linfedema , Humanos , Sistema Linfático/cirurgia , Vasos Linfáticos/cirurgia , Linfedema/diagnóstico , Linfedema/genética , Linfedema/terapia , LinfocintigrafiaRESUMO
Background: Lymphedema results from inadequate lymphatic function causing swelling in subcutaneous tissues. Lymph is transported proximally through valved lymphatic channels and muscle contraction. The purpose of this study was to determine lymphatic function in nonambulatory patients with lower extremity neuromuscular disease. Methods and Results: Our Lymphedema Program database of 700 patients was reviewed for nonambulatory patients with lower extremity neuromuscular disease. Patient age, gender, disease, body mass index (BMI), and lymphoscintigram result were recorded. Eight patients were included in the study: myelomeningocele (n = 6), spinal muscle atrophy type 2 (n = 1), Charcot Marie Tooth (n = 1). Patient ages were between 15 and 36 years; five were female. BMI range for patients without swelling or a normal lymphoscintigram (n = 4) was 22-27. Four subjects with lymphatic dysfunction by lymphoscintigram all were obese (BMI 36-74; p = 0.03). Conclusions: Nonambulatory patients with lower extremity neuromuscular dysfunction and swelling can exhibit normal lymphatic function. Obesity is associated with abnormal lymphoscintigram result and lymphedema in this patient population. Individuals should be advised to maintain a normal BMI.
Assuntos
Vasos Linfáticos , Doenças Neuromusculares , Adolescente , Adulto , Feminino , Humanos , Extremidade Inferior , Linfa , Linfedema , Linfocintigrafia , Masculino , Adulto JovemRESUMO
Indications for lower extremity reconstruction in children are unique because most result from congenital conditions (eg, constriction ring, lymphedema, syndactyly, nevi, vascular anomalies). Like adults, pediatric patients also suffer from effects following extirpation and trauma. Principles of reconstruction are based on the condition and type of deformity. The pediatric population typically has fewer comorbidities than adults that can negatively affect outcomes (eg, diabetes, peripheral vascular disease), although children can be less compliant with postoperative care. Growth, development, appearance, and postoperative compliance are variables that especially influence operative management of children.