RESUMO
Breast cancer-related lymphedema results in chronic upper limb swelling with subcutaneous deposition of fluid and fibroadipose tissue. Morbidity includes psychosocial distress, infection, and difficulty using the extremity. Operative management includes excisional procedures such as suction-assisted lipectomy to reduce abnormal subcutaneous fibroadipose tissue to improve limb volume. Patients who have had postmastectomy breast reconstruction often benefit from fat grafting. This report introduces the concept of fat grafting the breast using the lymphedematous arm as a donor site. This technique improves the volume of the limb by removing the excess subcutaneous adipose, and at the same time reconstructs the breast without adding a donor site not related to the breast cancer-related lymphedema.
RESUMO
Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cß3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression.
Assuntos
Capilares/anormalidades , Síndrome de Sturge-Weber , Malformações Vasculares , Humanos , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Síndrome de Sturge-Weber/terapia , Células Endoteliais/metabolismo , Capilares/patologia , Macrófagos/metabolismo , Microambiente Tumoral , Proteínas de Transporte Vesicular/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismoRESUMO
Papillary hemangioma (PH) is a small, primarily dermal lesion occurring predominantly in the head and neck in both children and adults. Its signature characteristics are dilated thin-walled channels containing papillary clusters of mainly capillary-sized vessels and endothelial cytoplasmic eosinophilic inclusions. Given certain histopathologic similarities to congenital hemangioma which harbor mutations in GNAQ and GNA11 , we investigated whether similar mutations are present in PH. Seven PH specimens were studied. All presented in the first 4 years of life, with one being noted at birth. With the exception of one lesion, all were in the head and neck. Lesions were bluish and ranged in size from 0.5 to 2.8 cm. Four samples had GNA11 p.Q209L and 3 had GNAQ p.Q209L missense mutations. Mutations in GNA11 and GNAQ are associated with other types of somatic vascular lesions including capillary malformation, congenital hemangioma, anastomosing hemangioma, thrombotic anastomosing hemangioma, and hepatic small cell neoplasm. Shared mutations in GNA11 and GNAQ may account for some overlapping clinical and pathologic features in these entities, perhaps explicable by the timing of the mutation or influence of the germline phenotype.
Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP , Hemangioma , Mutação , Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Hemangioma/genética , Hemangioma/patologia , Hemangioma/cirurgia , Subunidades alfa de Proteínas de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Despite high satisfaction rates, reduction mammaplasty can have complications such as hematoma. Factors such as age, tobacco use, and comorbidities are known contributors, whereas the influence of race, BMI, certain medications, and blood pressure (BP) remain contentious. This study investigates hematoma risk factors in young women undergoing reduction mammaplasty. STUDY DESIGN: A retrospective review was conducted including all female patients who underwent bilateral reduction mammaplasty at a single institution between 2012 and 2022. Data on demographics, BMI, medical comorbidities, surgical techniques, medications, and perioperative BP were collected. Differences between patients who developed a hematoma and those who did not were assessed using chi-square, Fisher's exact, and t -tests. The relationship between perioperative BP and hematoma formation was assessed using logistic regression. RESULTS: Of 1,754 consecutive patients, 3% developed postoperative hematoma of any kind, with 1.8% returning to the operating room. Age (odds ratio [OR] 1.14, p = 0.01) and ketorolac use (OR 3.93, p = 0.01) were associated with hematoma development. Controlling for baseline BP, each 10 mmHg incremental increase in peak intraoperative BP (systolic BP [SBP]: OR 1.24, p = 0.03; mean arterial pressure: OR 1.24, p = 0.01) and postoperative BP (SBP: OR 1.41, p = 0.01; mean arterial pressure: OR 1.49, p = 0.01) escalated the odds of hematoma. Postoperative SBP variability also incrementally increased hematoma odds (OR 1.48, p < 0.01). Other factors, including race and surgical technique, were not significantly influential. CONCLUSIONS: Age, ketorolac use, and intra- and postoperative BP peaks and variability are risk factors for hematoma in reduction mammaplasty. This emphasizes the importance of perioperative BP management and optimizing pain management protocols.
Assuntos
Cetorolaco , Mamoplastia , Feminino , Humanos , Cetorolaco/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Hematoma/etiologia , Hematoma/induzido quimicamente , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Mastectomia/efeitos adversos , Fatores de Risco , Estudos RetrospectivosRESUMO
Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity. The presence of fibrosis led to our hypothesis that rosiglitazone, a PPARγ agonist that inhibits fibrosis, would reduce fibrosis in a mouse model of secondary lymphedema after hind limb lymphadenectomy. In vivo, rosiglitazone reduced fibrosis in the hind limb after lymphadenectomy. Our findings verified that rosiglitazone reestablished the adipogenic features of TGF-ß1-treated mesenchymal cells in vitro. Despite this, rosiglitazone led to a reduction in adipose tissue deposition. Single-cell RNA-Seq data obtained from human tissues and flow cytometric and histological evaluation of mouse tissues demonstrated increased presence of PDGFRα+ cells in lymphedema; human tissue analysis verified these cells have the capacity for adipogenic and fibrogenic differentiation. Upon treatment with rosiglitazone, we noted a reduction in the overall quantity of PDGFRα+ cells and LipidTOX+ cells. Our findings provide a framework for treating secondary lymphedema as a condition of fibrosis and adipose tissue deposition, both of which, paradoxically, can be prevented with a pro-adipogenic agent.
Assuntos
Linfedema , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Masculino , Feminino , Humanos , Camundongos , Animais , PPAR gama , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Linfedema/tratamento farmacológico , FibroseRESUMO
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
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
Lymphedema is a chronic, debilitating disease that has been described as the largest breast cancer survivorship burden. Debulking surgery has been shown to improve extremity volume, improve patient quality of life, and decrease the incidence of cellulitis in the literature. This procedure is routinely covered in numerous other developed countries, yet it is still inconsistently covered in the United States. Methods: Extremity volumes from all patients who underwent debulking surgery of the upper extremity at two institutions between December 2017 and January 2020 with at least 12 months follow-up were included. Procedural costs were calculated using Medicare reimbursement data. Average utility scores were obtained for each health state using a visual analog scale, then converted to quality-adjusted life years. A decision tree was generated, and incremental cost-utility ratios were calculated. Sensitivity analyses were performed to evaluate our findings. Results: Debulking surgery is associated with a higher clinical effectiveness (quality-adjusted life year) of 27.05 compared to conservative management (23.34), with a relative cost reduction of $74,487. Rollback analysis favored debulking surgery as the cost-effective option compared to conservative management. The resulting negative incremental cost-utility ratio of -20,115.07 favored debulking surgery and indicated a dominant strategy. Conclusion: Our study supports the use of debulking surgery for the treatment of chronic lymphedema of the upper extremity.
RESUMO
Lymphedema in children is rare; however, it is usually a progressive and chronic condition. Accurate diagnosis of lymphedema in the pediatric population often takes several months and sometimes is delayed for years. Lymphedema can be isolated or associated with genetic syndromes, thus it is very important to identify the correct diagnosis, to select carefully which patients to refer for genetic testing, and to initiate appropriate treatment in a timely fashion. In this article, we review key information about diagnosis of lymphedema, associated conditions and syndromes, and current treatment modalities.
Assuntos
Linfedema , Criança , Humanos , Linfedema/diagnóstico , Linfedema/etiologia , Linfedema/terapia , SíndromeRESUMO
Lymphedema in children is rare; however, it is usually a progressive and chronic condition. Accurate diagnosis of lymphedema in the pediatric population often takes several months and sometimes is delayed for years. Lymphedema can be isolated or associated with genetic syndromes, thus it is very important to identify the correct diagnosis, to select carefully which patients to refer for genetic testing, and to initiate appropriate treatment in a timely fashion. In this article, we review key information about diagnosis of lymphedema, associated conditions and syndromes, and current treatment modalities.
Assuntos
Linfedema , Criança , Humanos , Linfedema/diagnóstico , Linfedema/etiologia , Linfedema/terapia , Modalidades de Fisioterapia , SíndromeRESUMO
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
OBJECTIVE: Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in GNAQ (c.548G>A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant Gαq (G-protein αq subunit) alters EC signaling and disrupts capillary morphogenesis. Approach and Results: We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) ß3, a downstream effector of Gαq. Activated PLCß3 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-κB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by quantitative PCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 as well as siRNA targeted to PLCß3 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT. CONCLUSIONS: Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCß3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.
Assuntos
Angiopoietina-2/metabolismo , Capilares/metabolismo , Células Progenitoras Endoteliais/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Neovascularização Patológica , Síndrome de Sturge-Weber/metabolismo , Adolescente , Adulto , Idoso , Angiopoietina-2/genética , Animais , Capilares/anormalidades , Células Cultivadas , Criança , Pré-Escolar , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/transplante , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Nus , Mutação , Fenótipo , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Regulação para CimaRESUMO
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
Parkes Weber syndrome is a vascular malformation overgrowth condition typically involving the legs. Its main features are diffuse arteriovenous fistulas and enlargement of the limb. The condition has been associated with pathogenic germline variants in RASA1 and EPHB4 We report two individuals with Parkes Weber syndrome of the leg and primary lymphedema containing a somatic KRAS variant (NM_004985.5:c.35G > A; p.Gly12Asp). KRAS variants, which cause somatic intracranial and extracranial arteriovenous malformations, also result in Parkes Weber syndrome with lymphatic malformations.
Assuntos
Fístula Arteriovenosa , Malformações Arteriovenosas , Linfedema , Síndrome de Sturge-Weber , Humanos , Proteínas Proto-Oncogênicas p21(ras) , Proteína p120 Ativadora de GTPaseRESUMO
Bockenheimer disease is a venous malformation involving all tissues of an extremity. Patients have significant morbidity, and treatment is palliative. The purpose of this study was to identify the cause of Bockenheimer disease to develop pharmacotherapy for the condition. Paraffin-embedded tissue from nine individuals with Bockenheimer disease obtained during a clinically indicated operation underwent DNA extraction. Droplet digital polymerase chain reaction (ddPCR) was used to screen for variants most commonly associated with sporadic venous malformations (TEK [NM_000459.5:c.2740C > T; p.Leu914Phe], PIK3CA [NM_006218.4:c.1624G > A; p.Glu542Lys and NM_006218.4:c.3140A > G; p.His1047Arg]). ddPCR detected a TEK L914F variant in all nine patients (variant allele fraction 2%-13%). PIK3CA E542K and H1047R variants were not identified in the specimens. Sanger sequencing and restriction enzyme digestion confirmed variants identified by ddPCR. A pathogenic variant in the endothelial cell tyrosine kinase receptor TEK is associated with Bockenheimer disease. Pharmacotherapy targeting the TEK signaling pathway might benefit patients with the condition.
Assuntos
Receptor TIE-2 , Malformações Vasculares , Alelos , Humanos , Mutação , Reação em Cadeia da Polimerase , Malformações Vasculares/genéticaRESUMO
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
BACKGROUND: Verrucous venous malformation (VVM), previously called "verrucous hemangioma," typically involves the dermis and the subcutaneous fat. We have encountered patients with VVM confined to the hypodermis. MATERIALS AND METHODS: During a nearly 20-year period, 13 patients, aged 2-17 years, presented with a subcutaneous mass in the limb without clinically obvious epidermal alterations. Consequently, operative excisions did not include the skin. RESULTS: Histopathologically, the specimens were composed of blood-filled channels with morphologic characteristics of capillaries and veins that infiltrated adipose tissue. Aggregates often formed nodules with variable fibrosis and a component of large and radially oriented vessels. A diagnosis of VVM was supported by endothelial immunopositivity for GLUT-1 (25%-75% immunopositive channels in 16/16 specimens); D2-40 (1%-25% channels in 14/15 specimens); and Prox-1 (1%-50% of channels in 14/16 specimens). A MAP3K3 mutation was identified by droplet digital PCR in 3 of the 6 specimens. CONCLUSIONS: Diagnosis of VVM in this uncommon location is challenging because of absence of epidermal changes and lack of dermal involvement. Imaging is not pathognomonic, and mimickers are many. Appropriate immunohistochemical stains and molecular analysis contribute to the correct diagnosis.