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Miikka Vikkula - One of the best experts on this subject based on the ideXlab platform.
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Antenatal presentation of Hereditary Lymphedema type I.
European Journal of Medical Genetics, 2015Co-Authors: E. Boudon, Miikka Vikkula, Y. Levy, T. Abossolo, François Cartault, Pascal Brouillard, M. Kieffer-traversier, Duksha Ramful, J.-l. AlessandriAbstract:Fetal edema can present as limited subcutaneous edema, fluid accumulation in body cavities or hydrops fetalis. Hydrops fetalis is the end stage of a variety of fetal/maternal disorders and nonimmune etiology represents more than 3/4 of cases. Lymphatic dysplasia may account for a subset of patients with nonimmune and "idiopathic" hydrops fetalis, fetal chylous ascites or chylothorax. We present two unrelated patients with antenatal features of Hereditary Lymphedema syndrome, in whom Milroy disease was diagnosed after birth. At least, 20 genes have been identified to cause primary Lymphedema, with sometimes antenatal features. Hereditary Lymphedema syndrome should be considered in cases of nonimmune hydrops fetalis/fetal edema after ruling out the more common etiologies.
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Hereditary Lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations
Clinical Genetics, 2006Co-Authors: Arash Ghalamkarpour, Susanne Morlot, Algirdas Utkus, Annick Raas-rothschild, Laurence M. Boon, John B. Mulliken, Miikka VikkulaAbstract:Mutations in the vascular endothelial growth factor receptor 3 gene, VEGFR3/FLT4, have been identified in a subset of families with Hereditary Lymphedema type I or Milroy disease (MIM 153100). Individuals carrying a VEGFR3 mutation exhibit congenital edema of the lower limbs, usually bilaterally and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, upturned toenails, and hydrocele. In this study, we report the first de novo VEGFR3 mutation in a patient with sporadic congenital Lymphedema. We also describe three other families with a VEGFR3 mutation. In each family, one individual had an atypical clinical presentation of Hereditary Lymphedema type I, whereas the others had the classical VEGFR3 mutation-caused phenotype. The atypical presentations included pre-natal pleural effusion, spontaneous resorption of Lymphedema and elephantiasis. Three of the four identified mutations were novel. These data show that de novo VEGFR3 mutations may be present in patients without family history of congenital Lymphedema. This has implications for follow-up care, as such individuals have nearly a 50% risk for occurrence of Lymphedema in their children. Our findings also indicate that although most patients with a VEGFR3 mutation have the well-defined phenotype for Hereditary Lymphedema type I, there are exceptions that should be considered in genetic counseling. Because VEGFR3 mutation can cause generalized lymphatic dysfunction and can thus result in hydrops fetalis, VEGFR3 screening should be added to the investigation of cases of hydrops fetalis of an unknown etiology.
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Wide clinical spectrum in a family with Hereditary Lymphedema type I due to a novel missense mutation in VEGFR3
Journal of Human Genetics, 2006Co-Authors: Ronen Spiegel, Arash Ghalamkarpour, Miikka Vikkula, Etty Daniel-spiegel, Stavit A ShalevAbstract:Hereditary Lymphedema type I (HL-I), also known as Milroy disease, is an autosomal dominant disorder characterized by typical phenotype of infantile onset lower-limb Lymphedema accompanied by variable expression of recurrent episodes of cellulites, toenail changes, and papillomatosis. Mutations in the vascular endothelial growth factor receptor 3 ( VEGFR3 ), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb Lymphedema. Wide intrafamilial phenotypic variability included two asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication, yet unreported, of chronic degenerative joint disease of the knees. This report broadens the known “classic” phenotype of HL-I.
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mutations in the transcription factor gene sox18 underlie recessive and dominant forms of hypotrichosis Lymphedema telangiectasia
American Journal of Human Genetics, 2003Co-Authors: Alexandre Irrthum, Koenraad Devriendt, David Chitayat, Gert Matthijs, Conrad P Glade, Peter M Steijlen, J P Fryns, Maurice A M Van Steensel, Miikka VikkulaAbstract:Hereditary Lymphedema is a developmental disorder characterized by chronic swelling of the extremities due to dysfunction of the lymphatic vessels. Two responsible genes have been identified: the vascular endothelial growth factor receptor 3 (VEGFR3) gene, implicated in congenital Lymphedema, or Milroy disease, and the forkhead-related transcription factor gene FOXC2, causing Lymphedema-distichiasis. We describe three families with an unusual association of hypotrichosis, Lymphedema, and telangiectasia. Using microsatellite analysis, we first excluded both VEGFR3 and FOXC2 as causative genes; we then considered the murine ragged phenotype, caused by mutations in the Sox18 transcription factor, as a likely counterpart to the human disease, because it presents a combination of hair and cardiovascular anomalies, including symptoms of lymphatic dysfunction. Two of the families were consanguineous; in affected members of these families, we identified homozygous missense mutations in the SOX18 gene, located in 20q13. The two amino acid substitutions, W95R and A104P, affect conserved residues in the first α helix of the DNA-binding domain of the transcription factor. In the third family, the parents were nonconsanguineous, and both the affected child and his brother, who died in utero with hydrops fetalis, showed a heterozygous nonsense mutation that truncates the SOX18 protein in its transactivation domain; this substitution was not found in genomic DNA from either parent and hence constitutes a de novo germline mutation. Thus, we show that SOX18 mutations in humans cause both recessive and dominant hypotrichosis-Lymphedema-telangiectasia, suggesting that, in addition to its established role in hair and blood vessel development, the SOX18 transcription factor plays a role in the development and/or maintenance of lymphatic vessels.
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congenital Hereditary Lymphedema caused by a mutation that inactivates vegfr3 tyrosine kinase
American Journal of Human Genetics, 2000Co-Authors: Alexandre Irrthum, Marika J Karkkainen, Koen Devriendt, Kari Alitalo, Miikka VikkulaAbstract:Hereditary Lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, also known as "Milroy disease," has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. This region contains a good candidate gene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiology of the disease, we have analyzed a family with Hereditary Lymphedema. We show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegregates with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro expression, that this mutation inhibits the autophosphorylation of the receptor. Thus, defective VEGFR3 signaling seems to be the cause of congenital Hereditary Lymphedema linked to 5q34-q35.
Carlo Crosti - One of the best experts on this subject based on the ideXlab platform.
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lymphangiosarcoma of the pubic region a rare complication arising in congenital non Hereditary Lymphedema
European Journal of Dermatology, 1998Co-Authors: Andrea Cerri, Campatelli Gianni, Massimo Pizzuto, Mario Corbellino, Laura Moneghini, Carlo CrostiAbstract:Lymphangiosarcoma (LAS) is a rare, vascular tumour, frequently associated with post-mastectomy Lymphedema (Stewart Treves's syndrome) [1]. Exceptionally, this form of very aggressive neoplasm arises in congenital Lymphedema, commonly classified into Hereditary (Milroy's syndrome and Meige's syndrome) and non-Hereditary Lymphedemas [2-4]. Until now, only four cases of LAS arising in a non-Hereditary congenital Lymphedema of the lower [...]
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lymphangiosarcoma of the pubic region a rare complication arising in congenital non Hereditary Lymphedema
European Journal of Dermatology, 1998Co-Authors: Andrea Cerri, Campatelli Gianni, Massimo Pizzuto, Mario Corbellino, Laura Moneghini, Carlo CrostiAbstract:Lymphangiosarcoma is a rare, aggressive, vascular neoplasm arising in chronic congenital or acquired Lymphedema. Although it is most frequently associated with post-mastectomy Lymphedema (Stewart-Treves's syndrome), lymphangiosarcoma can exceptionally arise in congenital Hereditary Lymphedema (Milroy's syndrome and Meige's syndrome) and non-Hereditary Lymphedema (congenital, praecox or forme tarde Lymphedemas). We report a case of lymphangiosarcoma of the pubic region, supported by immunohistochemical studies, in a 42-year-old woman affected by congenital, non-Hereditary Lymphedema of the left genital region and homolateral lower limb. In addition, molecular analysis demonstrated the absence of Kaposi's sarcoma-associated Herpes virus (KSHV) DNA sequences in tumour lesions. To our knowledge, this is the first case of lymphangiosarcoma associated with congenital non-Hereditary Lymphedema confined to the pubic region. The literature concerning the cases of lymphangiosarcoma arising in congenital Hereditary and non-Hereditary Lymphedema is reviewed. Moreover, we emphasized the importance of regular clinical controls in all patients affected by chronic Lymphedema. In fact, although the prognosis of this neoplasm is very poor, a prompt diagnosis and a rapid, ablative surgery associated with radiation therapy can increase the possibility of survival of these patients.
Moshe Bronshtein - One of the best experts on this subject based on the ideXlab platform.
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prenatal diagnosis of milroy s primary congenital Lymphedema
Prenatal Diagnosis, 2002Co-Authors: Imad R Makhoul, Nadir Ghanem, Polo Sujov, Moshe BronshteinAbstract:Milroy's primary congenital Lymphedema (PCL) (Hereditary Lymphedema type I, Milroy disease) is present at birth, and mostly affects the dorsal aspects of feet. It is mostly a life-long condition but does not affect longevity. Complications are rare except for chronic discomfort and warmness of affected areas. PCL is an autosomal dominant disease with incomplete penetrance due to a mutation in the gene locus encoding for VEGFR3 with resultant dysgenesis of microlymphatic vessels. We report on two fetuses where ultrasonographic examination at 15 weeks of gestation showed significant edema of the dorsal aspects of both feet with no evidence of other major malformations. Whereas in one fetus the edema resolved completely, it persisted in the second fetus and proved after birth to be of Lymphedematous nature. To the best of our knowledge, this is the first report of early prenatal diagnosis of primary congenital Lymphedema via fetal ultrasonographic examination and of spontaneous resolution of Lymphedema during fetal life. Copyright © 2002 John Wiley & Sons, Ltd.
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Prenatal diagnosis of Milroy's primary congenital Lymphedema
Prenatal diagnosis, 2002Co-Authors: Imad R Makhoul, Nadir Ghanem, Polo Sujov, Moshe BronshteinAbstract:Milroy's primary congenital Lymphedema (PCL) (Hereditary Lymphedema type I, Milroy disease) is present at birth, and mostly affects the dorsal aspects of feet. It is mostly a life-long condition but does not affect longevity. Complications are rare except for chronic discomfort and warmness of affected areas. PCL is an autosomal dominant disease with incomplete penetrance due to a mutation in the gene locus encoding for VEGFR3 with resultant dysgenesis of microlymphatic vessels. We report on two fetuses where ultrasonographic examination at 15 weeks of gestation showed significant edema of the dorsal aspects of both feet with no evidence of other major malformations. Whereas in one fetus the edema resolved completely, it persisted in the second fetus and proved after birth to be of Lymphedematous nature. To the best of our knowledge, this is the first report of early prenatal diagnosis of primary congenital Lymphedema via fetal ultrasonographic examination and of spontaneous resolution of Lymphedema during fetal life.
Andrea Cerri - One of the best experts on this subject based on the ideXlab platform.
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lymphangiosarcoma of the pubic region a rare complication arising in congenital non Hereditary Lymphedema
European Journal of Dermatology, 1998Co-Authors: Andrea Cerri, Campatelli Gianni, Massimo Pizzuto, Mario Corbellino, Laura Moneghini, Carlo CrostiAbstract:Lymphangiosarcoma (LAS) is a rare, vascular tumour, frequently associated with post-mastectomy Lymphedema (Stewart Treves's syndrome) [1]. Exceptionally, this form of very aggressive neoplasm arises in congenital Lymphedema, commonly classified into Hereditary (Milroy's syndrome and Meige's syndrome) and non-Hereditary Lymphedemas [2-4]. Until now, only four cases of LAS arising in a non-Hereditary congenital Lymphedema of the lower [...]
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lymphangiosarcoma of the pubic region a rare complication arising in congenital non Hereditary Lymphedema
European Journal of Dermatology, 1998Co-Authors: Andrea Cerri, Campatelli Gianni, Massimo Pizzuto, Mario Corbellino, Laura Moneghini, Carlo CrostiAbstract:Lymphangiosarcoma is a rare, aggressive, vascular neoplasm arising in chronic congenital or acquired Lymphedema. Although it is most frequently associated with post-mastectomy Lymphedema (Stewart-Treves's syndrome), lymphangiosarcoma can exceptionally arise in congenital Hereditary Lymphedema (Milroy's syndrome and Meige's syndrome) and non-Hereditary Lymphedema (congenital, praecox or forme tarde Lymphedemas). We report a case of lymphangiosarcoma of the pubic region, supported by immunohistochemical studies, in a 42-year-old woman affected by congenital, non-Hereditary Lymphedema of the left genital region and homolateral lower limb. In addition, molecular analysis demonstrated the absence of Kaposi's sarcoma-associated Herpes virus (KSHV) DNA sequences in tumour lesions. To our knowledge, this is the first case of lymphangiosarcoma associated with congenital non-Hereditary Lymphedema confined to the pubic region. The literature concerning the cases of lymphangiosarcoma arising in congenital Hereditary and non-Hereditary Lymphedema is reviewed. Moreover, we emphasized the importance of regular clinical controls in all patients affected by chronic Lymphedema. In fact, although the prognosis of this neoplasm is very poor, a prompt diagnosis and a rapid, ablative surgery associated with radiation therapy can increase the possibility of survival of these patients.
Marika J Karkkainen - One of the best experts on this subject based on the ideXlab platform.
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VEGFR3 gene structure, regulatory region, and sequence polymorphisms
2013Co-Authors: Kristiina Iljin, Mark A. Kimak, Elizabeth C. Lawrence, Marika J Karkkainen, Katri Pajusola, Marko Uutela, Jussi Taipale, Leena Alhonen, Maria Halmekytö, David N. FinegoldAbstract:ABSTRACT Vascular endothelial growth factor receptor 3 (VEGFR-3) is required for cardiovascular development during embryogenesis. In adults, this receptor is expressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have been implicated in human Hereditary Lymphedema. To better understand the basis of its specific endothelial lineage-restricted expression, we have characterized the VEGFR3 gene and its regulatory 5 � flanking region. The human gene contains 31 exons, of which exons 30a and 30b are alternatively spliced. The VEGFR3 proximal promoter is TATA-less and contains stretches of sequences homologous with the mouse Vegfr3 promoter region. In transfection experiments of cultured cells, the Vegfr3 promoter was shown to control endothelial cell-specific transcription of downstream reporter genes. This result was further confirmed in vivo; in a subset of transgenic mouse embryos, a 1.6 kb Vegfr3 promoter fragment directed weak lymphatic endothelial expression of the LacZ marker gene. This suggests that endothelial cell-specific elements occur in the proximal promoter, although further enhancer elements are probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the molecular genetic analysis of the lymphatic system and its disorders.—Iljin, K., Karkkainen
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adenoviral vegf c overexpression induces blood vessel enlargement tortuosity and leakiness but no sprouting angiogenesis in the skin or mucous membranes
The FASEB Journal, 2002Co-Authors: Anne Saaristo, Marika J Karkkainen, Katri Pajusola, Tanja Veikkola, Berndt Enholm, Maija Hytonen, Johanna Arola, Paivi Turunen, Michael Jeltsch, Dontscho KerjaschkiAbstract:Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with Hereditary Lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels...
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Lymphangiogenic gene therapy with minimal blood vascular side-effects
2002Co-Authors: Anne Saaristo, Marika J Karkkainen, Katri Pajusola, Hansruedi Büeler, Tanja Veikkola, Berndt Enholm, Tuomas Tammela, Kari AlitaloAbstract:Recent work from many laboratories has demonstrated that the vascular endothelial growth factor-C/VEGF-D/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and that mutations of the Vegfr3 gene are associated with Hereditary Lymphedema. Furthermore, VEGF-C gene transfer to the skin of mice with Lymphedema induced a regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF-C cause blood vessel growth and leakiness, resulting in tissue edema. To avoid these blood vascular side effects of VEGF-C, we constructed a viral vector for a VEGFR-3–specific mutant form of VEGF-C (VEGF-C156S) for Lymphedema gene therapy. We demonstrate that VEGF-C156S potently induces lymphangiogenesis in transgenic mouse embryos, and when applied via viral gene transfer, in normal and Lymphedema mice. Importantly, adenoviral VEGF-C156S lacked the blood vascular side effects of VEGF and VEGF-C adenoviruses. In particular, in the Lymphedema mice functional cutaneous lymphatic vessels of normal caliber and morphology were detected after long-term expression of VEGF-C156S via an adeno associated virus. These results have important implications for the development of gene therapy for human Lymphedema. Key words: Lymphedema • lymphatic endothelium • VEGF-C • VEGFR-2 • VEGFR-
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A model for gene therapy of human Hereditary Lymphedema
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Marika J Karkkainen, Elizabeth C. Lawrence, Anne Saaristo, Lotta Jussila, Kaisa Karila, Katri Pajusola, Hansruedi Büeler, Anne Eichmann, Risto A. Kauppinen, Mikko I. KettunenAbstract:Primary human Lymphedema (Milroy's disease), characterized by a chronic and disfiguring swelling of the extremities, is associated with heterozygous inactivating missense mutations of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3). Here, we describe a mouse model and a possible treatment for primary Lymphedema. Like the human patients, the Lymphedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line, and swelling of the limbs because of hypoplastic cutaneous, but not visceral, lymphatic vessels. Neuropilin (NRP)-2 bound VEGF-C and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia, suggesting that it may participate in the pathogenesis of Lymphedema. By using virus-mediated VEGF-C gene therapy, we were able to generate functional lymphatic vessels in the Lymphedema mice. Our results suggest that growth factor gene therapy is applicable to human Lymphedema and provide a paradigm for other diseases associated with mutant receptors.
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congenital Hereditary Lymphedema caused by a mutation that inactivates vegfr3 tyrosine kinase
American Journal of Human Genetics, 2000Co-Authors: Alexandre Irrthum, Marika J Karkkainen, Koen Devriendt, Kari Alitalo, Miikka VikkulaAbstract:Hereditary Lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, also known as "Milroy disease," has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. This region contains a good candidate gene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiology of the disease, we have analyzed a family with Hereditary Lymphedema. We show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegregates with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro expression, that this mutation inhibits the autophosphorylation of the receptor. Thus, defective VEGFR3 signaling seems to be the cause of congenital Hereditary Lymphedema linked to 5q34-q35.