FLT4/VEGFR3and Milroy Disease: Novel Mutations, a Review of Published Variants and Database Update

Gordon, Kristiana; Spiden, Sarah L.; Connell, Fiona; Brice, Glen; Cottrell, S; Short, John; Taylor, Rohan; Jeffery, Steve; Mortimer, Peter; Mansour, Sahar; Østergaard, Pia

doi:10.1002/humu.22223

Cited by 78 publications

(70 citation statements)

References 56 publications

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“…Missense mutations in the tyrosine kinase domain of VEGFR3 are responsible for about 70% of cases of an autosomal dominant primary congenital lymphedema known as Milroy disease (22,23). Additionally, a homozygous recessive mutation has been identified in a lymphedema patient (24,25).…”

Section: Lymphangiogenic Pathways and Mechanisms Vegfc/d And Vegfr3mentioning

confidence: 99%

Lymphangiogenic factors, mechanisms, and applications

Zheng¹,

Aspelund²,

Alitalo³

2014

J. Clin. Invest.

273

244

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Lymphangiogenesis, the growth of lymphatic vessels, is essential in embryonic development. In adults, it is involved in many pathological processes such as lymphedema, inflammatory diseases, and tumor metastasis. Advances during the past decade have dramatically increased the knowledge of the mechanisms of lymphangiogenesis, including the roles of transcription factors, lymphangiogenic growth factors and their receptors, and intercellular and intracellular signaling cascades. Strategies based on these mechanisms are being tested in the treatment of various human diseases such as cancer, lymphedema, and tissue allograft rejection. This Review summarizes the recent progress on lymphangiogenic mechanisms and their applications in disease treatment.

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Section: Lymphangiogenic Pathways and Mechanisms Vegfc/d And Vegfr3mentioning

confidence: 99%

Lymphangiogenic factors, mechanisms, and applications

Zheng¹,

Aspelund²,

Alitalo³

2014

J. Clin. Invest.

273

244

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“…VEGFR-3 tyrosine kinase activity is crucial for lymphatic vessel growth (Zarkada et al 2015), but recently there were reported controversial data concerning its involvement in angiogenesis, mainly by controlling tip to stalk conversion at vessel fusion site (Nilsson et al 2010;Tammela et al 2011) and also by supporting sprouting, vessel branching, and endothelial cell proliferation (Cao et al 1998;Tammela et al 2008). In 2013, Gordon et al (2013b) reported for the first time in humans that VEGFR-3 mutations or impairment of its phosphorylation during embryonic lymphangiogenesis correlated with mutation in VEGF-C (Gordon et al 2013a) is causative for a defective lymphatic vessel development and primary lymphedema from Milroy disease. The VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumor cells.…”

Section: Lymphangiogenesis: Step By Step From Friendship To Hostilitymentioning

confidence: 99%

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

Cimpean

Raica

2015

Arch. Immunol. Ther. Exp.

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Several papers about lymphangiogenesis and inflammation focused on the detailed and complicated descriptions of the molecular pathways accompanying both non-tumor and tumor inflammatory-induced lymphatic vessel development. Many authors are tempted to present inflammatory-induced lymphangiogenesis in pathologic conditions neglecting the role of inflammatory cells during embryonic lymphatic vessel development. Some of the inflammatory cells are largely characterized in inflammatory-induced lymphangiogenesis, while others as mast cells, eosinophils, or plasma cells are less studied. No phenotypic characterization of inflammation-activated lymphatic endothelial cell is available in this moment. Another paradox is related to the existence of few papers regarding lymphangiogenesis inside lymphoid organs and for their related pathology. There are still several "missing pieces of such a big puzzle" of lymphangiogenesis and inflammation, with a direct impact on the ineffectiveness of the anti-inflammatory therapy as lymphangiogenesis inhibitors. The present paper will focus on the controversial issues of lymphangiogenesis and inflammation.

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“…15,16 Granulocyte macrophage-colony-stimulating factor (GM-CSF) autoantibodies and mutations in the GM-CSF receptor may lead to PAP, 17 whereas FLT4 and other mutations may underlie congenital lymphedema. 18 Considerable clinical heterogeneity exists among patients with GATA2 deficiency. Age at disease onset ranges from early childhood to late adulthood, and clinical presentations range from asymptomatic to life-threatening infections, leukemia, and respiratory failure.…”

Section: Introductionmentioning

confidence: 99%

GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity

Spinner¹,

Sanchez²,

Hsu³

et al. 2014

Blood

619

821

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Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.

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FLT4/VEGFR3and Milroy Disease: Novel Mutations, a Review of Published Variants and Database Update

Cited by 78 publications

References 56 publications

Lymphangiogenic factors, mechanisms, and applications

Lymphangiogenic factors, mechanisms, and applications

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity

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