Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Tuesday, January 24, 2006

Klippel Trenaunay Weber - Genetics

Klippel-Trenaunay syndrome in a monozygotic male twin: supportive evidence for the concept of paradominant inheritance.

Sept/Oct 2005 European Journal Dermatology

Hofer T, Frank J, Itin PH.

Winkelriedstrasse 10, Dermatology FMH, CH-5430 Wettingen Switzerland.

Klippel-Trenaunay-syndrome (KTS) (OMIM 149000) is a congenital slow-flow capillary lymphaticovenous malformation often affecting the lower extremities and accompanied by bone and soft tissue hypertrophy. The cutaneous lesions are always surrounded by regions of unaffected skin in a mosaic pattern. Usually, KTS occurs sporadically but rare reports of familial segregation exist, contributing to the ongoing debate on the issue of heredity in this disease. Herein, we report on identical monozygotic male twins discordant for KTS. This observation strongly supports the model of paradominant inheritance that was recently proposed for this and similar disorders.

Publication Types:
Case Reports

Pub Med Abstract


Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis.

Abstract - Cell Mol Life Sci. 2005 Jul

Timur AA, Driscoll DJ, Wang Q.

Center for Molecular Genetics, ND40, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.

Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining 'increased angiogenesis' as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.

Publication Types:

ReviewPMID: 15905966

[PubMed - indexed for MEDLINE]


Identification and molecular characterization of a de novo supernumerary ring chromosome 18 in a patient with Klippel-Trenaunay syndrome.

Abstract - Annual of Human Genetics July 2004

Timur AA, Sadgephour A, Graf M, Schwartz S, Libby ED, Driscoll DJ, Wang Q.

Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular disorder comprised of capillary, venous and lymphatic malformations associated with overgrowth of the affected tissues. In this study, we report the identification of a de novo supernumerary ring chromosome in a patient with mild mental retardation, long tapering fingers, elongated, thin feet and Klippel-Trenaunay syndrome (KTS). The ring marker chromosome was found to be mosaic, present in 24% of cells, and was later shown to be derived from chromosome 18, r(18). Fluorescence in situ hybridization (FISH) was used to define the breakpoints involved in the formation of r(18). The chromosome 18p breakpoint was localized between the markers WI-9619 and D18S1150, which is less than 10 cM to the centromere. The 18q breakpoint was localized between the centromere and BAC clone 666n19, which is a region of less than 40 kb. These data suggest that the r(18) mostly originated from 18p, with an estimated size of less than 10 cM. These studies identify and characterize a new marker chromosome 18, provide insights into the understanding of the relationships between the clinical phenotypes and marker chromosomes, and establish a framework for finding a potential vascular and/or overgrowth gene located on chromosome 18.

Publication Types:

Case Reports

PMID: 15225160

[PubMed - indexed for MEDLINE]


Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome.

Abstract - Nature. 2004 Feb 12;427(6975):592-4.

Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, Chen Q, Szafranski P, Rao S, Wu L, Housman DE, DiCorleto PE, Driscoll DJ, Borrow J, Wang Q.

Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA.

Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.PMID: 14961121

[PubMed - indexed for MEDLINE]


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