•
Publication Date: 2015
Publication Name: Orphanet Journal of Rare Diseases
•
Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13more
by M. Vikkula
Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and... more
Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis rather than a disorder of matrix structure. Consequently, identification of the OPS gene and its protein product could provide insights regarding common osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds. Studies in 10 additional families narrowed the candidate region, supported locus homogeneity, and did not detect founder effects. The OP...
Publication Date: 1996
Publication Name: American journal of human genetics
Research Interests:
•
Vascular anomalies are localized defects of vascular development. Most of them occur sporadically (ie, there is no familial history of lesions, yet in a few cases clear inheritance is observed). These inherited forms are often... more
Vascular anomalies are localized defects of vascular development. Most of them occur sporadically (ie, there is no familial history of lesions, yet in a few cases clear inheritance is observed). These inherited forms are often characterized by multifocal lesions that are mainly small in size and increase in number with patients' age. The authors review the known (genetic) causes of vascular anomalies and call attention to the concept of Knudson's double-hit mechanism to explain incomplete penetrance and large clinical variation in expressivity observed in inherited vascular anomalies. The authors also discuss the identified pathophysiological pathways involved in vascular anomalies and how it has opened the doors toward a more refined classification of vascular anomalies and the development of animal models that can be tested for specific molecular therapies.
Publication Date: 2011
Publication Name: Clinics in plastic surgery
Research Interests:
•
Publication Date: 2006
Publication Name: Seminars in Plastic Surgery
Research Interests:
•
Vascular anomalies are developmental defects of the vasculature and encompass a variety of disorders. The majority of these occur sporadically, yet a few are reported to be familial. The identification of genes mutated in the different... more
Vascular anomalies are developmental defects of the vasculature and encompass a variety of disorders. The majority of these occur sporadically, yet a few are reported to be familial. The identification of genes mutated in the different malformations provides insight into their etiopathogenic mechanisms and the specific roles the associated proteins play in vascular development and maintenance. It is becoming evident that somatic mosaicism plays a major role in the formation of vascular lesions. The importance of utilizing Next-Generating Sequencing (NGS) for high-throughput and "deep" screening of both blood and lesional DNA and RNA is thus emphasized, as the somatic changes are present in low quantities. There are several examples where NGS has already accomplished discovering these changes. The identification of all the causative genes and unraveling of a holistic overview of the pathogenic mechanisms should enable generation of in vitro and in vivo models and lead to development of more effective treatments, not only targeted on symptoms.
Publication Date: 2014
Publication Name: Seminars in Pediatric Surgery
Research Interests:
•
•
Publication Date: 2008
Publication Name: Nature Genetics
Research Interests:
•
Publication Date: 2006
Publication Name: Vascular Pharmacology
Research Interests:
•
Publication Date: 1998
Publication Name: Trends in Cardiovascular Medicine
•
Publication Date: 2011
Publication Name: Nature Genetics
Research Interests:
•
Vascular malformations are localized errors of angiogenic development. Most are cutaneous and are called vascular 'birthmarks'. These anomalies are usually obvious in the newborn, grow commensurately with the child, and... more
Vascular malformations are localized errors of angiogenic development. Most are cutaneous and are called vascular 'birthmarks'. These anomalies are usually obvious in the newborn, grow commensurately with the child, and gradually expand in adulthood (Mulliken and Glowacki, 1982). Vascular malformations also occur in visceral organs, such as the respiratory and gastrointestinal tract, but are more common in the brain (Mulliken and Young, 1988). These anomalies are composed of tortuous vascular channels of varying size and shape, lined by a continuous endothelium and surrounded by abnormal complement of mural cells. Vascular malformation can be life threatening due to obstruction, bleeding or congestive heart failure. Most anomalies occur sporadically, but there are families exhibiting autosomal dominant inheritance. Genetic studies of such families have resulted in the identification of mutated genes, directly giving proof of their important role in the regulation of angiogenesis.
Publication Date: 2001
Publication Name: Matrix Biology
Research Interests:
•
To investigate the genetic causes of idiopathic sporadic prenatal generalized edema. In a series of 12 patients, in whom in utero generalized skin edema or hydrops fetalis had been diagnosed, we screened 3 lymphangiogenic genes, VEGFR3,... more
To investigate the genetic causes of idiopathic sporadic prenatal generalized edema. In a series of 12 patients, in whom in utero generalized skin edema or hydrops fetalis had been diagnosed, we screened 3 lymphangiogenic genes, VEGFR3, FOXC2, and SOX18. In 3 of the patients, we identified a mutation: 2 in VEGFR3 and 1 in FOXC2. Two of the mutations were de novo and one was either de novo or nonpenetrant inherited. In these patients, the generalized edema resorbed spontaneously, either in utero or after birth. In the 2 individuals with a VEGFR3 mutation, edema remained limited to lower limbs. Mutations in the VEGFR3 and FOXC2 genes account for a subset of patients with unexplained in utero generalized subcutaneous edema and hydrops fetalis without family history of lymphedema. Lymphangiogenic genes should be screened for mutations in sporadic patients diagnosed with fetal edema.
Publication Date: 2009
Publication Name: The Journal of Pediatrics
Research Interests:
•
Publication Date: 2011
Publication Name: Journal of Investigative Dermatology
Research Interests:
•
Publication Date: 2009
Publication Name: Journal of Craniofacial Surgery
Research Interests:
•
Publication Date: 2008
Publication Name: Human Mutation
Research Interests:
•
Publication Date: 2009
Publication Name: Human Molecular Genetics
Research Interests:
•
by Laurence Boon and M. Vikkula
Venous malformation is the most common type of vascular anomaly. Depending upon size and location, these slow-flow anomalies may cause pain, anatomic distortion, or threaten life. Most venous malformations occur sporadically and present... more
Venous malformation is the most common type of vascular anomaly. Depending upon size and location, these slow-flow anomalies may cause pain, anatomic distortion, or threaten life. Most venous malformations occur sporadically and present as solitary lesions. They also occur in several syndromes, some of which demonstrate Mendelian inheritance. We have mapped the locus for an autosomal dominant disorder in a three generation family that manifests as multiple cutaneous and mucosal venous malformations. This locus lies within a 24 cM interval on chromosome 9p, defined by the markers D9S157 and D9S163. The alpha and beta interferon gene cluster and the putative tumor suppressor genes MTS1 and MTS2 are also in this region. Characterization of the gene responsible for this disorder should yield insights into the precise pathogenic mechanisms for venous malformations.
Publication Date: 1994
Publication Name: Human Molecular Genetics
Research Interests:
•
Publication Date: 2008
Publication Name: Human Molecular Genetics
Research Interests:
•
Publication Date: 2003
Publication Name: Head & Neck
Research Interests:
•
Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in... more
Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.
Publication Date: 2010
Publication Name: European Journal of Human Genetics
Research Interests:
•
Publication Date: 2002
Publication Name: European Journal of Human Genetics
Research Interests:
•
Publication Date: 2005
Publication Name: Current Opinion in Genetics & Development
Research Interests:
•
Publication Date: 2006
Publication Name: Clinical Genetics
Research Interests:
•
Publication Date: 1996
Publication Name: Cell
Research Interests: Signal Transduction, Biological Sciences, Humans, Smooth muscle, Sequence alignment, and 15 moreHaplotypes, Female, Cell, Male, Vascular endothelium, Phosphorylation, Proteins, Pedigree, Veins, Endothelial cell, Protein Expression, Amino Acid Sequence, Recombinant Proteins, Ligands, and Receptor Tyrosine Kinase
•
Publication Date: 2001
Publication Name: Cell
Research Interests: Bone Morphogenetic Proteins, Signal Transduction, Biological Sciences, Cercopithecus aethiops, Osteoporosis, and 25 moreHumans, Child, Mice, Wnt Signaling, Female, Animals, Skull, Cell, Male, Bone Density, Proteins, Risk factors, Lipoprotein(a), Eye, Adult, Stromal Cells, Transforming Growth Factor Beta, Risk Factors, Transfection, Species Specificity, Osteoblasts, Autosomal Recessive, Recombinant Proteins, Syndrome, and Lipoprotein a
•
Publication Date: 2004
Publication Name: Cardiovascular Pathology
Research Interests:
•
Publication Date: 2004
Publication Name: Archives of Dermatology
Research Interests:
•
Publication Date: 2008
Publication Name: Archives of Dermatology
Research Interests:
•
To evaluate if elevated D-dimer level is specific for venous malformations (VMs) and thus useful for differential diagnosis, which can be problematic even in specialized interdisciplinary centers. Localized intravascular coagulopathy,... more
To evaluate if elevated D-dimer level is specific for venous malformations (VMs) and thus useful for differential diagnosis, which can be problematic even in specialized interdisciplinary centers. Localized intravascular coagulopathy, characterized by elevated D-dimer levels, has been observed in approximately 40% of patients with VMs. Prospective convenience sample accrued from 2 interdisciplinary sites. Two interdisciplinary centers for vascular anomalies in Brussels, Belgium, and Caen, France The study population comprised 280 patients with clinical data, Doppler ultrasonograms (for 251 patients), and coagulation parameter measurements. Main Outcome Measure Measurement of D-dimer levels. A VM was diagnosed in 195 of 280 patients (69.6%), and 83 of them had elevated D-dimer levels; the sensitivity of D-dimer dosage was 42.6% (95% confidence interval, 35.6%-49.5%). Among the 85 patients without VM, D-dimer levels were elevated only in 3 patients; the specificity of the dosage was 96.5% (95% confidence interval, 92.5%-100%). Elevated D-dimer level is highly specific for VMs (pure, combined, or syndromic), and therefore this easy and inexpensive biomarker test should become part of the clinical evaluation of vascular anomalies. It can detect hidden VMs and help differentiate glomuvenous malformation (normal D-dimer levels) from other multifocal venous lesions. Elevated D-dimer level also differentiates a VM from a lymphatic malformation. Moreover, slow-flow Klippel-Trenaunay syndrome (capillaro-lymphatico-venous malformation with limb hypertrophy) can be distinguished from fast-flow Parkes Weber syndrome (capillary malformation with underlying multiple microfistulas and limb hypertrophy). For these reasons, D-dimer level measurement is a useful complementary tool for diagnosing vascular anomalies in everyday practice.
Publication Date: 2009
Publication Name: Archives of Dermatology
Research Interests: Dermatology, Risk assessment, Adolescent, France, Probability, and 21 moreBelgium, Prospective studies, Humans, Capillaries, Female, Male, Confidence intervals, Young Adult, Follow-up studies, Differential Diagnosis, Clinical Sciences, Veins, Adult, Arteriovenous Malformations, Sex Factors, Analysis of Variance, Age Factors, Biological markers, Internal medicine Doppler ultrasonography, Risk Assessment, and Lymphatic Diseases
•
Microcephaly, intellectual impairment, bilateral vesicoureteral reflux, distichiasis, and glomuvenous malformations associated with a 16q24.3 contiguous gene deletion and a Glomulin mutationmore
by M. Vikkula
Publication Date: 2012
Publication Name: American Journal of Medical Genetics Part A
Research Interests:
•
Publication Date: 2003
Publication Name: The American Journal of Human Genetics
Research Interests:
•
Publication Date: 2002
Publication Name: The American Journal of Human Genetics
Research Interests:
•
Publication Date: 1999
Publication Name: The American Journal of Human Genetics
Research Interests:
•
Objectives:Todevelopclinicalcriteriathatpermitclini- cal distinction between inherited glomuvenous malfor- mation (GVM), known as glomangioma, and inherited cutaneomucosal venous malformation and to test these criteria on sporadic... more
Objectives:Todevelopclinicalcriteriathatpermitclini- cal distinction between inherited glomuvenous malfor- mation (GVM), known as glomangioma, and inherited cutaneomucosal venous malformation and to test these criteria on sporadic lesions. Design:Clinicaldatawerecompiledfor1685patientswith inherited or sporadic cutaneous venous anomalies. Based on a cohort of patients with a mutation in theTIE2 or glo- mulin gene or a histologic diagnosis, we defined clinical criteriaforinheritedGVMandcutaneomucosalvenousmal- formation.Wethenappliedthesecriteriatosporadiccases in a blinded manner