Glomuvenous Malformations Research Articles

Glomuvenous malformation (GVM)

Other names: Venous malformation with glomus cells (VMGLOM); Glomangioma; Multiple glomus tumor. Note: Glomuvenous malformation (GVM) is a localized bluish-purple cutaneous vascular lesion, histologically consisting of distended venous channels with flattened endothelium surrounded by variable number of maldifferentiated smooth muscle-like “glomus cells” in the wall. GVM account for 5% of venous anomalies referred to centers for vascular anomalies. Previously, these lesions have been called “multiple glomus tumors” or “glomangioma”. Inheritance: GVM is often, if not always, hereditary (64%), and transmitted as an autosomal dominant disorder. Expressivity varies, as does penetrance, which is age dependent and maximal (93%) by 20 years of age.

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Venous malformations are mainly of sporadic origin, but a small proportion, including glomuvenous malformations (OMIM #138000) and cutaneomucosal venous malformations (VMCMs; OMIM #600195), are inherited. VMCMs present as bluish patches mainly at the mucosa, and are caused by dilation of blood vessels. VMCMs have been genetically linked to endothelial-specific receptor tyrosine kinase 2 (TIE2; also known as TEK): several different mutations in this gene have been identified in VMCM patients. In line with the proposed roles of TIE2 in vascular remodeling and maintenance of mammalian vessel integrity, VMCM patients have a relative lack of mural cells in affected regions of the endothelium, and some VMCM patients have ventricular septal defects. Tie-2−/−mice die during embryogenesis mainly owing to heart defects, providing clues about the role of TIE2 in the pathology of VMCM in humans. However, the precise functions of TIE2 in vascular stability and development are still not fully understood.In this study, the authors generate a zebrafish tie-2 loss-of-function mutant and show that, in contrast to the phenotype of Tie-2−/− mice, tie-2 mutant zebrafish are viable and show no defects in embryonic angiogenesis. However, morpholino-mediated knockdown of Tie-1 function in tie-2 zebrafish mutants shows that combined loss of Tie-1 and Tie-2 function results in defects of myocardial-endocardial contact. Given that a role has been proposed for Tie-2 in vascular permeability, the authors also challenge vessel stability in tie-2 mutants by using statins, which have been shown to induce hemorrhages in specific vascular regions of the zebrafish embryo. Surprisingly, tie-2 mutants are resistant to statin-induced bleeding, and further experiments indicate that this effect depends on VE cadherin, an important intercellular junction protein.This work introduces an additional vertebrate model in which to study the function of Tie-2 in vivo. Because Tie-1 and Tie-2 have redundant roles in cardiac development in zebrafish, this model will allow the study of Tie-2 function in vivo without the complication of cardiac defects. Tie-2 is generally considered to be a vascular stabilizing factor, because it recruits support cells to the endothelium; however, the effect of statins in tie-2 mutants observed in this study suggest that the function of Tie-2 and/or its ligands might be more context-dependent than previously appreciated.

Congenital Plaque‐Type Glomuvenous Malformations Associated with Fetal Pleural Effusion and Ascites

Glomuvenous malformations are hereditary vascular anomalies, usually without extracutaneous involvement. We report two cases of extensive thoracic plaque-type glomuvenous malformation in newborns who had previously been diagnosed in utero with pleural effusion and ascites, suggesting a pathogenic link between the two conditions.

Differentiation of vascular tumors from vascular malformations by expression of Wilms tumor 1 gene: Evaluation of 126 cases

Vascular tumors and malformations can be challenging to diagnose. Although they may initially appear very similar, they have distinct clinical courses and management. Wilms tumor 1 (WT1) gene expression has been reported in many different tumors including hematologic malignancies and some solid tumors. We sought to evaluate the expression of WT1 in 126 vascular lesions (64 vascular tumors, one Masson tumor, and 61 vascular malformations). Based on the International Society for the Study of Vascular Anomalies classification of vascular anomalies, we studied the expression of WT1 in vascular tumors composed of infantile hemangioma, congenital hemangiomas (non-involuting, rapidly involuting, and not otherwise specified), pyogenic granuloma, tufted angioma, cherry angioma, Kaposi sarcoma, and angiosarcoma. We also studied WT1 expression in vascular malformations composed of angiokeratoma/verrucous hemangioma, combined vascular malformations, venous malformations, glomuvenous malformations, lymphatic malformations/lymphangioma, telangiectasia, and targetoid hemosiderotic hemangioma. All vascular tumors and proliferations had positive WT1 cytoplasmic endothelial immunostaining whereas only 3 vascular malformations were WT1 positive. Moreover the positivity of WT1 in these vascular malformations was focal and involved only re-endothelialized neovessels within thrombi. The low number of malignant vascular tumors is a limitation. Immunohistochemical detection of WT1 could be a useful tool to routine evaluation of vascular anomalies allowing the distinction of vascular tumors and proliferations from vascular malformations. Staining for WT1 may guide the clinician in difficult cases, as positive results would suggest a proliferative vascular lesion whereas negative results might point to a vascular malformation.

Glomuvenous Malformations in the Buccal Area

Glomuvenous malformations (GVMs) are relatively rare lesions in the head and neck area. A 30-year-old woman presented to our clinic with a large mass on the right buccal area with tenderness and hypersensitivity to palpation. The lesion was excised totally under general anesthesia. Microscopic evaluation and immunostaining method confirmed the diagnosis of GVM. We concluded that a solitary form of GVMs as a large mass on the buccal region could occur, and a mass with tenderness and hypersensitivity on palpation could be significant in its differential diagnosis.

Congenital Plaque-Type Glomuvenous Malformation Associated with Chylous Ascites

Congenital plaque-type glomuvenous malformation (GVM) is caused by loss of function mutations in glomulin gene. We report a newborn with this rare vascular disorder associated with chylous ascites. The common mesenchymal origin of GVM and lymphatic vessels as well as the glomulin expression in vascular smooth muscle cells in utero could help explain this unusual prenatal complication of glomuvenous malformations.

Venous malformation: update on aetiopathogenesis, diagnosis and management.

The aim of this review was to discuss the current knowledge on aetiopathogenesis, diagnosis and therapeutic management of venous malformations (VMs). VMs are slow-flow vascular anomalies. They are simple, sporadic or familial (cutaneomucosal VMs or glomuvenous malformations), combined (e.g. capillaro-venous and capillaro-lymphaticovenous malformations) or syndromic (Klippel-Trenaunay, blue rubber bleb naevus and Maffucci). Genetic studies have identified causes of familial forms and of 40% of sporadic VMs. Another diagnostic advancement is the identification of elevated D-dimer level as the first biomarker of VMs within vascular anomalies. Those associated with pain are often responsive to low-molecular-weight heparin, which should also be used to avoid disseminated intravascular coagulopathy secondary to intervention, especially if fibrinogen level is low. Finally, development of a modified sclerosing agent, ethylcellulose-ethanol, has improved therapy. It is efficient and safe, and widens indications for sclerotherapy to sensitive and dangerous areas such as hands, feet and periocular area.

Type 2 segmental glomangiomas

Glomangiomas of the skin, currently named glomuvenous malformations (GVMs), are benign vascular lesions composed of thin-walled distorted blood vessels, surrounded by variable rows of glomus cells. These cells resemble the modified smooth muscle cells of the normal glomus body. Glomuvenous malformations occur after both alleles of the gene encoding for glomulin, a molecule involved in smooth muscle cell differentiation, are hit by a loss-of-function mutation. Multiple GVMs are rare and often congenital, but they may also appear later in life. In this report we describe a 39-year-old man who developed unilateral segmental GVMs on his trunk in early childhood, with the histological features of glomangiomas. As several satellite lesions emerged at distant skin sites later in life, our case probably represents type 2 segmental GVMs, caused by localized loss of heterozygosity in an individual carrying a heterozygous germline mutation in the glomulin gene.

A collection of rare anomalies: multiple digital glomuvenous malformations, epidermal naevus, temporal alopecia, heterochromia and abdominal lipoblastoma

Glomuvenous malformations are a subtype of venous malformations, which present in infancy or childhood. We describe a teenage girl who presented with multiple digital glomuvenous malformations from birth. In addition, she had an epidermal naevus on the upper lip, an area of congenital alopecia of the scalp, heterochromia irides and an abdominal lipoblastoma. We are unaware of any reports of the association of multiple glomuvenous malformations with the other uncommon developmental anomalies seen in our patient, and a common link eludes us.

Elevated D-dimer Level in the Differential Diagnosis of Venous Malformations

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.

Glomuvenous Malformation in a Boy with Transposition of the Great Vessels: A Case Report and Review of Literature

We report a case of glomuvenous malformation (GVM) in an 11-year-old boy with a history of transposition of the great vessels. The glomulin gene was discovered in 1999, and multiple mutations have been identified with some of the mutations resulting in GVM. The molecular genetics, clinical presentation, histopathology, differential diagnosis, and management of GVM are reviewed. To our knowledge, no case of glomuvenous malformation in the setting of transposition of the great vessels has ever been reported in the literature.

Vascular anomalies

Vascular anomalies

Genetic analysis of a family with hereditary glomuvenous malformations

Glomuvenous malformations (MIM 138000) are rare vascular malformations consisting of glomus cells, and in affected individuals, lesions may appear in any number anywhere on the body. We analysed the DNA of one family with hereditary glomuvenous malformations and identified the mutation causing the disease in the glomulin gene on chromosome 1 p22. The deletion started at base pair 157: 157delAAGAA, which is a deletion of five base pairs. This mutation has been found in Europe, the USA and Australia, suggesting a founder effect with common ancestry. Thus far, no second-hit mutation for the 157delAAGAA mutation has been identified.

Genetic causes of vascular malformations

Vascular malformations are localized defects of vascular development. They usually affect a limited number of vessels in a restricted area of the body. Although most malformations are sporadic, inheritance is observed, enabling genetic analysis. Usually, sporadic forms present with a single lesion whereas multiple lesions are observed in familial cases. The last decade has seen unraveling of several causative genes and beginning of elucidation of the pathophysiological pathways involved in the inherited forms. In parallel, definition of the clinical phenotypes has improved and disorders such as Parkes-Weber syndrome (PKWS), first thought to be sporadic, is now known to be part of a more common inheritable phenotype. In addition, the concept of double-hit mechanism that we proposed earlier to explain the incomplete penetrance, variable expressivity and multifocality of lesions in inherited venous anomalies is now becoming confirmed, as some somatic mutations have been identified in venous, glomuvenous and cerebral cavernous malformations. It is thus tempting to suggest that familial forms of vascular malformations follow paradominant inheritance and that sporadic forms, the etiopathogenic causes of which are still unelucidated, are caused by somatic mutations in the same genes.

Nd:YAG lasers (1,064 nm) in the treatment of venous malformations of the face and neck: challenges and benefits

Neodymium:yttrium aluminum garnet (Nd:YAG) laser therapy for venous malformations (VMs) of the head and neck is a rather new therapeutical option in addition to sclerotherapy and surgery. One hundred forty-six patients (age 2 months to 77.5 years) with VMs in the head/neck (localized, diffuse, and multifocal) were retrospectively analyzed with regard to number and quality of treatments and laser parameters used. Of these patients, 72 had no prior treatment of any kind, and 74 were pretreated. Laser treatment of mucosa and tongue was done with a mean fluence of 103.1 J/cm(2), of skin with 90.7 J/cm(2), and of glomuvenous malformations with 81.2 J/cm(2). Complex VM can mostly be controlled but rarely cured. Initial Nd:YAG laser therapy is important in the treatment of VMs regarding shrinkage of the tissue, discoloration, and induction of the desired dermal fibrosis that facilitates the surgical handling of the skin and reduces the risk of skin loss in surgery and sclerotherapy.

Glomuvenous malformations

A 9-year-old girl presented with a congenital, blue-purple, partially compressible plaque with a cobblestone surface on the left lateral foot and ankle. Similar, solitary, blue nodules later appeared elsewhere on the extremities. The lesions were tender to palpation and were associated with spontaneous paroxysms of pain and paresthesias. Histopathologic evaluation of a skin biopsy specimen showed rows of glomus cells that surrounded thin-walled vascular channels, which confirmed the diagnosis of glomuvenous malformations. This autosomal dominant condition, which is due to mutations in the GLMN gene, presents with clinical findings that are distinct from those of familial, multiple, cutaneous and mucosal venous malformations. Treatment options include excision, sclerotherapy, and laser therapy (ablative or pulsed dye).

Lack of glomulin, a specific marker of vascular smooth muscle cell differentiation, causes glomuvenous malformations

Lack of glomulin, a specific marker of vascular smooth muscle cell differentiation, causes glomuvenous malformations

Les malformations veineuses : aspects cliniques et diagnostic différentiel

Venous malformations (VM) are localized defects of blood vessels that are due to vascular dysmorphogenesis. These slow-flow lesions can affect any tissue or organ. Clinically, a cutaneous VM is characterized by a bluish mass that is compressible on palpation. Phleboliths are commonly present. Symptoms depend on location and size. VM are often sporadic and isolated, however, they can be associated with other malformations and be part of a syndrome; Klippel-Trenaunay (capillary-lymphatico-venous malformation with limb hypertrophy) is the most common. Glomuvenous malformation (GVM) is another type of venous anomaly. In contrast to VM, GVM is often painful on palpation and not compressible. Clinical diagnosis of VM is often made in the presence of a bluish cutaneous lesion: however, other lesions can mimick VM. The most frequent anomalies are a blue naevus, a hemorrhagic lymphatic malformation, a sub-cutaneous hemangioma or even the presence of dilated superficial normal veins due to underlying venous stenoses. This chapter will detail the clinical characteristics of venous anomalies and their differential diagnosis.

Pathogénie et génétique des anomalies vasculaires

Vascular anomalies, divided into vascular tumors and vascular malformations, are localized defects of angiogenesis. Hemangiomas appear soon after birth, grow quickly, and then spontaneously, but slowly, disappear. In contrast, vascular malformations are congenital defects of vascular development that grow proportionately with the child. Most vascular anomalies are considered non-hereditary. However, due to detailed analysis inherited forms have been observed, which has led to identify mutations in three genes causing familial vascular malformations: in the angiopoietin receptor TIE2 in mucocutaneous venous malformations (VMCM), in glomulin in glomuvenous malformations (GVM) and in RASA1 in the newly recognized phenotype capillary malformation–arteriovenous malformation (CM–AVM). Identification of the causative genes has permitted more precise diagnosis and differential diagnosis, evaluation of phenotypic variability among patients with a proven mutation, study of used treatments in more homogeneous patient groups, and elucidation of the etiopathogenic mechanisms behind vascular malformations. Further studies are needed to unravel the role of genetic variations in the various vascular malformations and to unravel the precise molecular mechanisms that lead to development of these vascular lesions. This should provide development of new-targeted therapies.

Molecular Basis of Vascular Birthmarks

Vascular anomalies affect up to 10% of newborns, largely because of the high incidence of hemangioma of infancy. Vascular anomalies also frequently occur in adults; there is high prevalence of capillary malformations (0.3%). These cutaneous stains often cause psychosocial problems related to their visibility. Venous malformations occur in the skin and in internal organs and may cause destruction. Primary lymphedema causes lifelong morbidity, and arteriovenous malformations, in addition to causing distortion, obstruction, and pain, can be life endangering. The pathophysiology of these anomalies has stayed largely unknown, but genetic studies have revealed clues to their etiology. Genetic defects cause hereditary types of venous malformation, cutaneous and mucosal (VMCM); glomuvenous malformation (GVM); primary congenital lymphedema (Milroy disease); lymphedema-distichiasis syndrome; hypotrichosis-lymphedema-telangiectasia (HLT) syndrome; hereditary hemorrhagic telangiectasia (HHT); cerebral cavernous malformation (CCM); and a newly recognized disorder, capillary malformation–arteriovenous malfor- mation (CM-AVM). These seminal discoveries have not only permitted a more precise clinical classification and diagnosis (a prerequisite for corrective measures for prevention, treatment, and follow-up) but also pointed the way to the identification of factors that play an important role in vasculogenesis or angiogenesis, or both.