Glomuvenous Malformation

A rare vascular anomaly or angioma characterized by the presence of small, multifocal bluish-purple venous lesions mainly involving the skin.

Epidemiology

Glomuvenous malformations (GVMs) prevalence is unknown; over 200 families or cases have been reported in the literature. It is estimated that GVMs account for 70-80% of inherited venous-type malformations ; the rest being cutaneomucosal venous malformations (VMCMs).

Clinical description

GVMs may be present at birth, and slowly expand during childhood. New small lesions appear with time. They are usually hyperkeratotic, raised and nodular with a cobblestone surface. Color varies from pink to purplish-dark blue. However, in some cases (especially in newborns) the lesions may be flat and purple in color; this plaque-like GVM usually darkens with time. GVMs are often painful on palpation and cannot be completely emptied by compression. They are usually multifocal and are located mainly on the extremities, involving the skin and subcutis. They are rarely encountered in mucosae and intestinal hemorrhage is not a feature of this condition. There is significant clinical variation with respect to the size, location and number of lesions, even between affected individuals from the same family. For example, plaque-like GVM-lesions on the thorax can be associated with pleural effusions. Patients with GVMs have normal mental and physical development.

Etiology

GVMs are caused by mutations in the gene encoding glomulin (GLMN; 1p22.1). Inheritance pattern is autosomal dominant. The inherited mutations cause loss-of-function of glomulin. The lesions develop in areas where a double-hit mutation has occurred, indicating that GVM lesions are due to complete localized loss of glomulin. The most frequent somatic second hit is an acquired uniparental isodisomy, which leads to loss of the normal copy, and duplication of the mutated copy in cells within the lesion.

Diagnostic methods

Diagnosis of GVM is based on clinical evaluation of the cutaneous lesions. Confirmation can be obtained via a blood sample for molecular genetic testing. Doppler ultrasound examination and MRI can be used to confirm the venous component and the common superficial extent of the lesions. Histologically, GVMs are characterized by the presence of abnormal mural cells called "glomus cells'' which help differentiate from common venous malformations and VMCM.

Differential diagnosis

The differential diagnosis should include mucocutaneous venous malformations (VMCMs, which are also commonly seen on mucosal membranes, are lighter purple in color than GMVs, and are compressible and generally not painful on palpation, and caused by inherited TIE2/TEK mutations) and Blue rubber bleb nevus syndrome (characterized by the association of cutaneous and mucosal venous-like lesions with gastrointestinal lesions, and caused by somatic TIE2/TEK mutations).

Antenatal diagnosis

Prenatal diagnosis is feasible for affected families in which the disease-causing mutation has been identified, but is not widely available.

Genetic counseling

GVMs are inherited in an autosomal dominant manner. Genetic counseling should be provided for affected families, informing patients of a 50% risk of inheriting the disease-causing mutation and of the variability in clinical expression.

Management and treatment

The most effective treatment is plastic and reconstructive surgery, used depending on the size and location of the lesions. Laser can be effective, especially for small flat lesions as well as plaque-like lesions. Sclerotherapy may be indicated in some cases: the sclerosing agent such as foam aethoxysclerol is associated with less skin necrosis than ethanol (96%). Another sclerosing agent is ethanol (96%) in the form of a gel for injection, which obtained EU orphan drug designation in April 2005 for the treatment of congenital venous malformations.

Prognosis

The prognosis for patients is good, malignant transformation has not been reported and the life expectancy for patients is not reduced.