Glomuvenous malformations, also known as 'venous malformations with glomus cells' or glomangiomas, are similar to mucocutaneous venous malformations (VMCM; 600195), but clinically are distinguishable: they have a cobble-stone appearance, they have a consistency harder than that of venous ... Glomuvenous malformations, also known as 'venous malformations with glomus cells' or glomangiomas, are similar to mucocutaneous venous malformations (VMCM; 600195), but clinically are distinguishable: they have a cobble-stone appearance, they have a consistency harder than that of venous malformations, and they are painful on palpation (Brouillard et al., 2002). Histologically, GVMs are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels. The term glomus (Latin for ball) stems from the morphologically similar contractile cells of the Sucquet-Hoyer arteriovenous anastomoses in glomus bodies that are involved in cutaneous thermoregulation. Glomus cells in GVMs appear to be incompletely or improperly differentiated vascular smooth muscle cells, since they stain positively with smooth muscle cell alpha-actin (102620) and vimentin (193060). The genetic distinctness of glomuvenous malformations from mucocutaneous venous malformations is indicated by the fact that mutations have been found in the TIE2/TEK gene (600221) in mucocutaneous venous malformations and not in glomuvenous malformations. Glomus tumors are benign cutaneous neoplasms that are derived from specialized arteriovenous shunts that occur normally in many parts of the body. Gorlin et al. (1960) reported 5 affected members in 2 generations of a family. The lesions tend to resemble cavernous hemangiomas. The distinctive feature is the presence of multiple layers of glomus cells lining the blood-filled cavities. The tumors are present at birth or appear in the first 2 decades. Isolated glomus tumor usually develops later (at about age 33 years on the average), is more frequently subungual than is the case with multiple tumors, and has no particular familial occurrence. Reed (1970) presented a pedigree of 4 persons with multiple glomus tumors in 2 generations. Beasley et al. (1986) reported 4 cases in 3 generations. The 9-year-old proposita had had 6 soft, blue-black skin lesions from birth, on the forearm, thigh, and buttocks. All but one were raised. As pointed out by Boon et al. (1999), glomus tumors, or glomangiomas, are a clinical and radiologic subtype of venous malformations. Their pathognomonic characteristic is the presence of undifferentiated smooth muscle cells (glomus cells) surrounding convoluted venous channels. Although clinically they look like any venous malformation, they are more painful on palpation, only partially compressible, and usually not found in mucosa. In addition, familial aggregation is more common than in venous malformations generally, and several pedigrees showing autosomal dominant inheritance have been reported. Iqbal et al. (1998) estimated that penetrance rises from 70% at age 5 years to 100% by age 30 years.
In various autosomal dominant skin disorders, segmental forms reflecting mosaicism have been reported. Happle (1997) delineated 2 different types of mosaic manifestation. Type 1 reflects heterozygosity for the underlying mutation and shows the same degree of severity as ... In various autosomal dominant skin disorders, segmental forms reflecting mosaicism have been reported. Happle (1997) delineated 2 different types of mosaic manifestation. Type 1 reflects heterozygosity for the underlying mutation and shows the same degree of severity as that observed in the corresponding nonmosaic phenotype. In the case of cutaneous disorders, the skin other than that in the segmental area is normal. Type 2 originates from loss of heterozygosity and shows an excessively severe involvement in a segmental area, usually superimposed on the disseminated lesions of the ordinary trait. Happle and Konig (1999) surveyed the literature on multiple glomus tumors and found 5 cases suggesting a type 2 segmental involvement. In all of these cases, a unilateral band-like or patchy arrangement of excessively pronounced glomus tumors was associated with disseminated lesions corresponding to the ordinary phenotype, and in 3 cases other family members were affected with disseminated glomus tumors. The unilateral agminated (i.e., gathered in clusters) lesions were reported to be present in early childhood, whereas the disseminated lesions appeared later. In connection with the demonstration of mutations in glomulin (601749) as the cause of this disorder, Brouillard et al. (2002) found a somatic 'second hit' mutation in affected tissue of a patient with an inherited genomic deletion. Furthermore, since all but one of the 14 different germline mutations identified in patients with GVMs resulted in premature stop codons, and since the localized nature of the lesions could be explained by the Knudson 2-hit model, GVMs are likely caused by complete loss of function of glomulin.