Dermatology Online Journal

Type 2 segmental glomangiomas
Rick Hoekzema^1,2, Ingrid M Zonneveld³, Allard C van der Wal⁴
Dermatology Online Journal 16 (1): 8

1. Department of Dermatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. r.hoekzema@olvg.nl
2. Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
3. Department of Dermatology, Tergooiziekenhuizen, Hilversum, The Netherlands
4. Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

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Abstract

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.

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Case report

An otherwise healthy 39-year-old man presented with multiple skin papules on the right side of his trunk that had been present since early childhood. Later in life, he had developed several lesions with a similar appearance on his left wrist and on both thighs. The lesions were asymptomatic and not painful on palpation. The patient had no family history of such a disorder. Physical examination revealed more than a hundred blue-purple papules and nodules clustered in a linear, band-like pattern on the right side of the trunk at the level of the nipple (Figure 1). On close examination of the rest of the skin, similar nodules were found on his left wrist (Figure 2) and on both thighs.

Figure 1	Figure 2
Figure 1. Unilateral band-like cluster of blue-purple papules and nodules on the trunk Figure 2. Solitary bluish nodule on the left wrist

A typical lesion from the trunk was biopsied and examined histologically after staining with hematoxylin and eosin. It showed dilated, irregular vascular spaces lined by a single layer of flat endothelial cells and one or several rows of round glomus cells, surrounded by adjacent layers of spindle-shaped smooth muscle cells. These are the histological features of glomangioma (Figure 3).

Figure 3	Figure 4
Figure 3. Histology of a typical lesion from the trunk, demonstrating features of glomangioma (H&E, x200) Figure 4. Immunostaining with α-SMA-1 antibody, demonstrating positive staining of glomus cells and adjacent smooth muscle cells in agreement with glomangioma (H&E, x100)

Immunohistochemical analysis for α1-smooth muscle actin (with α-SMA-1 antibody) demonstrated positive staining of glomus cells and surrounding layers of smooth muscle cells, confirming the diagnosis of glomangioma (Figure 4).

Discussion

Cutaneous glomuvenous malformations (GVMs, Online Mendelian Inheritance of Man [OMIM] 138000) are benign vascular lesions that represent a variant of venous vascular malformations [1]. They are composed of mature but morphologically aberrant venous vessels, surrounded by variable numbers of glomus cells. Glomus cells resemble the modified smooth muscle cells of the normal glomus body, a specialized arteriovenous anastomosis with thermoregulatory function. Glomuvenous malformations are caused by mutations in glomulin, a molecule considered important for smooth muscle cell differentiation; induction of these vascular malformations is thought to occur only after both alleles of the gene are hit by a loss-of-function mutation, resulting in complete localized loss of functional glomulin [2, 3, 4]. Depending on the proportion of glomus cells, blood vessels, and smooth muscle tissue, glomangiomas are distinguished from glomangiomyomas. Glomangiomyomas represent the least common form of GVMs, containing conventional spindled smooth muscle cells in gradual transition with typical glomus cells. It has been suggested that glomangioma and glomangiomyoma designate the same lesion, with only subtle quantitative differences regarding the presence of these transitional areas from glomus cells to conventional smooth muscle cells [5].

Since early childhood our patient had a unilateral segmental plaque on the trunk, consisting of multiple agminated papules and nodules with the histological features of GVM, in particular glomangioma. Later in life, he developed disseminated lesions on his left wrist an on both thighs. Several years before the patient consulted us, two larger lesions on his left thigh had been excised in another hospital and were shown to be glomangiomas by histological examination. The combination of a severely affected segmental plaque or patch, present at birth or occurring in early childhood, and milder disseminated lesions developing later in life, is typical for a type 2 segmental manifestation of an autosomal dominant skin disorder, a concept introduced by Rudolph Happle [6, 7, 8, 9]. It is explained by a 'second hit,' occurring in an embryo with a heterozygous germline mutation that results in loss of the remaining 'wild-type' allele (loss of heterozygosity, LOH) [8]. In the case of GVMs, the localized complete loss of glomulin function leads to a pronounced mosaic phenotype that may be present at birth or occur in early childhood, with multiple and/or severe GVMs distributed in a linear, patchy or otherwise circumscribed arrangement. Later in life, these individuals can develop disseminated lesions as a result of localized LOH at distant sites of the skin [9].

In retrospect, the first published case of multiple GVMs with a type 2 segmental manifestation was probably by Berger and Hundeiker in 1967 [10]. Since then, a number of case reports on multiple GVMs have been published that may represent a type 2 segmental manifestation [10-20]. Reported cases from which clinical details could be obtained are summarized in Table 1, including our case.

We classify our patient as having a type 2 segmental manifestation of GVMs with histological features of glomangiomas; we expect him to develop new GVMs at other sites of the skin as a result of localized LOH. Also, we are aware of the risk that he may develop internal GVMs, like the patient reported by Schneller with glomangiomyomas in the chest wall [21]. Attempts were made to treat our patient's GVMs with sclerotherapy, but without success. At the moment, different vascular lasers are being tested for their therapeutic effect.

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