A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling.

Keywords:
Anomaly, Gene, Glomulin, Glomuvenous malformation, Vascular
1.
Al Dhaybi R, Powell J, McCuaig C, Kokta V: Differentiation of vascular tumors from vascular malformations by expression of Wilms tumor 1 gene: evaluation of 126 cases. J Am Acad Dermatol 63:1052-1057 (2010).
2.
Amyere M, Aerts V, Brouillard P, McIntyre BAS, Duhoux FP, et al: Somatic Uniparental Isodisomy: an Explanation for Multifocality of Glomuvenous Malformations. Am J Hum Genet 92:188-196 (2013).
3.
Blume-Peytavi U, Adler YD, Geilen CC, Ahmad W, Christiano A, et al: Multiple familial cutaneous glomangioma: a pedigree of 4 generations and critical analysis of histologic and genetic differences of glomus tumors. J Am Acad Dermatol 42:633-639 (2000).
4.
Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, et al: A gene for inherited cutaneous venous anomalies (‘glomangiomas') localizes to chromosome 1p21-22. Am J Hum Genet 65:125-133 (1999).
5.
Boon LM, Mulliken JB, Enjolras O, Vikkula M: Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol 140:971-976 (2004).
6.
Borroni RG, Narula N, Diegoli M, Grasso M, Concardi M, et al: A novel mutation of the glomulin gene in an Italian family with autosomal dominant cutaneous glomuvenous malformations. Exp Dermatol 20:1032-1034 (2011).
7.
Brauer JA, Anolik R, Tzu J, Meehan S, Lieber CD, Geronemus RG: Glomuvenous malformations (familial generalized multiple glomangiomas). Dermatol Online J 17:9 (2011).
8.
Brouillard P, Vikkula M: Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340-351 (2003).
9.
Brouillard P, Olsen BR, Vikkula M: High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics 67:96-101 (2000).
10.
Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibé M, et al: Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘glomangiomas'). Am J Hum Genet 70:866-874 (2002).
11.
Brouillard P, Ghassibé M, Penington A, Boon LM, Dompmartin A, et al: Four common glomulin mutations cause two thirds of glomuvenous malformations (‘familial glomangiomas'): evidence for a founder effect. J Med Genet 42:e13 (2005).
12.
Brouillard P, Enjolras O, Boon LM, Vikkula M: Glomulin and glomuvenous malformation, in Epstein CJ, Erickson RP and Wynshaw-Boris A (eds): Inborn Errors of Development, ed 2 (Oxford University Press, New York 2008).
13.
Butler MG, Dagenais SL, Garcia-Perez JL, Brouillard P, Vikkula M, et al: Microcephaly, intellectual impairment, bilateral vesicoureteral reflux, distichiasis, and glomuvenous malformations associated with a 16q24.3 contiguous gene deletion and a Glomulin mutation. Am J Med Genet A 158A:839-849 (2012).
14.
Chen AY, Eide M, Shwayder T: Glomuvenous malformation in a boy with transposition of the great vessels: a case report and review of literature. Pediatr Dermatol 26:70-74 (2009).
15.
Dompmartin A, Ballieux F, Thibon P, Lequerrec A, Hermans C, et al: Elevated D-dimer level in the differential diagnosis of venous malformations. Arch Dermatol 145:1239-1244 (2009).
16.
Dompmartin A, Vikkula M, Boon LM: Venous malformation: update on aetiopathogenesis, diagnosis and management. Phlebology 25:224-235 (2010).
17.
Goodman TF, Abele DC: Multiple glomus tumors. A clinical and electron microscopic study. Arch Dermatol 103:11-23 (1971).
18.
Gorlin RJ, Fusaro RM, Benton JW: Multiple glomus tumor of the pseudocavernous hemangioma type. Arch Dermatol 82:776-778 (1960).
19.
Goujon E, Cordoro KM, Barat M, Rousseau T, Brouillard P, et al: Congenital plaque-type glomuvenous malformations associated with fetal pleural effusion and ascites. Pediatr Dermatol 28:528-531 (2011).
20.
Henning JS, Kovich OI, Schaffer JV: Glomuvenous malformations. Dermatol Online J 13:17 (2007).
21.
Hill S, Rademaker M: A collection of rare anomalies: multiple digital glomuvenous malformations, epidermal naevus, temporal alopecia, heterochromia and abdominal lipoblastoma. Clin Exp Dermatol 34:e862-864 (2009).
22.
Hoekzema R, Zonneveld IM, van der Wal AC: Type 2 segmental glomangiomas. Dermatol Online J 16:8 (2010).
23.
Irrthum A, Brouillard P, Enjolras O, Gibbs NF, Eichenfield LF, et al: Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC. Eur J Hum Genet 9:34-38. (2001).
24.
Laymon CW, Peterson WC Jr: Glomangioma (glomus tumor). A clinicopathologic study with special reference to multiple lesions appearing during pregnancy. Arch Dermatol 92:509-514 (1965).
25.
Mallory SB, Enjolras O, Boon LM, Rogers E, Berk DR, et al: Congenital plaque-type glomuvenous malformations presenting in childhood. Arch Dermatol 142:892-896 (2006).
26.
Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69:412-422 (1982).
27.
O'Hagan AH, Maloney FJ, Buckley C, Bingham EA, Walsh MY, et al: Mutation analysis in Irish families with glomuvenous malformations. Br J Dermatol 154:450-452 (2006).
28.
Ostberg A, Moreno G, Su T, Trisnowati N, Marchuk D, Murrell DF: Genetic analysis of a family with hereditary glomuvenous malformations. Australas J Dermatol 48:170-173 (2007).
29.
Soblet J, Limaye N, Uebelhoer M, Boon LM, Vikkula M: Variable somatic TIE2 mutations in half or sporadic venous malformations. Mol Sydromol, DOI: 10.1159/000348327 (2013).
30.
Tejedor M, Martin-Santiago A, Gomez C, Fiol M, Benitez-Segura I: Congenital plaque-type glomuvenous malformation associated with chylous ascites. Pediatr Dermatol 27:673-675 (2010).
31.
Torchia D, Palleschi GM, Urso C: Unilateral glomuvenous malformations. J Eur Acad Dermatol Venereol 21:552-553 (2007).
32.
Vercellino N, Nozza P, Oddone M, Bava GL: Large plaque-like glomuvenous malformation (glomangioma) simulating venous malformation. Clin Exp Dermatol 31:538-541 (2006).
33.
Yoruk O, Ucuncu H, Aktan B, Calik M, Kilic K: Glomuvenous malformations in the buccal area. J Craniofac Surg 21:2001-2003 (2010).
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2013
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