Glomuvenous malformation (GVM)

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Glomuvenous malformation (GVM)

Identity

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".

Other names venous malformation with glomus cells (VMGLOM)
glomangioma
multiple glomus tumor
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.

Clinics

Phenotype and clinics There is a wide phenotypic variation between GVM patients, even within the same family (with the same germline mutation). An individual can have an extensive lesion, affecting for example a whole extremity or most of the trunk, while others have minor, scattered papulonodular lesions of a few millimetres in diameter. The lesions are often multiple, and they can affect any body part.
Seven features characterize GVM lesions :
(1) Colour: GVMs can be pink in infants, the most are bluish-purple
(2) Affected tissues: the lesions are localized to the skin and subcutis, and they are rarely mucosal and never extend deeply into muscles
(3) Localization: lesions are more often located on the extremities, although they can be found all over the body
(4) Appearance : lesions are usually nodular and multifocal, raised with a cobblestone-like appearance, except for the rare plaque-like variant. They are often hyperkeratotic
(5) The lesions are not compressible
(6) The lesions are painful on palpation
(7) New lesions can appear with time, likely after trauma
At the histological level, the mural glomus cells are positive for smooth muscle alpha-actin and vimentin, but negative for desmin, Von Willebrand factor and S-100. Under electron microscopy, glomus cells show smooth muscle myofibrils and "dense bodies", characteristics of vascular smooth muscle cells (vSMCs). Thus, these cells are most likely incompletely or improperly differentiated vSMCs.

Examples of GVMs: (A) Extended GVM on leg. (B) Small GVM on knee.

Neoplastic risk GVM has no neoplastic histological characteristics and never becomes malignant.

Treatment The gold-standard treatment for GVM consists of surgical resection, as lesions are superficial and rarely affect deeply the underlying muscle, and sometimes sclerotherapy. In contrast to venous malformations, the use of elastic compressive garments often aggravate pain and should thus be avoided.

Evolution GVM is a developmental lesion that grows proportionally with the child. After partial resection, recurrence is frequent. New small lesions can appear with time. The red plaque-like lesions of the young darken with age.

Cytogenetics

Note No cytogenetic abnormally has been reported for GVM

Genes involved and Proteins

Gene Name Glomulin

Location 1p22.1

DNA/RNA
Description The glomulin gene spans about 55 kbp and contains 19 exons coding for 1785 bp.

Protein
Note Glomulin was identified by reverse genetics, and its function is currently unknown.

Description Glomulin gene encodes a protein of 594 amino acids (68 kDa).

Expression The high level of glomulin expression in the murine vasculature indicates that glomulin may have an important role in blood vessel development and/or maintenance.

Localisation Glomulin is likely an intracellular protein.

Function The exact function of glomulin is unknown.
Glomulin has been described to interact with FKBP12, an immunophilin that binds the immunosuppressive drugs FK506 and rapamycin. FKBP12 interacts with the TGFbeta type I receptor, and prevents its phosphorylation. Thus, FKBP12 safeguards against the ligand-independent activation of this pathway. Glomulin, through its interaction with FKBP12, could act as a repressor of this inhibition.
Glomulin has also been described to interact with c-MET. Glomulin interacts with the inactive, non phosphorylated form of c-MET. When c-MET is activated by HGF, glomulin is released in a phosphorylated form. This leads to p70 S6 protein kinase (p70S6K) phosphorylation. It is not known whether glomulin activates p70S6K directly or indirectly. The p70S6K is a key regulator of protein synthesis. Glomulin could thereby control cellular events such as migration and cell division.
The third reported glomulin partner is Cul7. This places glomulin in an SCF-like complex, which is implicated in protein ubiquitination and degradation.

Mutations
Note There is no phenotype-genotype correlation in GVM.

Schematic representation of glomulin : The two stars indicate the start and the stop codons, in exon 2 and 19 respectively. All known mutations are shown. Somatic second hit is in blue.

Germinal To date, 29 different inherited mutations (deletions, insertions and nonsense substitutions) have been identified. The most 5' mutation are located in the first coding exon. The majority of them cause premature truncation of the protein and likely result in loss-of-function. One mutation deletes 3 nucleotides resulting in the deletion of an asparagine at position 394 of the protein.
More than 70% of GVMs are caused by eight different mutations in glomulin: 157delAAGAA (40,7%), 108C to A (9,3%), 1179delCAA (8,1%), 421insT and 738insT (4,65% each), 554delA+556delCCT (3,5%), 107insG and IVS5-1(G to A) (2,3% each).

Somatic The phenotypic variability observed in GVM could be explained by the need of a somatic second-hit mutation. Such a mechanism was discovered in one GVM (somatic mutation 980delCAGAA), suggesting that the lesion is due to a complete localized loss-of-function of glomulin. This concept can explain why some patients have bigger lesions than others, why new lesions appear, and why they are multifocal. This could also explain, why some mutation carriers are unaffected.

Bibliography

Multiple glomus tumors. A clinical and electron microscopic study.

Goodman TF, Abele DC

Archives of dermatology. 1971 ; 103 (1) : 11-23.

PMID 4321799

FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin.

Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski K, Baulieu EE

The Journal of biological chemistry. 1996 ; 271 (51) : 32923-32929.

PMID 8955134

Mechanism of TGFbeta receptor inhibition by FKBP12.

Chen YG, Liu F, Massague J

The EMBO journal. 1997 ; 16 (13) : 3866-3876.

PMID 9233797

A gene for inherited cutaneous venous anomalies (glomangiomas) localizes to chromosome 1p21-22.

Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, Rudolph R, Mulliken JB, Olsen BR, Vikkula M

American journal of human genetics. 1999 ; 65 (1) : 125-133.

PMID 10364524

High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22.

Brouillard P, Olsen BR, Vikkula M

Genomics. 2000 ; 67 (1) : 96-101.

PMID 10945476

Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor.

Grisendi S, Chambraud B, Gout I, Comoglio PM, Crepaldi T

The Journal of biological chemistry. 2001 ; 276 (49) : 46632-46638.

PMID 11571281

Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC.

Irrthum A, Brouillard P, Enjolras O, Gibbs NF, Eichenfield LF, Olsen BR, Mulliken JB, Boon LM, Vikkula M

European journal of human genetics : EJHG. 2001 ; 9 (1) : 34-38.

PMID 11175297

Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (glomangiomas).

Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibˆ© M, Warman ML, Tan OT, Olsen BR, Vikkula M

American journal of human genetics. 2002 ; 70 (4) : 866-874.

PMID 11845407

Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis.

Arai T, Kasper JS, Skaar JR, Ali SH, Takahashi C, DeCaprio JA

Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (17) : 9855-9860.

PMID 12904573

Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities.

Boon LM, Mulliken JB, Enjolras O, Vikkula M

Archives of dermatology. 2004 ; 140 (8) : 971-976.

PMID 15313813

Glomulin is predominantly expressed in vascular smooth muscle cells in the embryonic and adult mouse.

McIntyre BA, Brouillard P, Aerts V, Gutierrez-Roelens I, Vikkula M

Gene expression patterns : GEP. 2004 ; 4 (3) : 351-358.

PMID 15053987

Four common glomulin mutations cause two thirds of glomuvenous malformations (familial glomangiomas): evidence for a founder effect.

Brouillard P, Ghassibˆ© M, Penington A, Boon LM, Dompmartin A, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed S, Boralevi F, TaˆØeb A, Danda S, Baselga E, Enjolras O, Mulliken JB, Vikkula M

Journal of medical genetics. 2005 ; 42 (2) : page e13.

PMID 15689436

[Medical and surgical treatment of venous malformations]

Boon LM, Vanwijck R

Annales de chirurgie plastique et esthetique. 2006 ; 51 (4-5) : 403-411.

PMID 17005307

Congenital plaque-type glomuvenous malformations presenting in childhood.

Mallory SB, Enjolras O, Boon LM, Rogers E, Berk DR, Blei F, Baselga E, Ros AM, Vikkula M

Archives of dermatology. 2006 ; 142 (7) : 892-896.

PMID 16847206

GLMN and Glomuvenous Malformation.

Brouillard P, Enjolras O, Boon LM, Vikkula M

Inborn Errors of Development 2e, edited by Charles Epstein, Robert Erickson and Anthony Wynshaw..

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Contributor(s)

Written 07-2007 Virginie Aerts, Pascal Brouillard, Laurence M. Boon, Miikka Vikkula

Human Molecular Genetics (GEHU) de Duve Institute, Universite catholique de Louvain, Avenue Hippocrate 74(+5), bp. 75.39, B-1200 Brussels, Belgium

Citation

This paper should be referenced as such :
Aerts V, Brouillard P, Boon LM, Vikkula M . Glomuvenous malformation (GVM). Atlas Genet Cytogenet Oncol Haematol. July 2007 .
URL : http://AtlasGeneticsOncology.org/Kprones/GlomuvenousID10120.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon May 12 18:13:47 2008

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For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

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".
Other names	venous malformation with glomus cells (VMGLOM)
	glomangioma
	multiple glomus tumor
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.

Phenotype and clinics	There is a wide phenotypic variation between GVM patients, even within the same family (with the same germline mutation). An individual can have an extensive lesion, affecting for example a whole extremity or most of the trunk, while others have minor, scattered papulonodular lesions of a few millimetres in diameter. The lesions are often multiple, and they can affect any body part. Seven features characterize GVM lesions : (1) Colour: GVMs can be pink in infants, the most are bluish-purple (2) Affected tissues: the lesions are localized to the skin and subcutis, and they are rarely mucosal and never extend deeply into muscles (3) Localization: lesions are more often located on the extremities, although they can be found all over the body (4) Appearance : lesions are usually nodular and multifocal, raised with a cobblestone-like appearance, except for the rare plaque-like variant. They are often hyperkeratotic (5) The lesions are not compressible (6) The lesions are painful on palpation (7) New lesions can appear with time, likely after trauma At the histological level, the mural glomus cells are positive for smooth muscle alpha-actin and vimentin, but negative for desmin, Von Willebrand factor and S-100. Under electron microscopy, glomus cells show smooth muscle myofibrils and "dense bodies", characteristics of vascular smooth muscle cells (vSMCs). Thus, these cells are most likely incompletely or improperly differentiated vSMCs.


	Examples of GVMs: (A) Extended GVM on leg. (B) Small GVM on knee.

Neoplastic risk	GVM has no neoplastic histological characteristics and never becomes malignant.
Treatment	The gold-standard treatment for GVM consists of surgical resection, as lesions are superficial and rarely affect deeply the underlying muscle, and sometimes sclerotherapy. In contrast to venous malformations, the use of elastic compressive garments often aggravate pain and should thus be avoided.
Evolution	GVM is a developmental lesion that grows proportionally with the child. After partial resection, recurrence is frequent. New small lesions can appear with time. The red plaque-like lesions of the young darken with age.

DNA/RNA
Description	The glomulin gene spans about 55 kbp and contains 19 exons coding for 1785 bp.

Protein
Note	Glomulin was identified by reverse genetics, and its function is currently unknown.
Description	Glomulin gene encodes a protein of 594 amino acids (68 kDa).
Expression	The high level of glomulin expression in the murine vasculature indicates that glomulin may have an important role in blood vessel development and/or maintenance.
Localisation	Glomulin is likely an intracellular protein.
Function	The exact function of glomulin is unknown. Glomulin has been described to interact with FKBP12, an immunophilin that binds the immunosuppressive drugs FK506 and rapamycin. FKBP12 interacts with the TGFbeta type I receptor, and prevents its phosphorylation. Thus, FKBP12 safeguards against the ligand-independent activation of this pathway. Glomulin, through its interaction with FKBP12, could act as a repressor of this inhibition. Glomulin has also been described to interact with c-MET. Glomulin interacts with the inactive, non phosphorylated form of c-MET. When c-MET is activated by HGF, glomulin is released in a phosphorylated form. This leads to p70 S6 protein kinase (p70S6K) phosphorylation. It is not known whether glomulin activates p70S6K directly or indirectly. The p70S6K is a key regulator of protein synthesis. Glomulin could thereby control cellular events such as migration and cell division. The third reported glomulin partner is Cul7. This places glomulin in an SCF-like complex, which is implicated in protein ubiquitination and degradation.

Mutations
Note	There is no phenotype-genotype correlation in GVM.


	Schematic representation of glomulin : The two stars indicate the start and the stop codons, in exon 2 and 19 respectively. All known mutations are shown. Somatic second hit is in blue.

Germinal	To date, 29 different inherited mutations (deletions, insertions and nonsense substitutions) have been identified. The most 5' mutation are located in the first coding exon. The majority of them cause premature truncation of the protein and likely result in loss-of-function. One mutation deletes 3 nucleotides resulting in the deletion of an asparagine at position 394 of the protein. More than 70% of GVMs are caused by eight different mutations in glomulin: 157delAAGAA (40,7%), 108C to A (9,3%), 1179delCAA (8,1%), 421insT and 738insT (4,65% each), 554delA+556delCCT (3,5%), 107insG and IVS5-1(G to A) (2,3% each).
Somatic	The phenotypic variability observed in GVM could be explained by the need of a somatic second-hit mutation. Such a mechanism was discovered in one GVM (somatic mutation 980delCAGAA), suggesting that the lesion is due to a complete localized loss-of-function of glomulin. This concept can explain why some patients have bigger lesions than others, why new lesions appear, and why they are multifocal. This could also explain, why some mutation carriers are unaffected.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	07-2007	Virginie Aerts, Pascal Brouillard, Laurence M. Boon, Miikka Vikkula
		Human Molecular Genetics (GEHU) de Duve Institute, Universite catholique de Louvain, Avenue Hippocrate 74(+5), bp. 75.39, B-1200 Brussels, Belgium