Abstract
One in 10 infants are born with a vascular birthmark each year. Some vascular birthmarks,
such as infantile hemangiomas, are common, while vascular malformations, such as capillary,
lymphatic, venous, and arteriovenous malformations, are less so. Diagnosing uncommon
vascular birthmarks can be challenging, given the phenotypic heterogeneity and overlap
among these lesions. Both sporadic and germline variants have been detected in various
genes associated with vascular birthmarks. Identification of these genetic variants
offers insight into both diagnosis and underlying molecular pathways and can be fundamental
in the discovery of novel therapeutic approaches. The PIK3/AKT/mTOR and RAS/MEK/ERK
signaling pathways, which mediate cell growth and angiogenesis, are activated secondary
to genetic variations in vascular malformations. Somatic variants in TEK (TIE2) and PIK3CA cause venous malformations. Variants in PIK3CA also cause lymphatic malformations as well as a number of overgrowth syndromes associated
with vascular anomalies. Variants in GNAQ and GNA11 have been identified in both so-called “congenital” hemangiomas and capillary malformations.
RASA1 and EPHB4 variants are associated with capillary malformation-arteriovenous malformation syndrome.
This review discusses the genetics of vascular birthmarks, including the various phenotypes,
genetic variants, pathogenesis, associated syndromes, and new diagnostic techniques.
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References
- Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics.Plast Reconstr Surg. 1982; 69: 412-422
- Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies.Pediatrics. 2015; 136: e203-e214
- Hemangiomas in children.N Engl J Med. 1999; 341: 173-181
- Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies.Br J Dermatol. 2014; 170: 907-913
- Congenital hemangioma: evidence of accelerated involution.J Pediatr. 1996; 128: 329-335
- Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma.ArchDermatol. 2001; 137: 1607-1620
- Rapidly involuting congenital hemangioma: clinical and histopathologic features.Pediatr Dev Pathol. 2003; 6: 495-510
- Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly.Plast Reconstr Surg. 2001; 107: 1647-1654
- Partially involuting congenital hemangiomas: a report of 8 cases and review of the literature.J Am Acad Dermatol. 2014; 70: 75-79
- Somatic activating mutations in GNAQ and GNA11 are associated with congenital hemangioma.Am J Hum Genet. 2016; 98: 789-795
- Symptomatic congenital hemangioma and congenital hemangiomatosis associated with a somatic activating mutation in GNA11.JAMA Dermatol. 2016; 152: 1015-1020
- De novo MYH9 mutation in congenital scalp hemangioma.Cold Spring Harb Mol Case Stud. 2018; 4a002998
- The incidence of birthmarks in the neonate.Pediatrics. 1976; 58: 218-222
- Facial port-wine stains and Sturge-Weber syndrome.Pediatrics. 1985; 76: 48-51
- New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk.Br J Dermatol. 2014; 171: 861-867
- Sturge-Weber syndrome: from the past to the present.Eur J Paediatr Neurol. 2014; 18: 257-266
- Diffuse capillary malformation with overgrowth: a clinical subtype of vascular anomalies with hypertrophy.J Am Acad Dermatol. 2013; 69: 589-594
- Endothelial cells from capillary malformations are enriched for somatic GNAQ mutations.Plast Reconstr Surg. 2016; 137: 77e-82e
- Novel genetic mutations in a sporadic port-wine stain.JAMA Dermatol. 2014; 150: 1336-1340
- The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome.J Hum Genet. 2014; 59: 691-693
- Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.N Engl J Med. 2013; 368: 1971-1979
- Gαq and hyper-phosphorylated ERK expression in Sturge-Weber syndrome leptomeningeal blood vessel endothelial cells.Vasc Med. 2019; 24: 72-75
- Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations.Am J Hum Genet. 2003; 73: 1240-1249
- RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation.Hum Mutat. 2013; 34: 1632-1641
- Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations.Hum Mutat. 2008; 29: 959-965
- Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.Circulation. 2017; 136: 1037-1048
- Regulation of angiogenesis by Eph-ephrin interactions.Trends Cardiovasc Med. 2007; 17: 145-151
- A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth.Angiogenesis. 2017; 20: 303-306
- RASA1: variable phenotype with capillary and arteriovenous malformations.Curr Opin Genet Dev. 2005; 15: 265-269
- Molecular and functional characterization of three different postzygotic mutations in PIK3CA-related overgrowth spectrum (PROS) patients: effects on PI3K/AKT/mTOR signaling and sensitivity to PIK3 inhibitors.PLoS One. 2015; 10e0123092
- Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP.Am J Med Genet C Semin Med Genet. 2013; 163C: 122-130
- De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.Nat Genet. 2012; 44: 934-940
- Cervicofacial vascular anomalies. II. Vascular malformations.Semin Pediatr Surg. 2006; 15: 133-139
- Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.J Pediatr. 2015; 166 (e1041-1045): 1048-1054
- AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation.Angiogenesis. 2015; 18: 151-162
- Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations.Hum Mol Genet. 2015; 24: 926-938
- Molecular genetics of vascular malformations.Matrix Biol. 2001; 20: 327-335
- Elevated D-dimer level in the differential diagnosis of venous malformations.Arch Dermatol. 2009; 145: 1239-1244
- Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.Nat Genet. 2009; 41: 118-124
- Variable somatic TIE2 mutations in half of sporadic venous malformations.Mol Syndromol. 2013; 4: 179-183
- Blue rubber bleb nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations.J Invest Dermatol. 2017; 137: 207-216
- Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.Cell. 1996; 87: 1181-1190
- Common and specific effects of TIE2 mutations causing venous malformations.Hum Mol Genet. 2015; 24: 6374-6389
- Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB.Hum Mol Genet. 2013; 22: 3438-3448
- Somatic activating PIK3CA mutations cause venous malformation.Am J Hum Genet. 2015; 97: 914-921
- Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.Eur J Hum Genet. 2010; 18: 414-420
- Sequencing technologies - the next generation.Nat Rev Genet. 2010; 11: 31-46
- Clinical application of amplicon-based next-generation sequencing in cancer.Cancer Genet. 2013; 206: 413-419
- Molecular diagnosis of mosaic overgrowth syndromes using a custom-designed next-generation sequencing panel.J Mol Diagn. 2017; 19: 613-624
- Evaluation of a droplet digital polymerase chain reaction format for DNA copy number quantification.Anal Chem. 2012; 84: 1003-1011
- Proc Natl Acad Sci U S A. 1999; 96: 9236-9241
- Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-Weber syndrome.Sci Rep. 2016; 6: 22985
- Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge-Weber Syndrome.Pediatr Neurol. 2017; 67: 59-63
- Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes.Am J Med Genet A. 2014; 164A: 2633-2637
- Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.Am J Hum Genet. 2012; 90: 1108-1115
- Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies.Pediatrics. 2016; 137e20153257
- Sirolimus for the treatment of complicated vascular anomalies in children.Pediatr Blood Cancer. 2011; 57: 1018-1024
- Response of blue rubber bleb nevus syndrome to sirolimus treatment.Pediatr Blood Cancer. 2016; 63: 1911-1914
- Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects.J Clin Invest. 2015; 125: 3491-3504
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Published online: February 15, 2022
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