Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.3 | {?Hemangioma, capillary infantile, susceptibility to} | 602089 | Autosomal dominant | 3 | ANTXR1 | 606410 |
| 4q12 | {Hemangioma, capillary infantile, susceptibility to} | 602089 | Autosomal dominant | 3 | KDR | 191306 |
| 4q12 | Hemangioma, capillary infantile, somatic | 602089 | 3 | KDR | 191306 | |
| 5q35.3 | Hemangioma, capillary infantile, somatic | 602089 | 3 | FLT4 | 136352 |
A number sign (#) is used with this entry because evidence suggests that susceptibility to the development of infantile hemangioma can be conferred by germline mutation in the VEGFR2 (KDR; 191306) gene.
One patient with infantile hemangioma has been reported with a germline mutation in the TEM8 (ANTXR1; 606410) gene.
In addition, somatic mutations in the VEGFR2, VEGFR3 (FLT4; 136352), and DUSP5 (603069) genes have been identified in hemangioma tumor tissue.
Capillary hemangiomas are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births (Mulliken and Young, 1988). Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma. Hemangiomas are classified as distinct from vascular malformations (see, e.g., CMC1, 163000; 108010; and CCM, 116860), in that the latter are present from birth, tend to grow with the individual, do not regress, and show normal rates of endothelial cell turnover (Spring and Bentz, 2005; Legiehn and Heran, 2006). Legiehn and Heran (2006) noted that the term 'hemangioma' in adults is considered inaccurate and should be discarded.
Most hemangiomas occur sporadically, but some families with autosomal dominant inheritance have been reported (Walter et al., 1999).
Walter et al. (1997, 1999) reported 5 families in which individuals had capillary hemangiomas; 3 families had affected individuals spanning 3 generations. Hemangiomas were defined as lesions that were present at birth or shortly thereafter, displayed a proliferative growth phase, and showed evidence of regression subsequent to infancy.
Waner et al. (2003) mapped sites of occurrence of 232 facial infantile hemangiomas in 205 patients and correlated these with the pattern of tumor growth, clinical complications, and proximity to structural and developmental landmarks. Two patterns of tumor growth were evident among the hemangiomas analyzed: focal (177 lesions, or 76.3%) and diffuse (55 lesions, or 23.7%). The focal hemangiomas mapped to 22 sites of occurrence, all near lines of mesenchymal or mesenchymal-ectodermal embryonic fusion. The 55 diffuse hemangiomas showed a segmental tissue distribution and thus were designated as frontonasal (15 lesions, 27%), maxillary (19 lesions, 35%), or mandibular (21 lesions, 38%). Ulceration was 3 times more common in patients with diffuse hemangiomas (21 of 41, 51%) than in patients with focal hemangiomas (28 of 164, 17%). Airway obstruction was characteristic of diffuse mandibular hemangiomas. Waner et al. (2003) concluded that facial infantile hemangiomas occur in 2 distinct patterns of tissue involvement: a focal type with a tumor-like appearance and a less common diffuse type with a plaque-like appearance. The diffuse lesions are more likely to be complicated by ulceration or airway obstruction and show a strikingly segmental distribution pattern. Focal hemangiomas, in contrast, show a predilection for regions of embryologic fusion.
Blei et al. (1998) identified 6 families in which childhood hemangiomas segregated as an autosomal dominant trait. Additionally, family members with vascular malformations were identified in these kindreds.
By genomewide linkage analysis of 3 unrelated families with capillary hemangiomas, Walter et al. (1999) found linkage to a 38-cM interval on chromosome 5q31-q33 between markers D5S1469 and D5S211 (maximum multipoint lod score of 4.773 at D5S1456). Walter et al. (1999) stated that the candidate region contained the FLT4 gene. All 3 linked families contained at least 1 member affected with another type of vascular anomaly, but not a hemangioma. Two additional families did not show linkage to this region, indicating genetic heterogeneity.
Hemangiomas progress through distinct phases, thus providing an opportunity for studying endothelial cell biology and angiogenesis. Using DNA microarrays representing approximately 10,000 human genes, Ritter et al. (2002) identified insulin-like growth factor-2 (IGF2; 147470) as a potentially important regulator of hemangioma growth. IGF2 was highly expressed during the proliferative phase and substantially decreased during involution. This finding was confirmed at the level of mRNA by quantitative reverse transcription-PCR and at the protein level by immunohistochemistry. IGF2 protein was localized primarily to tumor vessels or vascular channels. Using a human hemangioma explant model, the authors showed that IGF2 promotes sprouting from intact hemangioma tissue. In addition, several angiogenesis-related factors, including integrins ITGAV (193210)/ITGB3 (173470) and ITGA5 (135620)/ITGB1 (135630), are present in proliferating hemangiomas. During the involuting phase, an increase in several interferon-induced genes was observed. These studies identified potential regulators of hemangioma growth and involution and provided a foundation on which to build further mechanistic investigations into angiogenesis, using hemangiomas as a model.
Breugem et al. (2002) tentatively suggested that congenital capillary malformation syndrome (CMC1) was separate and distinct from capillary infantile hemangioma, but admitted the possibility that vascular tumors (hemangiomas) and vascular malformations, which are classified into 2 separate categories (Mulliken and Young, 1988), may have similar etiologies.
Germline Mutations
In hemangioma endothelial cells, Jinnin et al. (2008) found that expression of VEGFR1 (FLT1; 165070) was markedly reduced, and that VEGFR2 activity was increased, compared to controls. In normal endothelial cells, FLT1 transcription is dependent on NFAT (see, e.g., NFATC2; 600490) activation. Further studies indicated that low VEGFR1 expression in hemangioma cells was caused by reduced activity of a pathway involving ITGB1 (135630), TEM8, VEGFR2, and NFAT. Jinnin et al. (2008) identified germline mutations in the TEM8 gene (606410.0001) and in the VEGFR2 gene (191306.0002) in patients with infantile hemangioma. These mutations disrupted the normal association of this molecular complex. Jinnin et al. (2008) postulated that these mutations conferred increased susceptibility to the formation of hemangiomas, but were probably associated with a secondary somatic event to trigger the expansion of endothelial cells within the lesions.
Somatic Mutations
In 1 of 15 infantile hemangioma specimens, Walter et al. (2002) identified a mutation in the FLT4 gene (136352.0007). This result, and the finding of a somatic missense mutation in the VEGFR2 gene (191306.0001) in another of the 15 specimens, suggested that alteration of the FLT4 signaling pathway in endothelial and/or pericytic cells may be a mechanism involved in hemangioma formation.
Pramanik et al. (2009) identified an apparently somatic ser147-to-pro (S147P) mutation in the DUSP5 gene (603069) in 1 of 3 infantile hemangioma samples and in 12 of 17 lymphatic, arteriovenous, and venous malformation samples. The mutation was not found in normal human placenta, control human umbilical vein endothelial cells, or tonsillar tissue from unrelated individuals. In zebrafish, the authors demonstrated that Dusp5 was expressed in angioblasts and played a role in vascular development, suggesting that variation in this gene may provide susceptibility to the development of vascular anomalies in humans.
Blei, F., Walter, J., Orlow, S. J., Marchuk, D. A. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch. Derm. 134: 718-722, 1998. Note: Erratum: Arch. Derm. 134: 1425 only, 1998. [PubMed: 9645641] [Full Text: https://doi.org/10.1001/archderm.134.6.718]
Breugem, C. C., Alders, M., Salieb-Beugelaar, G. B., Mannens, M. M. A. M., Van Der Horst, C. M., Hennekam, R. C. M. A locus for hereditary capillary malformations mapped on chromosome 5q. Hum. Genet. 110: 343-347, 2002. [PubMed: 11941483] [Full Text: https://doi.org/10.1007/s00439-002-0700-z]
Jinnin, M., Medici, D., Park, L., Limaye, N., Liu, Y., Boscolo, E., Bischoff, J., Vikkula, M., Boye, E., Olsen, B. R. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Med. 14: 1236-1246, 2008. [PubMed: 18931684] [Full Text: https://doi.org/10.1038/nm.1877]
Legiehn, G. M., Heran, M. K. S. Classification, diagnosis, and interventional radiologic management of vascular malformations. Orthop. Clin. N. Am. 37: 435-474, 2006. [PubMed: 16846771] [Full Text: https://doi.org/10.1016/j.ocl.2006.04.005]
Mulliken, J. B., Young, A. E. (eds.). Vascular Birthmarks: Hemangiomas and Malformations. Philadelphia: W. B. Saunders Co. 1988.
Pramanik, K., Chun, C. Z., Garnaas, M. K., Samant, G. V., Li, K., Horswill, M. A., North, P. E., Ramchandran, R. Dusp-5 and Snrk-1 coordinately function during vascular development and disease. Blood 113: 1184-1191, 2009. [PubMed: 18927432] [Full Text: https://doi.org/10.1182/blood-2008-06-162180]
Ritter, M. R., Dorrell, M. I., Edmonds, J., Friedlander, S. F., Friedlander, M. Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc. Nat. Acad. Sci. 99: 7455-7460, 2002. [PubMed: 12032304] [Full Text: https://doi.org/10.1073/pnas.102185799]
Spring, M. A., Bentz, M. L. Cutaneous vascular lesions. Clin. Plast. Surg. 32: 171-186, 2005. [PubMed: 15814115] [Full Text: https://doi.org/10.1016/j.cps.2004.11.004]
Walter, J. W., Blei, F., Anderson, J. L., Orlow, S. J., Speer, M. C., Marchuk, D. A. Genetic mapping of a novel familial form of infantile hemangioma. Am. J. Med. Genet. 82: 77-83, 1999. [PubMed: 9916848] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990101)82:1<77::aid-ajmg15>3.0.co;2-a]
Walter, J. W., Blei, F. M., Marchuk, D. A. Description of a novel hereditary form of capillary hemangioma and genetic mapping of predisposing chromosomal loci. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A299 only, 1997.
Walter, J. W., North, P. E., Waner, M., Mizeracki, A., Blei, F., Walker, J. W. T., Reinisch, J. F., Marchuk, D. A. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 33: 295-303, 2002. [PubMed: 11807987] [Full Text: https://doi.org/10.1002/gcc.10028]
Waner, M., North, P. E., Scherer, K. A., Frieden, I. J., Waner, A., Mihm, M. C., Jr. The nonrandom distribution of facial hemangiomas. Arch. Derm. 139: 869-875, 2003. [PubMed: 12873881] [Full Text: https://doi.org/10.1001/archderm.139.7.869]