Published online December 31, 2007
PEDIATRICS Vol. 121 No. 1 January 2008, pp. e135-e140 (doi:10.1542/peds.2007-1316)
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ARTICLE

Risk of Vascular Anomalies With Down Syndrome

Arin K. Greene, MD, MMSca,b, Sendia Kim, MDc, Gary F. Rogers, MD, JD, MBA, MPHa,b, Steven J. Fishman, MDa,c, Bjorn R. Olsen, MD, PhDd and John B. Mulliken, MDa,b

a Vascular Anomalies Center and Departments of
b Plastic Surgery
c Surgery
d Developmental Biology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Patients with Down syndrome have a reduced risk of developing solid tumors. This protective effect has been attributed to increased gene dosage from an additional copy of chromosome 21, and elevated expression of endostatin has been implicated. We hypothesized that vascular anomalies, including infantile hemangioma, an angiogenesis-dependent vascular tumor, and vascular malformations might be similarly inhibited in patients with Down syndrome.

PATIENTS AND METHODS. The Children's Hospital Boston Vascular Anomalies Center database was searched for patients with Down syndrome between 1999 and 2007. In addition, the records of patients with Down syndrome treated at Children's Hospital Boston and the National Birth Defects Center between 1985 and 2007 were reviewed to find concurrent vascular anomalies. Two-sided exact binomial tests were used to evaluate whether patients with vascular anomalies are at reduced risk for Down syndrome or if patients with Down syndrome are at less risk for vascular anomalies compared with the general population. Ninety-five–percent confidence intervals were calculated on the basis of the risk of Down syndrome (1 in 800) and vascular anomalies (1 in 22) in the general population.

RESULTS. Two of the 7354 patients evaluated in our vascular anomalies unit had Down syndrome. Both patients had a lymphatic malformation: one in the orbit and the other in the lower extremity. Six of the 633 patients with Down syndrome had a vascular anomaly (infantile hemangioma [n = 4] or lymphatic malformation [n = 2]). The risk of concurrent Down syndrome and vascular anomalies was different from the corresponding risk in the general population.

CONCLUSIONS. Patients with Down syndrome have a reduced risk of vascular anomalies compared with the general population. Elevated expression of antiangiogenic proteins may protect these patients from developing vascular anomalies, as well as solid tumors.

Key Words: angiogenesis • Down syndrome • endostatin • hemangioma • malformations • vascular anomalies

Abbreviations: CI—confidence interval • VEGF—vascular endothelial growth factor • COL18A1—encoding collagen XVIII/endostatin • DSCR1—Down syndrome candidate region 1 • NFAT—nuclear factor of activated T cells

More than 80 anomalies have been associated with Down syndrome, and virtually every organ can be affected. Malformations are presumed to be results of an increased gene product from the duplicated portion of chromosome 21.1 Although >283 protein-encoding genes have been located, the relatively limited number of candidate genes provides researchers with a nonspecific, although focused, model to study genotype-phenotype correlations.2 Candidate regions on chromosome 21 include those linked to congenital heart defects, cognitive dysfunction, and Alzheimer disease.3–5

One area of investigation is the risk of neoplasm in patients with Down syndrome. Because the average life span of patients with Down syndrome has increased from 25 to 49 years over the last 2 decades, epidemiologic studies in these older patients have shown a 50% to 90% risk reduction for solid tumors.6,7 Hypotheses suggested to explain the lower rate of solid tumors have included reduced exposure to carcinogens (sun, alcohol, and tobacco), slower replication of cells, increased apoptosis, enhanced metabolism of oxygen-free radicals, and the presence of a tumor suppressor gene on chromosome 21.6–8 Endostatin, a potent antiangiogenic fragment of collagen XVIII encoded on chromosome 21 (21q22.3), might also be responsible for diminished tumorigenesis in patients with Down syndrome. Recombinant forms of endostatin inhibit the formation of tumors in animals and humans.9–11 In addition, serum endostatin levels are 48% higher in patients with Down syndrome compared with the general population.12

Because patients with Down syndrome have a reduced risk of solid tumors and elevated levels of a circulating antiangiogenic protein, we hypothesized that this population might also be protected from vascular anomalies (hemangioma and vascular malformations). Hemangioma, the most common tumor of infancy, affects as many as 10% of white infants. However, the prevalence of this vascular lesion in patients with Down syndrome is unknown. Although population studies of patients with Down syndrome have failed to recognize hemangioma or vascular malformations,1,13 cases of vascular anomalies affecting patients with Down syndrome have been reported.14–26 To determine whether patients with Down syndrome are protected from vascular anomalies, like solid tumors, we investigated the risk of hemangioma and vascular malformations in these patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patient Groups
To determine the risk of Down syndrome in patients with vascular anomalies, the Children's Hospital Vascular Anomalies Center database was searched from 1999 to 2007 for patients with Down syndrome. All of the patients referred to the center are entered into the database along with their comprehensive past medical history. The database was queried using the key words "Down" or "syndrome" to locate patients with Down syndrome.

The risk of vascular anomalies in patients with Down syndrome was investigated by reviewing the records of patients with Down syndrome treated at Children's Hospital Boston and the National Birth Defects Center (Waltham, MA) between 1985 and 2007 for an associated vascular anomaly (Table 1). The search for vascular anomalies among patients with Down syndrome was done manually, reviewing the comprehensive serial physical examinations and medical histories recorded in the charts.


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  		TABLE 1 Binary Classification of Vascular Anomalies (International Society for the Study of Vascular Anomalies)

 
Statistical Analysis
A 2-sided exact binomial test was used to determine whether patients with Down syndrome have a reduced risk of vascular anomalies compared with the general population (SAS 9.0; SAS Institute, Inc, Cary, NC). Ninety-five–percent confidence intervals (CIs) were calculated to test whether the prevalence of vascular anomalies in patients with Down syndrome or the prevalence of Down syndrome in patients with vascular anomalies was different from that in the general population.

Estimates for the risk of Down syndrome and vascular anomalies were obtained from the literature. The prevalence of Down syndrome in the population is 1 in 800.7,27,28 The prevalence of vascular anomalies in the population was calculated from the sum of the risks of the most common vascular tumor, infantile hemangioma (4.1%–10.1%),29–31 and the risks of the most common vascular malformations: capillary (0.3%–0.6%),32,33 venous (0.12%),30 and lymphatic (0.05%–0.34%).34,35 Although the risk of vascular anomalies in the population ranges from ~4.55% to 11.16%, we used the most conservative estimate, 4.55% (1 in 22), to apply the strictest criteria for the statistical evaluation of a possible association between Down syndrome and vascular anomalies.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Two of the 7354 patients in our vascular anomalies database had Down syndrome; the expected number of cases was 9.2. One female underwent subtotal resection of a right orbital lymphatic malformation; the other female had a lymphatic malformation of the lower extremity. The 95% CI for 2 patients with Down syndrome in our population of vascular anomalies was (1/270000 to 1/1245). Because the prevalence of Down syndrome (1 in 800) is outside of this CI, the risk of Down syndrome in patients with vascular anomalies is different from the risk of Down syndrome in the general population (P = .03).

Six of 633 patients with Down syndrome were found to have a vascular anomaly. The expected number was 28.8, giving an 80% risk reduction. Four patients were reported to have a small hemangioma. Two patients had a lymphatic malformation: one involved the parotid gland and the other was in the upper extremity. The 95% CI for the 6 patients with vascular anomalies in the Down syndrome population was (1/588 to 1/62). Because the prevalence of vascular anomalies (1 in 22) is outside of this CI, the risk of vascular anomalies in patients with Down syndrome is different from the risk of vascular anomalies in the general population (P = .01; Table 2).


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  		TABLE 2 Association Between Vascular Anomalies and Down Syndrome

 

   DISCUSSION
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 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
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CONCLUSIONS
 REFERENCES
 
This study shows that vascular anomalies (infantile hemangioma and vascular malformations) are less common in patients with Down syndrome compared with the general population. Although these lesions may share similarities in appearance, they are different in their pathogenesis and behavior.36 Infantile hemangioma begins to grow after birth, is angiogenesis dependent, and is marked by endothelial proliferation and expression of the endothelial mitogens basic fibroblast growth factor and vascular endothelial growth factor (VEGF).37,38 In contrast, vascular malformations are errors in vasculogenesis that are present at birth, grow proportionately with the patient, and have anomalous channels with quiescent endothelium. Although angiogenesis has not been considered an important factor in the growth of vascular malformations, they can expand during adolescence, pregnancy, or after trauma. In addition, the proangiogenic markers matrix metalloproteinase, basic fibroblast growth factor, and VEFG have been found in the endothelium, tissue, and urine of patients with vascular malformations.39–42

If an increased gene dosage from a critical region of chromosome 21 is responsible for the reduced risk of both vascular tumors and vascular malformations in this population, the candidate gene(s) may have the potential to modulate both angiogenesis (proliferation and migration of endothelial cells from preformed vessels to form new vessels) and vasculogenesis (new vessels derived by in situ differentiation, aggregation, and migration of mesodermal angioblasts).43–45 Of the ~300 potential genes identified on chromosome 21, only encoding collagen XVIII/endostatin (COL18A1), DYRK1A, and Down syndrome candidate region 1 (DSCR1) are known to affect angiogenesis.

Although the antiangiogenic effects of endostatin are well established, its mechanism is unclear. Evidence suggests that endostatin suppresses the expression of VEGF, because the antitumor effect of endostatin involves downregulation of VEGF in tumor cells.46,47 In addition, the endothelial cell sprouting from murine aortic explants is stimulated by VEGF and suppressed by endostatin.48 An inverse correlation between endostatin and VEGF expression also has been shown in rat cardiac and skeletal musculature activity.49

Because of its inhibitory effects on VEGF and tumor growth, elevated endostatin levels may account for the low rate of solid tumors in patients with Down syndrome.12 Transgenic mice producing a 1.6-fold higher circulating level of endostatin have a reduced rate of tumor growth compared with wild-type mice.50 However, this explanation may be overly simplistic, because increased rates of malignancy are not observed in collagen XVIII/endostatin knockout mice or in patients with Knobloch syndrome who lack collagen XVIII, although the number of patients with Knobloch syndrome is small and long-term follow-up is not available.51,52 Collagen XVIII–deficient mice and patients with Knobloch syndrome also do not have obvious vascular malformations, except for ocular vessel abnormalities.52 In addition, endostatin has contradictory effects on endothelial cells, depending on the monomeric or trimeric form of endostatin, as well as the type and maturity of the endothelial cells.53–56

Although the role of endostatin in the prevention of vascular anomalies in patients with Down syndrome is unclear, DYRK1A and DSCR1, which also are overexpressed in patients with Down syndrome, might reduce the risk of tumors and vascular anomalies in this population. These mediators act synergistically to suppress calcineurin-mediated nuclear factor of activated T cells (NFAT) dephosphorylation and nuclear translocation, an important regulatory step in VEGF expression.43,57,58 Increased levels of VEGF selectively upregulate endothelial cell expression of DSCR1, which inhibits the catalytic subunit of calcineurin and negatively feeds back to regulate VEGF-induced endothelial proliferation,57,59 although 1 isoform (DSRC1-1L) may stimulate VEGF.60 We speculate that overexpression of DYRK1A and DSCR1 in Down syndrome inhibits NFAT translocation, decreases VEGF expression, and suppresses the growth of VEGF-dependent tumors, including infantile hemangioma.

Not only does VEGF stimulate tumor growth, but it seems to play a role in the pathogenesis of vascular malformations as well. Animal models of vascular malformations have been produced by manipulating VEGF expression during critical periods of vasculogenesis.61,62 For example, loss of a VEGF allele or a mutation in VEGF receptors causes structural anomalies in the developing vasculature.63,64 In addition, injection of exogenous VEGF or transfection of VEGF DNA or mRNA during vasculogenesis induces growth of supernumerary vessels and increases vascular fusion; the earlier the injection, the more severe the vascular malformation.65–67 Finally, infusion of VEGF can produce a localized venous malformation, potentially from the recruitment of circulating angioblasts and vasculogenesis, a process that occurs almost exclusively in embryonic development.68

In these animal models, VEGF overexpression in early embryogenesis is generally fatal, and it is, thus, unlikely that a human embryo would survive such a molecular alteration. Nevertheless, most human vascular malformations are regional and do not affect the entire body. They likely result from a somatic mutation (genetic mosaicism) in which the mutation is expressed only in cells derived from an affected progenitor.69 Because the affected area is localized, an otherwise lethal mutation can be compatible with life. It is conceivable that a somatic mutation resulting in increased VEGF expression, improved ligand/receptor affinity, or constitutive activation of VEGF receptors during early vasculogenesis could result in a vascular malformation. In patients with Down syndrome, increased expression of endostatin, DSCR1, or DYRK1A could suppress elevated tissue levels of VEGF in the mutated cells during a critical developmental period, preventing the formation of a vascular anomaly.

Although the overexpression of VEGF inhibitors endostatin, DSCR1, and DYRK1A may suppress vascular anomaly formation, increased gene product from these VEGF antagonists also may cause the cardiac and large arterial anomalies associated with Down syndrome.1 Unlike vascular anomalies, which are likely a result of a somatic mutation, cardiac and great vessel development is a tightly regulated process that begins with differentiation and migration of endothelial cells overlying the cardiac tissue into the cardiac jelly.70,71 Elevated expression of collagen XVIII/endostatin is present in cardiac tissue cells and endocardial cushion-derived structures during early cardiac development.72 Disturbance of collagen XVIII/endostatin expression could adversely impact cardiac tissue cell transformation, migration, and differentiation, resulting in a cardiac defect.72 However, the role of collagen XVIII/endostatin in the development of cardiac anomalies is controversial, because the gene that encodes for collagen XVIII may not be in the candidate region for congenital heart disease in Down syndrome.3

It is more likely that elevated DSCR1 and DYRK1A expression accounts for abnormal cardiac and large-vessel development in patients with Down syndrome. In a murine model, overexpression of DSCR1 and DYRK1A produces the entire Down phenotype, including typical cardiac anomalies.43 The combined inhibitory effects of these proteins on NFAT nuclear translocation could suppress VEGF expression during early vasculogenesis/cardiogenesis. Numerous studies confirm that normal cardiac and vascular development depends on tight spatial and temporal regulation of VEGF.73–76 Anomalies of the heart and great vessels have been noted in VEGF haploinsufficient mice63,77 and zebrafish78 and also have been associated with increased79,80 or decreased75,76 expression of VEGF. Furthermore, VEGF induction of NFAT nuclear translocation is a critical step in developing cardiac valves.81


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Individuals with Down syndrome have an 80% risk reduction of vascular anomalies, similar to their reduced risk of developing solid tumors. This protective effect is most likely because of increased gene product resulting from an extra copy of chromosome 21. Potential candidate genes on this chromosome include VEGF inhibitors COL18A1, DSCR1, or DYRK1A. Because VEGF is involved in the pathogenesis of both hemangioma and vascular malformations, increased gene product from COL18A1, DSCR1, or DYRK1A may protect patients with Down syndrome from vascular anomalies.


   ACKNOWLEDGMENTS
 
We thank Peter Forbes, Clinical Research Program at Children's Hospital Boston, for statistical expertise.


   FOOTNOTES
 
Accepted Jun 12, 2007.

Address correspondence to Arin K. Greene, MD, MMSc, Department of Plastic Surgery, Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115. E-mail: arin.greene{at}childrens.harvard.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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