search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Haggstrom, A. N. Articles by Frieden, I. J. Search for Related Content PubMed PubMed Citation Articles by Haggstrom, A. N. Articles by Frieden, I. J. Related Collections Heart & Blood Vessels

Patterns of Infantile Hemangiomas: New Clues to Hemangioma Pathogenesis and Embryonic Facial Development

^a Department of Dermatology, George Washington University, University Dermatology Associates, Washington, DC
^b Children's Hospital Oakland Research Institute, Oakland, California
^c Departments of Orthopedic Surgery
^e Dermatology and Pediatrics, University of California, San Francisco, California
^d Department of Orthopedic Surgery, San Francisco General Hospital, University of California, San Francisco, California

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVES. Large facial infantile hemangiomas have higher rates of complications than small localized hemangiomas, more often require treatment, and can be associated with neurological, ophthalmologic, and cardiac anomalies (PHACE syndrome). The anatomic patterns of these hemangiomas are often referred to as "segmental" despite a lack of precise anatomic definitions. Our study aims to define "segmental" hemangiomas based on clinically observed patterns. Our secondary goal is to relate the observed patterns to currently accepted developmental patterns to gain insight into hemangioma pathogenesis and craniofacial development.

METHODS. Photographic data were extracted from a large cohort of patients with infantile hemangiomas. We mapped 294 hemangiomas and recorded common morphologic patterns. Anatomic descriptions of the most common patterns were described and compared with accepted concepts of craniofacial development.

RESULTS. Four primary segments were identified (Seg1–Seg4). Seg2 and Seg3 correspond with the previously recognized maxillary and mandibular prominences. Seg1 and Seg4 differ from standard human embryology texts. The frontotemporal segment, Seg1, encompasses the lateral forehead, anterior temporal scalp, and lateral frontal scalp. The segment Seg4, encompassing the medial frontal scalp, nasal bridge, nasal tip, ala, and philtrum, is substantially narrower on the forehead than the previously described frontonasal prominence.

CONCLUSIONS. The patterns provide new clues regarding facial development. The observed patterns resemble previously described facial developmental units on the lower face but are distinctly different on the upper face. The patterns suggest that neural crest derivatives may play a role in the development of facial hemangiomas. Finally, these patterns (Seg1–Seg4) help standardize the nomenclature of facial segmental hemangiomas to analyze more effectively hemangioma risks and behavior.

Key Words: dermatology • hemangioma • segmental hemangioma • capillary hemangioma • vascular birthmark

INFANTILE HEMANGIOMAS are extremely common. They have unique growth characteristics, typically being absent or barely noticeable at birth, followed by a period of rapid growth and then subsequent involution. The majority of affected infants have an uncomplicated clinical course, but a significant subset have function-threatening complications or permanent and disfiguring scars that require medical or surgical interventions.

Three recent observations regarding infantile hemangiomas spurred our interest in studying their anatomic patterns. First, there is a clear association between hemangiomas, particularly large facial hemangiomas, and certain structural birth defects. This association, known as PHACE syndrome (Online Mendelian Inheritance in Man No. 606519), includes a group of abnormalities primarily affecting the central nervous system, cerebrovasculature, aorta, heart, eye, and sternum. Many of these birth defects originate between 6 and 8 weeks of gestation, which is surprising, because hemangiomas are absent at birth. Second, recent reports have divided hemangiomas into "localized" (arising from a central focus) and "segmental" (covering an anatomic territory) subtypes, noting a higher risk of complications and associated structural anomalies in segmental hemangiomas when compared with localized hemangiomas.¹ Third, Waner et al² demonstrated that facial hemangiomas are not random in their distribution and suggested that segmental facial hemangiomas correspond with known developmental units such as the mandibular and maxillary prominences.

We hypothesized that a systematic analysis of photographic data of patients with facial hemangiomas could enable us to determine whether segmental hemangiomas correspond to known developmental units,³ follow other purported subdivisions associated with embryogenesis such as dermatomes or the lines of Blaschko,⁴ or represent the functioning of additional unspecified mechanisms that pattern the craniofacial complex. Just as the recognition that a facial port-wine stain in the "V1" dermatome distribution confers a recognized risk of Sturge-Weber syndrome,⁵ clarification of segmental hemangioma patterns might aid in identifying those infants at greatest risk for certain complications and/or structural anomalies. Moreover, studying patterns of facial hemangiomas may not only provide insight into the underlying pathogenesis but also contribute more generally to our understanding of craniofacial development.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
We analyzed photographs collected as part of a large prospective cohort study of infantile hemangiomas. Patients were eligible if they had a facial hemangioma, were aged 12 years or younger, and were examined between September 2002 and October 2003. Lesions were classified by morphologic subtype as segmental, localized, indeterminate, or multifocal using criteria in a manual created for this study. "Segmental hemangiomas" were defined as those hemangiomas or clusters of hemangiomas with a configuration corresponding to a recognizable and/or significant portion of a developmental segment or involving a broad anatomic territory of skin. "Localized hemangiomas" were defined as those hemangiomas that seemed to grow from a single focal point or were localized to an area without any apparent linear or metameric configuration. "Indeterminate hemangiomas" were those that were not readily classified as either localized or segmental, and "multifocal hemangiomas" referred to those found on patients with 10 cutaneous lesions. A total of 294 hemangiomas were observed as being either segmental (115) or indeterminate (179). Seventy two of the segmental hemangiomas and 93 of the indeterminate hemangiomas were located on the face and were used for this analysis. Each facial hemangioma was mapped onto a facial template.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
A total of 294 hemangiomas (115 segmental and 179 indeterminate) were reviewed. Of these, 34 segmental and 68 indeterminate hemangiomas were excluded, because they were nonfacial. Nine segmental and 18 indeterminate hemangiomas were excluded because of poor image quality that precluded accurate assessment of anatomic boundaries. Therefore, a total of 165 facial hemangiomas (72 segmental and 93 indeterminate) were analyzed.

Initial image analysis revealed that the hemangiomas could be segregated into 8 categories based on location (Fig 1): (1) temporal ocular; (2) medial maxillary; (3) lateral mandiblular including the entire lower lip; (4) central mandibular; (5) nasal tip; (6) frontonasal; (7) lateral maxillary; and (8) retro-orbital/periorbital (Fig 1A). However, larger hemangiomas often encompassed >1 anatomic category, implying that certain contiguous anatomic categories could be combined. This led to the identification of 4 primary segments: Seg1–Seg4 (Fig 1B). Twenty patients had hemangiomas that encompassed >1 segment.

View larger version (32K): [in this window] [in a new window]   FIGURE 1 A, Eight initial patterns identified. B, Final 4 segmental patterns extracted from image analysis: Seg1 (frontotemporal), Seg2 (maxillary), Seg3 (mandibular), and Seg4 (frontonasal).

View larger version (50K): [in this window] [in a new window]   FIGURE 2 Frontotemporal segmental hemangiomas (Seg1). A, The inferior part of this Seg1 hemangioma respects the borders of Seg2 (lateral cheek) and Seg3 (preauricular region). B, More extensive upper eyelid involvement in the Seg1 hemangioma.

View larger version (60K): [in this window] [in a new window]   FIGURE 3 Maxillary segmental hemangiomas (Seg2). A, Unilateral upper lip involvement, respects the philtrum, which is part of the frontonasal segment, Seg4. B, Deeper components of this segmental hemangioma have resulted in upward displacement of the ipsilateral globe.

View larger version (69K): [in this window] [in a new window]   FIGURE 4 Mandibular segmental hemangiomas (Seg3). A, Extensive central Seg3 involvement including the entire lower lip. B and C, Bilateral Seg3 involvement is common in contrast to Seg1 and Seg2, which are usually unilateral.

View larger version (74K): [in this window] [in a new window]   FIGURE 5 Frontonasal segmental hemangiomas (Seg4). A, Superior Seg4 hemangioma demonstrating V-shaped morphology respecting border of Seg1. B, Inferior Seg4 hemangioma with slight extension laterally at Seg2 border. Small areas of overlap at the segment borders are common and analogous to dermatomal overlap.

"Incomplete" Segments
Although they respected segment boundaries, hemangiomas did not always encompass an entire segment. For example, some patients had a hemangioma located on the upper eyelid with only a small extension toward the lateral forehead, suggesting an incomplete segmental pattern.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The classification of infantile hemangiomas into segmental and localized forms arose from the observation that hemangiomas are clinically diverse. Some are small and localized, whereas others display a linear and/or geographic distribution, covering larger anatomic regions, which we refer to as "segmental." These segments do not correspond with facial dermatomes or lines of Blaschko, which are mosaic expressions of neuroectodermal migration.⁴ Waner et al² proposed that the patterns corresponded with embryological facial prominences.

Four segmental patterns were observed in this study: Seg1 (frontotemporal segment), Seg2 (maxillary segment), Seg3 (mandibular segment), and Seg4 (frontonasal segment). Some patterns have marked similarities to facial prominences described in embryology textbooks but with critical differences, particularly regarding lesions of the upper half of the face. Diagrams of the facial prominences usually depict the frontonasal prominence as extending to the lateral forehead.³ In contrast, our results showed that the frontonasal prominence was limited to an area on the medial forehead and scalp, whereas another developmental unit, termed Seg4, included the lateral forehead and temple.

Hemangiomas in the periorbital area occurred in isolation or contiguously with hemangiomas of the Seg1 or Seg2 distribution. Large plaques in the Seg1 distribution often extended onto the lateral half of the upper eyelid and occasionally extend across the entire width of the upper eyelid. Some hemangiomas in the Seg2 distribution extended onto the lower eyelid. The inconsistent association of periorbital hemangiomas with either Seg1 or Seg2 segments suggests an area of overlap between Seg1 and Seg2. This may reflect the independent development of the orbit, with its ventral emergence in the face. Conceptually, a variable region for segmental hemangiomas may be analogous to dermatomal variation seen in the distribution of V1 and V2 port-wine stains.⁵

The patterns of hemangiomas on the upper and lower lip reflect accepted models of central facial development. The frontonasal prominence forms the philtrum and separates the maxillary processes. The mandibular prominences fuse at the midline. Hemangiomas involving the upper lip were either limited to the philtrum or unilateral, respecting the lateral border of the philtrum. They did not extend from one commisure to the other as was observed with many lower lip hemangiomas. In contrast, segmental hemangiomas of the upper face did not resemble the shape of a single frontonasal metamere but suggested that there is 1 central (Seg4) and 2 lateral developmental segments (Seg1).

Some hemangiomas involved >1 segment, whereas others neither encompassed an entire segment nor arose from a single focus. Such lesions have been referred to as "indeterminate."¹ The borders of indeterminate hemangiomas respected the developmental segment boundaries we have observed, supporting the concept of "incomplete segmental" hemangiomas. Our findings address a clinically significant subset of all infantile hemangiomas. Approximately 50% of hemangiomas occur on the head and neck, and up to 20% of these are segmental. Segmental hemangiomas on the trunk and extremities may also resemble developmental units, but these were not addressed in this study.

Although specific cellular and molecular mechanisms underlying infantile facial hemangiomas remain obscure, the observed segmental patterns suggest that in each case some common developmental process has gone awry. In particular, the nonrandom distribution of these aberrant tissues indicates that on the cellular level they are responsive to the same morphogenetic mechanisms that establish boundaries among individual facial primordia. There are 5 distinct embryonic primordia in the developing face. The paired mandibular primordia give rise to the lower jaw, lips, and chin. The paired maxillary primordia produce the upper jaw and lip (excluding the philtrum), the secondary palate, and the cheeks. The frontonasal primordium generates the middle and upper face from the forehead to the philtrum of the lip, as well as the primary palate. The frontonasal primordium can be additionally subdivided into lateral and medial domains that, respectively, give rise to the sides and bridge of the nose. Each facial primordium is populated by mesenchymal cells derived predominantly from the cranial neural crest and is enclosed by an epithelium that originates from nonneural ectoderm.

Although these primordia share similarities in organization and constitution, the molecular mechanisms regulating their patterned outgrowth seem to be distinct.^6–8 This may be attributable, in part, to the origins of neural crest cells that populate each primordium, as well as to regional differences in overlying ectoderm.^9,10 For example, neural crest cells that occupy the frontonasal primordium come from a more rostral level of the neural tube than those that reside in the maxillary or mandibular primordia. As a result, each subpopulation of neural crest may have a unique molecular identity, hold different potential, and be regionally compartmentalized. Ultimately, this would affect the patterned growth and subsequent integration of the facial primordia and all of their constituents including skeletal, muscular, and vascular components. For some yet-to-be-determined reason, segmental hemangiomas seem to perpetuate embryonic boundaries that, in all other regards, have seemingly disappeared.

In addition to initial embryonic boundaries that exist among the various facial primordia, another important interface exists within the craniofacial complex that likely has a mechanistic bearing on delimitations of segmental hemangiomas. Experiments using tissue transplants between quail and chick embryos have revealed a boundary in the head that stretches from the anterior mesencephalic-prosencephalic junction to the laryngotracheal diverticulum and separates dorsal mesenchyme of mesodermal origin and ventral mesenchyme derived from the neural crest.¹¹ All of the skeletal and connective craniofacial tissues are generated by these mesenchymal populations, and they maintain their respective mesodermal or neural crest histories.

Extrapolating these avian fate map data to humans, we hypothesize that the juxtaposition of neural crest and mesodermally derived bones along the lateral margins of the skull (ie, lateral forehead and temples) can explain the discrete domains that we observe for hemangiomas in the Seg1 developmental unit. Such a conclusion is substantiated by transgenic experiments in mice, which have provided equivalent fate maps using indelibly labeled neural crest cells.¹² Analysis of these mice confirms that the mammalian interface between neural crest and mesoderm runs through the temporal region, which might explain why segmental facial hemangiomas respect this boundary given their association with neural crest mesenchyme.

The observation that infantile hemangiomas exhibit growth patterns that respect embryonic segments is intriguing, because angioblasts that form blood vessels do not obey segment-specific boundaries.^13,14 Rather, angioblasts arising within cephalic mesoderm migrate in all directions and contribute to blood vessels throughout the face. Thus, restriction of segmental hemangiomas to the derivatives of embryonic facial primordia does not seem to be the result of segmental identity imposed a priori on the endothelial cells. Segmental restriction more likely results from environmental influences that govern formation of the microvasculature of the skin. Proliferation of endothelial cells and growth of hemangiomas may occur in response to, or be constrained by, signals derived from cell types that exhibit segmental or regional identity, such as cranial neural crest cells. In this scenario, segmental restriction would be a secondary consequence of interactions between endothelial and neural crest cells.

A direct relationship between endothelial cells and neural crest cells exists. Pericytes, the connective tissue support cells of blood vessels, are derived from cranial neural crest cells,¹⁵ and interactions between pericytes and endothelial cells influence maintenance, maturation, and remodeling of blood vessels.¹⁶ Hence, the idea that formation of a hemangioma results from a primary defect in a segmentally or regionally restricted tissue, such as the neural crest, deserves additional exploration. In particular, a better understanding of cellular and molecular mechanisms that produce embryonic boundaries among facial primordia may explain the reasons for the observed correlation between segmental patterns of infantile facial hemangiomas and various facial regions.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Identifying hemangioma patterns should help standardize nomenclature for future studies that correlate risks and behaviors to specific sites and patterns. Preliminary evidence suggests that hemangiomas in the Seg1 distribution have a higher risk for associated brain anomalies of PHACE syndrome, whereas those involving Seg3 have a greater risk of cardiac defects.¹⁷ Future studies are needed to more effectively compare clinical outcomes in these groups of patients. The novel observation that hemangioma patterns along the dorsolateral margins of the face correspond precisely to boundaries present between mesenchyme derived from the cranial neural crest and that of mesodermal origin also raises fundamental questions about the origins of hemangiomas, which have typically been assumed to be because of a defect in the endothelial cells from which neoplastic blood vessels arise. These vessels have recently been recognized to have a unique vascular phenotype similar to placental microvasculature.¹⁸ The patterns observed suggest that other tissue components could be the real culprits and permit aberrant growth of these blood vessels after birth. We believe that a better understanding of the causes of segmental infantile hemangiomas can be achieved by focusing on molecular and cellular processes that regulate facial development. Identifying segmental patterns may also reveal novel mechanisms underlying normal and abnormal craniofacial patterning.

	ACKNOWLEDGMENTS

 
This work was supported by the Dermatology Foundation, which supported Dr Haggstrom's pediatric dermatology fellowship and granted her a clinical investigator award to fund this and other studies of infantile hemangiomas. The American Skin Association generously provided funding for data analysis.

We gratefully acknowledge the hard work and assistance of the Hemangioma Investigator Group (Beth A. Drolet, Eulalia Baselga, Sarah Chamlin, Nancy B. Esterly, Ilona J. Frieden, Maria Garzon, Anita N. Haggstrom, Kimberly A. Horii, Anne Lucky, Anthony J. Mancini, Denise Metry, Brandon Newell, and Amy Nopper), whose members were responsible for patient recruitment, data collection, and invaluable guidance. We also thank Sarajo Frieden for illustrating Fig 1.

	FOOTNOTES

 
Accepted Jul 13, 2005.

Address correspondence to Anita N. Haggstrom, MD, 5007 Benton Ave, Bethesda, MD 20814. E-mail: anitahaggstrom{at}yahoo.com

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

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002; 138: 1567–1576[Abstract/Free Full Text]
2. Waner M, North PE, Scherer KA, Frieden IJ, Waner A, Mihm MC Jr. The nonrandom distribution of facial hemangiomas. Arch Dermatol. 2003; 139: 869–875[Abstract/Free Full Text]
3. Larsen, WJ. Human Embryology. New York, NY: Churchill Livingstone; 1993:321;360–371
4. Happle R, Assim A. The lines of Blaschko on the head and neck. J Am Acad Dermatol. 2001; 44: 612–615[ISI][Medline]
5. Enjolras O, Riche MC, Merland JJ. Facial port-wine stains and Sturge-Weber syndrome. Pediatrics. 1985; 76: 48–51[Abstract/Free Full Text]
6. Wedden SE, Ralphs JR, Tickle C. Pattern formation in the facial primordia. Development. 1988; 103(suppl): 31–40
7. Francis-West P, Ladher R, Barlow A, Graveson A. Signalling interactions during facial development. Mech Dev. 1998; 75: 3–28[CrossRef][ISI][Medline]
8. Schneider RA, Hu D, Helms JA. From head to toe: conservation of molecular signals regulating limb and craniofacial morphogenesis. Cell Tissue Res. 1999; 296: 103–109[CrossRef][ISI][Medline]
9. Couly G, Le Douarin NM. Head morphogenesis in embryonic avian chimeras: evidence for a segmental pattern in the ectoderm corresponding to the neuromeres. Development. 1990; 108: 543–58[Abstract/Free Full Text]
10. Hu D, Marcucio R, Helms JA. A zone of frontonasal ectoderm regulates patterning and growth in the face. Development. 2003; 130: 1749–1758[Abstract/Free Full Text]
11. Noden DM. The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev Biol. 1978; 67: 296–312[CrossRef][ISI][Medline]
12. Jiang X, Iseki S, Maxson RE, Sucov HM, Morriss-Kay GM. Tissue origins and interactions in the mammalian skull vault. Dev Biol. 2002; 241: 106–116[CrossRef][ISI][Medline]
13. Noden DM. Origins and patterning of avian outflow tract endocardium. Development. 1991; 111: 867–876[Abstract/Free Full Text]
14. Noden DM. Origins and assembly of avian embryonic blood vessels. Ann N Y Acad Sci. 1990; 588: 236–249[Abstract]
15. Korn J, Christ B, Kurz, H. Neuroectodermal origin of brain pericytes and vascular smooth muscle cells. J Comp Neurol. 2002; 442: 78–88[CrossRef][ISI][Medline]
16. Allt G, Lawrenson JG. Pericytes: cell biology and pathology. Cells Tissues Organs. 2001; 169: 1–11[CrossRef][ISI][Medline]
17. Metry DW, Dowd CF, Barkovich AJ, Frieden IJ. The many faces of PHACE syndrome [published correction appears in J Pediatr. 2001;139:470]. J Pediatr. 2001; 139: 117–123.[CrossRef][ISI][Medline]
18. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001; 137: 559–570[Abstract/Free Full Text]

This article has been cited by other articles:

				M. C. Garzon, B. A. Drolet, E. Baselga, S. L. Chamlin, A. N. Haggstrom, K. Horii, A. W. Lucky, A. J. Mancini, D. W. Metry, B. Newell, et al. Comparison of Infantile Hemangiomas in Preterm and Term Infants: A Prospective Study Arch Dermatol, September 1, 2008; 144(9): 1231 - 1232. [Full Text] [PDF]

				L. C. Chang, A. N. Haggstrom, B. A. Drolet, E. Baselga, S. L. Chamlin, M. C. Garzon, K. A. Horii, A. W. Lucky, A. J. Mancini, D. W. Metry, et al. Growth Characteristics of Infantile Hemangiomas: Implications for Management Pediatrics, August 1, 2008; 122(2): 360 - 367. [Abstract] [Full Text] [PDF]

				M. Castillo PHACES Syndrome: From the Brain to the Face via the Neural Crest Cells AJNR Am. J. Neuroradiol., April 1, 2008; 29(4): 814 - 815. [Full Text] [PDF]

				V.S. Oza, E. Wang, A. Berenstein, M. Waner, D. Lefton, J. Wells, and F. Blei PHACES Association: A Neuroradiologic Review of 17 Patients AJNR Am. J. Neuroradiol., April 1, 2008; 29(4): 807 - 813. [Abstract] [Full Text] [PDF]

				G. L. Heyer, M. M. Dowling, D. J. Licht, S. K.-H. Tay, K. Morel, M. C. Garzon, and P. Meyers The Cerebral Vasculopathy of PHACES Syndrome Stroke, February 1, 2008; 39(2): 308 - 316. [Abstract] [Full Text] [PDF]

				E. Pope, B. R. Krafchik, C. Macarthur, D. Stempak, D. Stephens, M. Weinstein, N. Ho, and S. Baruchel Oral Versus High-Dose Pulse Corticosteroids for Problematic Infantile Hemangiomas: A Randomized, Controlled Trial Pediatrics, June 1, 2007; 119(6): e1239 - e1247. [Abstract] [Full Text] [PDF]

				A. N. Haggstrom, B. A. Drolet, E. Baselga, S. L. Chamlin, M. C. Garzon, K. A. Horii, A. W. Lucky, A. J. Mancini, D. W. Metry, B. Newell, et al. Prospective Study of Infantile Hemangiomas: Clinical Characteristics Predicting Complications and Treatment Pediatrics, September 1, 2006; 118(3): 882 - 887. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Haggstrom, A. N. Articles by Frieden, I. J. Search for Related Content PubMed PubMed Citation Articles by Haggstrom, A. N. Articles by Frieden, I. J. Related Collections Heart & Blood Vessels

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved.