Infantile Hemangioma

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Mappings

MONDO

MONDO:0011191 capillary infantile hemangioma

Primary MONDO disease identifier for this entry.

NCIT

NCIT:C6645 Infantile Hemangioma

NCIT concept for the same tumor, which MONDO lists as a cross-reference of MONDO:0011191.

ICD-10-CM

ICD10CM:D18.0 Hemangioma

The ICD-10-CM codes whose labels name hemangioma are D18 and its children, which are divided by site. None is specific to infantile hemangioma, and D18.0 covers hemangioma of any kind and at any age.

NCIT

NCIT:C6645 Infantile Hemangioma

NCIT concept for the same tumor, which MONDO lists as a cross-reference of MONDO:0011191.

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Inheritance

2

Sporadic HP:0003745

Most hemangiomas occur in a child with no affected relative. In a study of 202 sets of twins, identical twins were not more often both affected than non-identical twins (18 of 42 pairs against 52 of 146), which argues against a strong inherited cause. The authors conclude that the origin is multifactorial.

Sporadic

Show evidence (3 references)

PMID:9916848 SUPPORT DIRECT BACKGROUND Human clinical

"Although most hemangiomas occur sporadically and as single lesions, or in conjunction with pleiotropic genetic syndromes, we have previously identified six kindreds where hemangiomas appear to segregate as an autosomal dominant trait with high penetrance."

The introduction of a linkage study: most hemangiomas occur sporadically.

PMID:26863906 SUPPORT DIRECT PRIMARY RESULT Human clinical

"There was no statistically significant difference in rates of concordance between monozygotic twins (43%, 18/42) and dizygotic twins (36%, 52/146) (p = 0.50)."

The twin study: both twins were affected in 43 per cent of monozygotic and 36 per cent of dizygotic pairs, a difference that was not significant.

PMID:26863906 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"These findings suggest that the origin of IHs is multifactorial and that predisposing factors such as birthweight, sex, and GA may interact with one another such that a threshold is reached for clinical expression."

The authors' conclusion from the twin study: the origin is multifactorial.

Autosomal dominant in rare families HP:0000006

Six families have been described in which hemangiomas, and in some members vascular malformations, pass through two to four generations as an autosomal dominant trait with moderate to high penetrance. A genome-wide linkage search in five of them found linkage to chromosome 5q in three and evidence that the others map elsewhere. The papers cited name candidate genes in the region and identify no causal gene.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:9645641 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We report the rare familial occurrence of hemangiomas and/or vascular malformations in 6 kindreds, suggesting autosomal dominant inheritance."

The report of the six kindreds.

PMID:9645641 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The vascular lesions appeared to be transmitted in an autosomal dominant fashion with moderate to high penetrance."

The same report: autosomal dominant transmission with moderate to high penetrance.

PMID:9916848 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We established evidence for linkage to 5q in three families, and evidence for locus heterogeneity."

The linkage study in five of the families: linkage to 5q in three, and locus heterogeneity.

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Subtypes

1

Infantile hepatic hemangioma NCIT:C96840

NCIT NCIT:C96840

Infantile hemangioma of the liver. Its endothelium is GLUT1-positive, like that of the tumor in the skin. It is usually multifocal or diffuse; a single liver lesion present at birth is usually a congenital hemangioma. Most multifocal lesions cause no symptoms. The complications are heart failure from blood shunted through the tumors, hypothyroidism from an enzyme made by the tumor and, in diffuse disease, a liver large enough to compress the abdomen. In a prospective screening study, five or more hemangiomas of the skin was the best cut-off for examining the liver by ultrasound. The older name hepatic hemangioendothelioma should no longer be used for it.

NCIT: Liver Infantile Hemangioma (skos:exactMatch) NCIT:C96840

Show evidence (7 references)

PMID:14991538 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Our results indicate that there are two fundamentally different hepatic vascular lesions in infants and young children: GLUT1-positive hepatic infantile hemangioma (HIH) and GLUT1-negative hepatic vascular malformation with capillary proliferation (HVMCP)."

A pathology review of 19 liver vascular lesions of infants and young children: the infantile hemangioma of the liver is GLUT1-positive, and the lesion it was confused with, a vascular malformation with capillary proliferation, is GLUT1-negative.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Hepatic IHs usually present as a multifocal or diffuse hepatic distribution, whereas congenital hepatic hemangiomas present as a focal hepatic lesion"

A 2021 review: infantile hemangiomas of the liver are usually multifocal or diffuse, and congenital ones focal.

PMID:17208542 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We propose that hepatic hemangiomas do not represent a single entity but, rather, 3 principle categories of lesions: focal, multifocal, and diffuse."

The classification proposed in 2007 from radiology and pathology studies: focal, multifocal and diffuse lesions.

+ 4 more references

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Mechanistic Hypotheses

3

The tumor grows from a multipotent stem cell that forms its vessels and later its fat

stem_cell_origin ALTERNATIVE

Evidence balance 5 support

Proposed in 2008. In favour: stem cells from the tumor form GLUT1-positive human vessels in mice and later fat, which is the course the tumor takes in a child; and the endothelial cells of the tumor are clonal, as cells that descend from one cell would be. Against a settled answer: the experiments were done with cultured cells and with implants in immunodeficient mice, the studies cited identify no mutation that would make such a cell grow, and the hypothesis does not say what sets the cell off. Reviews list it beside the placental and hypoxia hypotheses, which are not exclusive of it, so none of the three is marked CANONICAL. Its two edges run from Hemangioma Stem Cell Vasculogenesis to Proliferating GLUT1-Positive Endothelium and to Involution with Fibrofatty Replacement.

Pathograph links

Hemangioma Stem Cell Vasculogenesis -> Proliferating GLUT1-Positive Endothelium DIRECT The stem cells are proposed to give rise to the endothelium of the tumor. Shown for human cells implanted in mice; the step has not been observed in a child.

Hemangioma Stem Cell Vasculogenesis -> Involution with Fibrofatty Replacement DIRECT The fat that replaces the tumor is proposed to come from the same stem cells. Shown for human cells implanted in mice.

Show evidence (5 references)

PMID:18535669 SUPPORT INDIRECT PRIMARY RESULT Model organism

"In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy."

The authors' conclusion: a stem cell is the cell of origin. An inference from cultured cells and from implants in mice.

PMID:18535669 SUPPORT INDIRECT PRIMARY RESULT Model organism

"Thus, when transplanted into immunodeficient mice, hemangioma-derived cells recapitulated the unique evolution of infantile hemangioma"

The implanted cells went through the course of the tumor, vessels first and fat later.

PMID:11254674 SUPPORT INDIRECT PRIMARY RESULT In vitro / ex vivo

"We conclude that hemangiomas constitute clonal expansions of endothelial cells. This is consistent with the possibility that these tumors are caused by somatic mutations in one or more genes regulating endothelial cell proliferation."

The 2001 clonality study: hemangiomas are clonal expansions of endothelial cells, which the authors call consistent with a somatic mutation. No mutation was shown.

+ 2 more references

The tumor cells come from the placenta or are programmed like placental vessels

placental_origin ALTERNATIVE

Evidence balance 8 support

Proposed in 2001, when the endothelium of the tumor was found to share four markers with the vessels of the placenta that the vessels of normal skin lack. In favour: the pattern of gene expression of the tumor is closer to that of the placenta than to that of any other tissue compared; abnormalities of the placenta are about twice as common in affected pregnancies; and hemangiomas were about three times as common after chorionic villus sampling, which disturbs the placenta, as after amniocentesis. The hypothesis exists in two forms, cells carried from the placenta to the child and cells of the child that take on a placental program, and the evidence does not separate them. No edge of the graph belongs to it, because no step of it has been observed.

Show evidence (8 references)

PMID:11346333 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"All of 66 hemangiomas (patients aged 22 days to 7 years) showed intense immunoreactivity for FcgammaRII, merosin, LeY, and GLUT1."

All 66 hemangiomas stained for the four antigens.

PMID:11346333 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"Microvascular immunoreactivity for all 4 markers was observed in placental chorionic villi, but was absent in microvessels of normal skin and subcutis."

The vessels of placental villi carried all four; the vessels of normal skin carried none.

PMID:11346333 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"A distinct constellation of tissue-specific markers is uniquely coexpressed by hemangiomas and placental microvessels. These findings imply a unique relationship between hemangioma and the placenta and suggest new hypotheses concerning the origin of these tumors."

The authors' conclusion: a relationship between hemangioma and placenta that suggests new hypotheses of origin.

+ 5 more references

Low oxygen in the tissue starts or drives the growth of the tumor

hypoxia_trigger ALTERNATIVE

Evidence balance 5 support

Low oxygen makes tissues release signals that call in and expand vessel-forming progenitor cells. In favour: these signals were raised in the blood and the tumors of ten children with growing hemangiomas; low oxygen and estrogen together made hemangioma endothelial cells divide faster in culture; and the conditions that raise the risk, among them prematurity, low birth weight, pre-eclampsia and placenta previa, are ones in which the fetus or the placenta is short of oxygen. The evidence is of association. The hypothesis can be combined with either of the other two. No edge of the graph belongs to it.

Show evidence (5 references)

PMID:17872454 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Surgical specimens and blood samples were obtained from children with proliferating hemangioma and age-matched controls (n=10, each group)."

A 2007 study: specimens and blood from ten children with proliferating hemangiomas and ten controls.

PMID:17872454 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"We found that all these mediators of EPC trafficking are elevated in blood and specimens from children with proliferating infantile hemangioma."

The mediators measured, which low oxygen induces, were raised in the blood and the tumors of the children with hemangiomas.

PMID:17872454 SUPPORT INDIRECT PRIMARY RESULT In vitro / ex vivo

"In vitro, the combination of hypoxia and estrogen demonstrated a synergistic effect on hemangioma endothelial cell proliferation."

In culture, hypoxia and estrogen together increased the proliferation of hemangioma endothelial cells.

+ 2 more references

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Discussions and Knowledge Gaps

2

What starts an infantile hemangioma: a stem cell that has gone wrong, cells from the placenta, a lack of oxygen, or a combination?

KNOWLEDGE GAP OPEN ih_origin_unknown

Attached to

mechanistic_hypotheses#stem_cell_origin mechanistic_hypotheses#placental_origin mechanistic_hypotheses#hypoxia_trigger pathophysiology#Hemangioma Stem Cell Vasculogenesis

The three hypotheses answer different questions and are not exclusive. The stem cell work shows which cell can build the tumor, in mice, and not why it starts to. The placental and hypoxia hypotheses rest on shared markers and on associations with events of pregnancy. No study cited follows a tumor from its first cell in a child, and none identifies a genetic change in the tumor. Until one of these is done, the first step of the disease cannot be drawn.

Show evidence (4 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The pathogenesis of IH has not yet been completely defined, and current studies support several hypotheses."

A 2021 review: the pathogenesis is not completely defined.

PMID:16365311 SUPPORT DIRECT BACKGROUND Human clinical

"The origin of the pathogenic endothelial cells in common infantile hemangioma is unknown."

The opening of the 2005 transcriptome study: the origin of the endothelial cells is unknown.

PMID:11254674 SUPPORT DIRECT BACKGROUND Human clinical

"Hemangioma, the most common tumor of infancy, is a benign vascular neoplasm of unknown etiology."

The opening of the 2001 clonality study: a neoplasm of unknown etiology.

+ 1 more reference

How does propranolol shrink an infantile hemangioma: by blocking beta-adrenergic receptors, by inhibiting the transcription factor SOX18, or both?

KNOWLEDGE GAP OPEN ih_propranolol_mechanism

Attached to

treatments#Oral Propranolol pathophysiology#Hemangioma Stem Cell Vasculogenesis

The effect of the drug on hemangiomas was noticed in infants treated for a heart condition, and it was adopted before its action was understood. A review lists five proposed actions. A laboratory study found that the R enantiomer, which has little beta-blocking activity, stops hemangioma stem cells from becoming endothelial cells as well as the mixture does, and attributes this to SOX18. If that is the action that matters in children, the R enantiomer alone might treat the tumor without the harms of beta-blockade, which the authors propose. Atenolol, which blocks beta-1 receptors selectively, worked as well as propranolol in a trial, which any account has to explain.

Show evidence (6 references)

PMID:31358114 SUPPORT DIRECT BACKGROUND Human clinical

"Propranolol use in obstructive hypertrophic cardiomyopathy revealed its beneficial effects in infantile hemangioma"

The 2019 study recalls how the effect was found: in the use of propranolol for obstructive hypertrophic cardiomyopathy.

PMID:31358114 SUPPORT DIRECT BACKGROUND Human clinical

"Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited."

The same study: the mechanism behind the clinical benefit is poorly understood.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The mechanism of action of propranolol on IHs is unclear; however, the hypothesized mechanisms are the induction of vasoconstriction, angiogenesis inhibition by decreased VEGF and bFGF levels, induction of endothelial cell apoptosis, inhibition of nitric oxide production, and suppression of the..."

A 2021 review: the mechanism is unclear, with the hypothesized actions listed.

+ 3 more references

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Pathophysiology

7

Hemangioma Stem Cell Vasculogenesis

The tumor contains multipotent stem cells, about 0.2 per cent of its cells, picked out by the marker CD133. Populations grown from single such cells formed human blood vessels within seven days of being implanted under the skin of immunodeficient mice, and the vessels carried GLUT1 and merosin, the markers of infantile hemangioma. The authors conclude that a stem cell, and not a mature endothelial cell, is the cell the tumor comes from. In culture, propranolol and its R enantiomer blocked the change of these stem cells into endothelial cells.

The tumor grows from a multipotent stem cell that forms its vessels and later its fat

hemangioma stem cell CL:0000048

vasculogenesis GO:0001570 ↑ INCREASED

Animal models

Hemangioma stem cell implant in nude mice Mouse recapitulates Human hemangioma stem cells form GLUT1-positive human vessels in the implant.

Downstream

Proliferating GLUT1-Positive Endothelium The stem cells are proposed to give rise to the endothelium of the tumor. Shown for human cells implanted in mice; the step has not been observed in a child.

Involution with Fibrofatty Replacement The fat that replaces the tumor is proposed to come from the same stem cells. Shown for human cells implanted in mice.

Show evidence (6 references)

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT Model organism

"Here, we have reported the isolation of multipotential stem cells from hemangioma tissue that give rise to hemangioma-like lesions in immunodeficient mice."

The stem cell study: stem cells isolated from hemangioma tissue gave rise to hemangioma-like lesions in immunodeficient mice.

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"Cells were isolated based on expression of the stem cell marker CD133 and expanded from single cells as clonal populations."

The cells were selected by CD133 and grown from single cells.

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"approximately 0.2% of the hemangioma cells were selected with anti-CD133–coated beads"

About 0.2 per cent of the cells of proliferating tumors were selected, in 28 specimens.

+ 3 more references

Suppressed NFAT-Dependent VEGFR1 Expression

Endothelial cells cultured from the hemangiomas of nine patients make little VEGFR1, the receptor that binds the growth factor VEGF without passing on a growth signal: its protein level was 10 to 20 per cent of that in control cells. The gene for VEGFR1 (FLT1) is switched on by the transcription factor NFAT, and NFAT is underactive in these cells because a pathway through beta-1 integrin, the integrin-like receptor TEM8 (ANTXR1) and VEGFR2 is underactive. Hemangioma tissue in the proliferating phase showed the same low ratio of VEGFR1 to VEGFR2 transcripts; involuting tissue did not.

hemangioma endothelial cell CL:0000071

FLT1 hgnc:3763

calcineurin-NFAT signaling cascade GO:0033173 ↓ DECREASED

vascular endothelial growth factor binding GO:0038085 ↓ DECREASED

Downstream

Constitutive VEGFR2 Signaling With little VEGFR1 to hold VEGF back, VEGF reaches VEGFR2 and keeps it active.

Show evidence (5 references)

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"We show that expression of vascular endothelial growth factor receptor-1 (VEGFR1) in hemangioma endothelial cells (hemECs) and hemangioma tissue is markedly reduced compared to controls."

The 2008 study: VEGFR1 expression is markedly reduced in hemangioma endothelial cells and in hemangioma tissue.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"The results showed that VEGFR1 protein levels in hemEC were only 10−20% of those in control cells"

VEGFR1 protein in the cultured cells of all nine patients was 10 to 20 per cent of control.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"In hemECs, transcription of the gene encoding VEGFR1 (FLT1) is dependent on nuclear factor of activated T cells (NFAT)."

Transcription of the VEGFR1 gene depends on NFAT in these cells.

+ 2 more references

Constitutive VEGFR2 Signaling

VEGF made by the tumor cells themselves keeps the receptor VEGFR2 switched on. The cultured hemangioma endothelial cells of all nine patients showed it, and they migrated and divided like normal endothelial cells that had been given VEGF. Soluble VEGFR1, or antibodies that neutralize VEGF, returned the signalling to normal. The finding rests on the cultured cells of nine patients in one study.

hemangioma endothelial cell CL:0000071

KDR hgnc:6307

vascular endothelial growth factor receptor signaling pathway GO:0048010 ↑ INCREASED

vascular endothelial growth factor receptor activity GO:0005021 ↑ INCREASED

Downstream

Proliferating GLUT1-Positive Endothelium Active VEGFR2 is proposed to drive the division and movement of the endothelial cells of the growing tumor. Shown in cultured cells.

Show evidence (2 references)

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"We report here that cultured hemEC from nine unrelated individuals with hemangioma (Supplementary Table 1 online) share a phenotype of constitutively active vascular endothelial growth factor receptor 2 (VEGFR2) signaling."

Cultured hemangioma endothelial cells from nine unrelated patients shared constitutively active VEGFR2 signalling.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"Normalization of the constitutive VEGFR2 signaling in hemECs with soluble VEGFR1 or antibodies that neutralize VEGF or stimulate beta1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment."

Soluble VEGFR1, or antibodies that neutralize VEGF or stimulate beta-1 integrin, normalized the signalling in the cultured cells.

Proliferating GLUT1-Positive Endothelium

In its growing phase the tumor is a dense mass of dividing endothelial cells that form capillaries. Endothelial cells cultured from growing hemangiomas are clonal, and they divide and move faster than normal endothelial cells. The endothelium stains strongly for the glucose transporter GLUT1 in every phase of the tumor, growing or shrinking: in a pathology study 139 of 143 hemangiomas were positive and none of 66 vascular malformations. GLUT1 is otherwise found in endothelium that forms a barrier between blood and tissue, as in the brain and the placenta, and the hemangioma shares three further markers with the vessels of the placenta.

hemangioma endothelial cell CL:0000071

endothelial cell proliferation GO:0001935 ↑ INCREASED

skin UBERON:0002097 liver UBERON:0002107 subglottis UBERON:0036068

Downstream

Cutaneous Hemangioma The dividing endothelium is the growing tumor seen in the skin.

Skin Ulcer Ulcers form while the tumor is growing. Why the skin over a growing hemangioma breaks down is not established in the sources cited.

Amblyopia A tumor of the eyelid can press on the eye and distort it, producing astigmatism, or cover the pupil. Either can leave the eye with poor vision.

Subglottic Hemangioma The same tumor can grow in the wall of the airway below the vocal cords.

Hepatic Hemangioma The same tumor can grow in the liver.

High-Flow Shunting Through Hepatic Hemangiomas The vessels of large or numerous liver tumors can carry blood past the liver tissue.

Type 3 Iodothyronine Deiodinase Activity in Tumor Tissue The tumor tissue itself makes the enzyme.

Show evidence (7 references)

PMID:10665907 SUPPORT DIRECT BACKGROUND Human clinical

"These lesions enlarge rapidly through cellular hyperplasia during the first year of life and then involute over several years."

The opening of the GLUT1 study: the tumors enlarge through cellular hyperplasia in the first year and then involute.

PMID:11254674 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"We show, for the first time to our knowledge, that endothelial cells from proliferating hemangioma are clonal, and we demonstrate that these hemangioma-derived cells differ from normal endothelial cells in their rates of proliferation and migration in vitro."

A 2001 study: endothelial cells from proliferating hemangiomas are clonal and differ from normal endothelial cells in how fast they proliferate and migrate in culture.

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We report here that high endothelial immunoreactivity for the erythrocyte-type glucose transporter protein GLUT1 is a specific feature of juvenile hemangiomas during all phases of these lesions."

High endothelial GLUT1 staining is a feature of the tumor in all its phases.

+ 4 more references

Involution with Fibrofatty Replacement

After the growing phase the vessels regress and the tumor is slowly replaced by fat and fibrous tissue. Two studies put the end of this process at about three and a half years: a median of 36 months in one, with 92 per cent of tumors finished by 48 months, and a mean of 3.5 years in the other. In mice, the vessels formed by implanted hemangioma stem cells thinned out after two months and human fat cells appeared in their place. What starts the regression is not known.

adipocyte CL:0000136

fat cell differentiation GO:0045444 ↑ INCREASED

Animal models

Hemangioma stem cell implant in nude mice Mouse partially recapitulates The vessels of the implant diminish and human fat cells appear, as in the involuting tumor.

Downstream

Residual Telangiectasia Fine dilated vessels are the commonest change left in the skin when the tumor has gone.

Anetoderma The skin over the former tumor can be left slack and thinned.

Show evidence (4 references)

PMID:18535669 SUPPORT DIRECT BACKGROUND Human clinical

"It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum."

The opening of the stem cell study: rapid growth after birth, then slow regression to a fibrofatty residuum.

PMID:22575857 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Kaplan-Meier analysis estimated that involution ceased at a median age of 36 months (interquartile range, 30 to 42 months), and 92 percent of tumors completed involution by 48 months."

A study of 81 patients, most of whom later had reconstructive surgery: improvement stopped at a median of 36 months, and 92 per cent of tumors had finished involuting by 48 months.

PMID:27540637 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The average age at which hemangioma completed involution was 3.5 years."

A study of 184 hemangiomas that had no systemic treatment: involution was complete at 3.5 years on average.

+ 1 more reference

High-Flow Shunting Through Hepatic Hemangiomas

Multifocal and diffuse hemangiomas of the liver can carry so much blood through large shunting vessels that the heart has to pump more than it can sustain.

liver UBERON:0002107

Downstream

High-Output Heart Failure The shunted blood returns to the heart at once, so the heart must raise its output.

Show evidence (2 references)

PMID:17208542 SUPPORT DIRECT BACKGROUND Human clinical

"Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."

The paper that classified hepatic hemangiomas: heart failure goes with high-volume shunting.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure"

A 2021 review: high-flow shunting through multiple hepatic hemangiomas causes high-output cardiac failure.

Type 3 Iodothyronine Deiodinase Activity in Tumor Tissue

Hemangioma tissue can make large amounts of type 3 iodothyronine deiodinase, the enzyme that inactivates thyroid hormone. When there is much tumor, as in multifocal or diffuse disease of the liver, the hormone is broken down faster than the thyroid gland can replace it. The condition is called consumptive hypothyroidism.

DIO3 hgnc:2885

thyroid hormone catabolic process GO:0042404 ↑ INCREASED

type 3 iodothyronine deiodinase activity GO:0033798 ↑ INCREASED

Downstream

Hypothyroidism Thyroid hormone is destroyed in the tumor faster than it is made.

Show evidence (3 references)

PMID:32508067 SUPPORT DIRECT BACKGROUND Human clinical

"Consumptive hypothyroidism is a rare paraneoplastic syndrome characterized by excessive inactivation of the thyroid hormones due to increased type 3 iodothyronine deiodinase activity of tumors."

The opening of a case report of 2020 defines the condition: thyroid hormone is inactivated by the type 3 deiodinase activity of a tumor.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"

A 2021 review: in multiple or diffuse hepatic hemangiomas the enzyme in the tumor tissue inactivates thyroid hormone.

PMID:21382982 SUPPORT INDIRECT BACKGROUND Human clinical

"Hepatic haemangioendotheliomata is capable of producing an excess of the thyroid hormone inactivating enzyme, type 3 iodothyronine deiodinase. The increased enzyme activity leads to rapid degradation of thyroid hormones, resulting in frank hypothyroidism."

A case report and review of 2011 states the mechanism. It uses the older name hepatic haemangioendothelioma. The case, an infant of three months with multiple liver tumors, fits infantile hepatic hemangioma, but the abstract reports no GLUT1 staining, so the item is graded indirect.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 5

Cutaneous Hemangioma Capillary hemangioma HP:0005306

Show evidence (11 references)

PMID:22826568 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Hemangioma precursors were present at birth in 65% of patients."

A study of parents' photographs of 30 infants with facial hemangiomas: a precursor was present at birth in 65 per cent.

PMID:22826568 SUPPORT DIRECT PRIMARY RESULT Human clinical

"IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age."

The same study: growth was fastest between 5.5 and 7.5 weeks of age.

PMID:18676554 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Eighty percent of hemangioma size was reached during the early proliferative stage at a mean age of 3 months."

A referral cohort with growth data on 526 hemangiomas: 80 per cent of the final size was reached at a mean age of three months.

+ 8 more references

Subglottic Hemangioma VERY_RARE HP:0410264

Show evidence (5 references)

PMID:30174006 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Analysis of 761 cases of infantile hemangiomas demonstrated only 13 patients with subglottic hemangiomas (1.7%)."

One center, 2013 to 2017: 13 of 761, which is 1.7 per cent and falls in the VERY_RARE band, below 5 per cent.

PMID:41860115 SUPPORT DIRECT PRIMARY RESULT Human clinical

"This study included 798 children with an IH visiting our paediatric vascular anomaly unit between 1.1.2008 and 31.12.2017."

A second center: 798 children seen between 2008 and 2017.

PMID:41860115 SUPPORT DIRECT PRIMARY RESULT Human clinical

"An airway IH was diagnosed in 1.6% of the cohort. When a segmental beard distribution hemangioma was present, the risk for an airway IH was 33.3%, and when a non-beard distribution segmental hemangioma on the face or neck was observed, the risk was 11.5%."

In that series an airway hemangioma was diagnosed in 1.6 per cent, also in the VERY_RARE band. The risk was 33.3 per cent with a segmental hemangioma in the beard distribution. The figure counts hemangiomas anywhere in the airway.

+ 2 more references

Hepatic Hemangioma HP:0031207

Sequelae: Hepatomegaly

Show evidence (3 references)

PMID:33285272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH."

The screening study: 31 infants with a hepatic hemangioma among 676 with three or more skin hemangiomas and 980 with one or two.

PMID:33285272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Screening for IHH is recommended in patients younger than 9 months who present with 5 or more cutaneous IHs."

Its conclusion: screen infants younger than nine months who have five or more skin hemangiomas.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Hepatic IHs usually present as a multifocal or diffuse hepatic distribution, whereas congenital hepatic hemangiomas present as a focal hepatic lesion"

A 2021 review: usually multifocal or diffuse.

High-Output Heart Failure High-output congestive heart failure HP:0001722

Show evidence (4 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure"

A 2021 review: high-flow shunting through multiple hepatic hemangiomas causes high-output cardiac failure.

PMID:17208542 SUPPORT DIRECT BACKGROUND Human clinical

"Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."

Congestive heart failure with high-volume shunting is among the presentations of hepatic hemangioma.

PMID:32508067 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."

A boy of one month with diffuse infantile hepatic hemangiomas presented with cardiac failure. One case.

+ 1 more reference

Residual Telangiectasia HP:0001009

No frequency band is set. The abstract reports telangiectasia in 145 hemangiomas, which it gives as 84.3 per cent. That percentage corresponds to 172 hemangiomas and not to the 184 included, and the abstract does not say what the 172 are.

Show evidence (3 references)

PMID:27540637 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Multicentric retrospective cohort study of images from 187 infantile hemangiomas that had not received systemic treatment and had follow-up pictures until regression"

The study: photographs of hemangiomas that had no systemic treatment, followed until regression, from four hospitals in three countries.

PMID:27540637 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."

Significant sequelae in 101 of 184; telangiectasia the commonest kind.

PMID:36434402 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Of 4448 articles initially identified, 62 underwent full-text review, and 17 met inclusion criteria. The overall rate of sequelae ranged from 5.3 to 93.5%."

A systematic review of 17 studies: overall rates of sequelae from 5.3 to 93.5 per cent.

Digestive 1

Hepatomegaly HP:0002240

Show evidence (2 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Diffuse hepatic IHs are rare but present as severe hepatomegaly leading to abdominal compartment syndrome causing abnormal ventilation and renal failure due to renal vein compression"

A 2021 review: severe hepatomegaly leading to abdominal compartment syndrome, with abnormal ventilation and renal failure from compression of the renal veins.

PMID:17208542 SUPPORT DIRECT BACKGROUND Human clinical

"Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."

The paper that classified hepatic hemangiomas lists abdominal compartment syndrome among the presentations.

Endocrine 1

Hypothyroidism HP:0000821

Show evidence (4 references)

PMID:32508067 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."

A boy of one month with diffuse infantile hepatic hemangiomas and severe consumptive hypothyroidism. One case.

PMID:32508067 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The patient was successfully treated with propranolol, prednisolone, and levothyroxine, and he showed normal thyroid function at 3 months of age and normal neurodevelopment at 9 months of age."

The same boy was treated with propranolol, prednisolone and levothyroxine and had normal thyroid function at three months and normal development at nine.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"

A 2021 review: hypothyroidism can occur in multiple or diffuse hepatic hemangiomas, so thyroid function is tested.

+ 1 more reference

Eye 1

Amblyopia HP:0000646

Show evidence (4 references)

PMID:29766557 SUPPORT DIRECT BACKGROUND Human clinical

"Although some children with periocular infantile hemangiomas do not require treatment, these lesions may result in amblyopia and visual impairment if not properly treated."

The opening of the study: these lesions may result in amblyopia and visual impairment if not treated.

PMID:29766557 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Ninety-six patients (74% female, median age of onset 0.48 months) were included."

The series: 96 patients seen by a dermatologist and an ophthalmologist.

PMID:29766557 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Periocular infantile hemangiomas larger than 1 cm in diameter, with a deep component, and with involvement of the upper eyelid were significantly associated with astigmatism (P = .002, P = .02, and P = .003, respectively) and amblyopia (P = .002, P = .02, and P = .04, respectively)."

Size above 1 cm, a deep component and upper eyelid involvement were each associated with astigmatism and with amblyopia.

+ 1 more reference

Integument 2

Skin Ulcer OCCASIONAL HP:0200042

Show evidence (5 references)

PMID:18035154 SUPPORT DIRECT PRIMARY RESULT Human clinical

"One thousand ninety-six patients were enrolled, and 173 (15.8%) patients experienced ulceration."

The referral cohort: 173 of 1,096 children, which is 15.8 per cent and falls in the OCCASIONAL band of 5 to 29 per cent. Children seen at specialist clinics have larger tumors than children in general, so the figure is an upper bound.

PMID:18035154 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Ulceration occurred at a median age of 4 months, most often during the proliferative phase."

Ulceration came at a median age of four months, most often in the proliferative phase.

PMID:18035154 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Hemangiomas with ulcerations were more likely large, mixed clinical type, segmental morphologic type, and located on the lower lip, neck, or anogenital region."

The tumors that ulcerated were more often large, mixed, segmental, or on the lower lip, neck or anogenital region.

+ 2 more references

Anetoderma HP:0032026

Show evidence (1 reference)

PMID:27540637 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."

Anetodermic skin in 56 hemangiomas, given as 32.6 per cent. As for telangiectasia, the denominator is not stated, so no frequency band is set.

🧬

Genetic Associations

2

KDR (Germline missense variant C482R of VEGFR2)

Gene: KDR hgnc:6307 gene page relationship_type: RISK_FACTOR variant_origin: GERMLINE

Show evidence (6 references)

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In a subset of individuals with hemangioma, we found missense mutations in the genes encoding VEGFR2 (KDR) and TEM8 (ANTXR1)."

The 2008 study: missense changes in KDR and ANTXR1 in a subset of patients.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Allele-specific PCR identified heterozygosity for the same change in 8 blood genomic DNA samples collected from an additional 105 individuals with a history of hemangioma (10 total out of 114 individuals) and in 12 DNA samples from 295 “controls” (all Caucasian)."

The count in blood samples: 10 of 114 people with a history of hemangioma and 12 of 295 controls.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The controls include individuals with hemangioma at the population frequency (10%) (see Methods)."

The controls include people who had a hemangioma, at the frequency of the general population.

+ 3 more references

ANTXR1 (Germline missense variant A326T of TEM8, found in one patient)

Gene: ANTXR1 hgnc:21014 gene page relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (4 references)

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A germline G-to-A transition replaces alanine with threonine in the transmembrane domain of the integrin-like molecule TEM8 in hemEC4"

A germline change in TEM8 in the cells of one patient.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Using allele-specific PCR, we screened for the A allele in blood genomic DNA samples collected from 110 individuals with a history of hemangioma and 295 “controls” (all Caucasian; see below). No other individual carrying the A allele was found."

No other carrier among 110 people with a history of hemangioma and 295 controls.

PMID:18931684 SUPPORT DIRECT PRIMARY RESULT Human clinical

"we found heterozygosity for nucleotide changes resulting in potential disease-associated amino acid substitutions in three of the nine individuals with hemangioma"

Three of the nine patients carried a change in one of the two genes.

+ 1 more reference

💊

Medical Actions

7

Active Observation

Category: Monitoring Action: active observation Ontology label: Observation Activity NCIT:C25598

Most hemangiomas are left to run their course. The family is told what to expect, and the child is seen often in the first weeks and months, which is when a tumor that will cause trouble shows itself. In a randomized trial of 121 infants with early uncomplicated hemangiomas, those who were only observed did as well at one year as those treated with a pulsed dye laser.

Show evidence (5 references)

PMID:28089471 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Most infantile haemangiomas do not require therapy. However, to identify at-risk haemangiomas, close follow-up is crucial in the first weeks of life; 80% of all haemangiomas reach their final size by 3 months of age."

A 2017 review: most need no therapy, and close follow-up in the first weeks finds those at risk.

PMID:30584062 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Infantile hemangiomas (IHs) occur in as many as 5% of infants, making them the most common benign tumor of infancy. Most IHs are small, innocuous, self-resolving, and require no treatment."

The 2019 guideline: most are small, harmless and resolve without treatment.

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Of note, 20% of identified IHs were abortive or telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention."

In the cohort followed from birth, only one hemangioma required intervention.

+ 2 more references

Oral Propranolol

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: propranolol CHEBI:8499

Platform: Small molecule

A beta-blocker taken by mouth, and the first-line treatment for a hemangioma that needs one. In the randomized trial of 456 infants, 3 mg per kg per day for six months cleared or nearly cleared the tumor in 60 per cent, against 4 per cent on placebo, and 88 per cent had improved by the fifth week. One in ten of those who responded needed treatment again. A meta-analysis of 18 studies estimated clearance at 95 per cent with propranolol, 43 per cent with oral corticosteroids and 6 per cent without treatment. The guideline dose is 2 to 3 mg per kg per day for at least six months. Low blood sugar, low blood pressure, a slow heart rate and bronchospasm are the known harms; in the trial they were infrequent. How the drug works is not settled (see the discussions).

Mechanism Target:

INHIBITS Hemangioma Stem Cell Vasculogenesis — In culture, propranolol stops hemangioma stem cells from turning into endothelial cells. The R enantiomer, which has little beta-blocking activity, does the same, and the authors attribute the effect to inhibition of the transcription factor SOX18. Whether this is how the drug shrinks a tumor in a child is not known.

Show evidence (3 references)

PMID:31358114 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"Propranolol significantly decreased VEGF-B induced expression of all five endothelial markers in HemSC to levels also achieved by Sm4 as compared to controls"

Propranolol reduced the endothelial markers induced in hemangioma stem cells, as did an inhibitor of SOX18.

PMID:31358114 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"The R(+) enantiomer recapitulated propranolol and Sm4-induced inhibition on all markers, whereas the S(-) enantiomer showed only weak or no inhibition on hemangioma markers"

The R enantiomer had the effect and the S enantiomer little or none.

PMID:31358114 SUPPORT INDIRECT PRIMARY RESULT In vitro / ex vivo

"These results are consistent with a SOX18-dependent, β-adrenergic receptor independent blockade of hemangioma endothelial differentiation, which strongly suggests that blockade of SOX18 activity is the main mode of action of propranolol in this setting."

The authors' reading: a blockade of endothelial differentiation that depends on SOX18 and not on the beta-adrenergic receptor. An inference from cultured cells.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (11 references)

PMID:25693013 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy."

The trial: randomized, double-blind, in infants of one to five months with a proliferating hemangioma that needed systemic treatment.

PMID:25693013 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Of 460 infants who underwent randomization, 456 received treatment."

460 infants were randomized and 456 treated.

PMID:25693013 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001)."

Success at week 24 in 60 per cent on 3 mg per kg per day for six months and 4 per cent on placebo.

+ 8 more references

Atenolol

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: atenolol CHEBI:2904

Platform: Small molecule

A cardioselective beta-blocker. A randomized trial of 377 infants in China found it as effective as propranolol at six months (a response in 92.5 against 93.7 per cent), with fewer adverse events (44.4 against 70.0 per cent). An earlier trial of 23 patients found no significant difference in complete response.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (6 references)

PMID:24656727 SUPPORT DIRECT BACKGROUND Human clinical

"Atenolol is a cardioselective beta-blocker that may have fewer adverse events."

The background of the first trial: atenolol is cardioselective and may have fewer adverse events.

PMID:33856430 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A total of 377 patients met the criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187 [49.6%]) groups."

The larger trial: 377 infants randomized to propranolol or atenolol.

PMID:33856430 SUPPORT DIRECT PRIMARY RESULT Human clinical

"After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%)."

Response at six months in 93.7 per cent on propranolol and 92.5 per cent on atenolol.

+ 3 more references

Topical Timolol

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: timolol CHEBI:39465

Platform: Small molecule

A beta-blocker applied to the skin. The guideline allows it for selected small, thin, superficial hemangiomas. A placebo-controlled trial of 69 infants younger than 60 days found no significant difference in clearance at 24 weeks, 11 infants in each group, and concluded that the benefit is limited when the drug is given that early.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (4 references)

PMID:30584062 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Topical timolol may be used to treat select small, thin, superficial IHs."

The 2019 guideline: it may be used for selected small, thin, superficial hemangiomas.

PMID:33825828 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days"

The trial: 69 infants with a mean age of 48 days.

PMID:33825828 REFUTE DIRECT PRIMARY RESULT Human clinical

"There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37)."

Complete or nearly complete resolution at 24 weeks in 11 infants on timolol and 11 on placebo. The trial enrolled fewer infants than planned.

+ 1 more reference

Systemic Corticosteroids

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: prednisolone CHEBI:8378

Platform: Small molecule

Corticosteroids by mouth were used before propranolol and are now kept for children who cannot take propranolol or do not respond to it. A randomized trial of 19 infants found prednisolone and propranolol similarly effective, but six of the eight infants on prednisolone left the trial early because of adverse events, and none of the 11 on propranolol. The meta-analysis estimated clearance at 43 per cent with oral corticosteroids.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (5 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Systemic corticosteroid therapy may be considered in IH patients in whom propranolol is contraindicated or ineffective"

A 2021 review: considered when propranolol is contraindicated or ineffective.

PMID:24526257 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Phase 2, investigator-blinded, multi-institutional RCT conducted in 3 academic vascular anomalies clinics on 19 of 44 eligible infants aged between 2 weeks and 6 months."

The trial: 19 infants in three vascular anomaly clinics.

PMID:24526257 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Both medications show similar efficacy for reducing the area of symptomatic, proliferating IH. Although prednisolone showed a faster response rate, propranolol was better tolerated with significantly fewer severe AEs."

Similar efficacy; propranolol was better tolerated, with fewer severe adverse events.

+ 2 more references

Pulsed Dye Laser

Category: Therapeutic Action: pulsed dye laser treatment Ontology label: Laser Therapy NCIT:C15466

Platform: Device

Laser treatment of the surface of the tumor. A randomized trial of 121 infants found that treating early uncomplicated hemangiomas with it was no better than waiting: 42 per cent of treated and 44 per cent of observed children had clear or nearly clear skin at one year, and the treated children had more skin atrophy and more loss of pigment. Its accepted use is for the changes left in the skin after involution.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (4 references)

PMID:30584062 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Surgery and/or laser treatment are most useful for the treatment of residual skin changes after involution and, less commonly, may be considered earlier to treat some IHs."

The 2019 guideline: laser and surgery are most useful for residual skin changes after involution.

PMID:12241656 REFUTE DIRECT PRIMARY RESULT Human clinical

"The number of children whose lesions showed complete clearance or minimum residual signs at 1 year was not significantly different in the PDL treated and observation groups (25, 42%, vs 27, 44%; p=0.92)."

The trial: clearance or minimal residual signs at one year in 25 treated and 27 observed infants.

PMID:12241656 REFUTE DIRECT PRIMARY RESULT Human clinical

"However, PDL treated infants were more likely to have skin atrophy (17, 28%, vs 5, 8%; p=0.008) and hypopigmentation (27, 45%, vs 9, 15%; p=0.001)."

Skin atrophy and hypopigmentation were more frequent after laser treatment.

+ 1 more reference

Surgical Excision

Category: Therapeutic Action: surgical excision Ontology label: Excision NCIT:C15232

Platform: Surgery

Surgery is rarely the first treatment. It is used mainly to remove or reshape what the involuted tumor leaves behind. One study suggests considering it at about three and a half years of age, when most tumors have stopped improving.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (3 references)

PMID:30584062 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Surgery and/or laser treatment are most useful for the treatment of residual skin changes after involution and, less commonly, may be considered earlier to treat some IHs."

The 2019 guideline: surgery is most useful for residual changes and is less often considered earlier.

PMID:22575857 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Most infantile hemangiomas do not improve significantly after 3.5 years of age."

A study of the involuting phase: most hemangiomas do not improve significantly after 3.5 years of age.

PMID:22575857 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Twenty-six percent of the cohort was treated with a corticosteroid during the proliferative phase and 87.6 percent underwent reconstruction for a residual deformity."

In that series, 87.6 per cent had reconstruction for a residual deformity. Most of the series had surgery, so the figure does not describe hemangiomas in general.

🔬

Diagnosis

6

Clinical Examination

Most hemangiomas are diagnosed from the history and the look of the lesion: a mark that was absent or faint at birth, grew in the first weeks, and is soft. Features that do not fit call for imaging or a biopsy. They include a mass that is fully formed at birth, a firm mass that cannot be compressed, and new lesions after the first months of life.

physical examination NCIT:C20989

Show evidence (3 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Most IHs can be diagnosed clinically through history taking and physical examinations."

A 2021 review: most are diagnosed clinically.

PMID:39640139 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Our report demonstrates that atypical features include lesions that are noncompressible or appear after the first few months of a child’s life."

A case report of neuroblastoma taken for hemangiomas names the atypical features: lesions that cannot be compressed or that appear after the first few months.

PMID:27910123 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Clinically, these tumors differ from hemangiomas in the time of onset, morphology, and growth pattern and must be evaluated histologically for definitive diagnosis."

A case report and review of infantile fibrosarcoma: it differs from hemangioma in time of onset, shape and growth, and needs histology.

Doppler Ultrasonography

The first imaging test. It is advised when the diagnosis is uncertain, when the tumor grows explosively or for too long, when there are five or more tumors of the skin, and when an associated anomaly is suspected. A hemangioma is a well-defined solid mass with high blood flow and no arteriovenous shunting. In a reported case, nodules that had been taken for deep hemangiomas showed no increase in blood flow, and the examination went on to find an adrenal mass.

Doppler ultrasonography NCIT:C62781

Show evidence (3 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"US with Doppler is the imaging modality of choice for IH assessment and is recommended when the diagnosis of IH is uncertain, when IHs show explosive or prolonged growth without involution, to differentiate IHs from malignant vascular tumors or vascular malformations, when there are 5 or more..."

A 2021 review: Doppler ultrasound is the imaging method of choice, with its indications.

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"On US with Doppler, IHs appear as well-defined solid masses with high-flow vascularity but without arteriovenous shunting"

The appearance of a hemangioma on Doppler ultrasound.

PMID:39640139 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The ultrasound revealed a lack of increased vascularity of the masses and an adrenal mass, leading to a biopsy and diagnosis of a neuroblastoma involving the adrenal gland, liver, and skin."

The case report: no increased vascularity in the nodules, and an adrenal mass.

GLUT1 Immunohistochemistry

A biopsy is seldom needed. When one is taken, staining of the endothelium for GLUT1 identifies infantile hemangioma at any stage, in the skin and in the liver, and separates it from congenital hemangioma, vascular malformations and pyogenic granuloma. The stain is not specific in an absolute sense: 3 of 12 angiosarcomas showed focal staining in the same study.

GLUT1 immunohistochemistry NCIT:C23020

Show evidence (5 references)

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"These findings establish GLUT1 immunoreactivity as a highly selective and diagnostically useful marker for juvenile hemangiomas."

The study that introduced the stain: a highly selective and diagnostically useful marker.

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In a retrospective study, we found intense endothelial GLUT1 immunoreactivity, involving more than 50% of lesional microvessels, in 97% (139 of 143) of juvenile hemangiomas from patients aged 1 month to 11 years."

Positive in 139 of 143 hemangiomas.

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."

Negative in all 66 vascular malformations and all 20 pyogenic granulomas.

+ 2 more references

MRI and MRA for Associated Anomalies

A segmental hemangioma, or one larger than 5 cm, on the face or scalp can be part of PHACE syndrome, in which the hemangioma comes with anomalies of the brain, the arteries of the head and neck, the heart and aorta, and the eyes. In a prospective study of 108 infants with large facial hemangiomas, 33 had the syndrome; anomalies of the arteries of the brain were found in 91 per cent of them and of the heart in 67 per cent. Magnetic resonance imaging and angiography of the head and neck, with echocardiography, look for them. A segmental hemangioma over the lower spine or pelvis calls for imaging of the spine, because it can be part of LUMBAR syndrome.

magnetic resonance imaging and angiography NCIT:C16809

Show evidence (7 references)

PMID:19858157 SUPPORT DIRECT BACKGROUND Human clinical

"A subgroup of patients with infantile hemangiomas have associated structural anomalies of the brain, cerebral vasculature, eyes, sternum, and/or aorta in the neurocutaneous disorder known as PHACE syndrome."

The opening of the 2009 consensus statement: a subgroup of patients have the associated anomalies.

PMID:19858157 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Definite PHACE requires the presence of a characteristic segmental hemangioma or hemangioma >5 cm on the face or scalp plus 1 major criterion or 2 minor criteria."

The consensus criteria: definite PHACE needs a segmental hemangioma, or one larger than 5 cm, on the face or scalp plus one major or two minor criteria.

PMID:20643720 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Thirty-three (31%) of 108 had PHACE."

The prospective study: 33 of 108 infants with large facial hemangiomas.

+ 4 more references

Ultrasound Screening of the Liver

Infants with many hemangiomas of the skin are screened for hemangiomas of the liver by abdominal ultrasound. A prospective study of 1,656 infants found that five skin tumors was the best cut-off and recommends screening infants younger than nine months who have five or more.

abdominal ultrasonography NCIT:C17230

Show evidence (3 references)

PMID:33285272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH."

The study: 31 hepatic hemangiomas among 1,656 infants.

PMID:33285272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Receiver operating characteristic curve analysis showed that 5 cutaneous IHs was the optimal cutoff point to screen for IHH, with an area under the curve of 0.872"

Five skin hemangiomas was the optimal cut-off, with an area under the curve of 0.872.

PMID:33285272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Screening for IHH is recommended in patients younger than 9 months who present with 5 or more cutaneous IHs."

The recommendation.

Thyroid Function Testing

Infants with multifocal or diffuse hemangiomas of the liver have their thyroid function tested, because the tumor can destroy thyroid hormone.

No diagnosis term is bound. A label search of the local NCIT build on 11 November 2026 for Thyroid Function returned 15 terms, all of them grades of adverse events. NCIT:C64813 Thyrotropin Measurement and NCIT:C81295 Thyroid Stimulating Hormone Measurement name one analyte each and are narrower than the test meant here.

Show evidence (2 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"

A 2021 review: thyroid function testing is required in multiple or diffuse hepatic hemangiomas.

PMID:32508067 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."

A case in which screening of thyroid function found severe hypothyroidism.

📈

Progression

4

Precursor mark

Age: At birth

Many tumors are announced by a faint mark that is present at birth. One was present in 65 per cent of 30 infants whose facial tumors were followed in their parents' photographs. In the cohort examined within 48 hours of birth, 3 of 34 lesions were seen at birth.

Show evidence (2 references)

PMID:22826568 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Hemangioma precursors were present at birth in 65% of patients."

Precursors at birth in 65 per cent of the photographed series.

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Three hemangiomas (9%) were noted on examination immediately after birth, 13 (38%) were present by 1 month and 18 (53%) were noted between 1 and 3 months of age."

The cohort followed from birth: 3 lesions seen at birth, 13 by one month and 18 between one and three months. The 34 lesions include two congenital hemangiomas.

Proliferative phase

Age: From the first weeks to about five months, up to nine months

The tumor grows fastest between five and a half and seven and a half weeks, reaches 80 per cent of its size at about three months and has stopped growing by five months in most children and by nine months in all of the cohort followed from birth. Deep tumors grow later and longer, and segmental tumors go on growing after three months. Ulceration, obstruction of the airway or of vision, and heart failure belong to this phase.

Show evidence (5 references)

PMID:22826568 SUPPORT DIRECT PRIMARY RESULT Human clinical

"IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age."

Fastest growth between 5.5 and 7.5 weeks.

PMID:18676554 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Eighty percent of hemangioma size was reached during the early proliferative stage at a mean age of 3 months."

Eighty per cent of the size at a mean age of three months.

PMID:18676554 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Differences in growth between hemangioma subtypes included that deep hemangiomas tend to grow later and longer than superficial hemangiomas and that segmental hemangiomas tended to exhibit more continued growth after 3 months of age."

Deep and segmental tumors grow for longer.

+ 2 more references

Involuting phase

Age: From the end of growth to about three and a half years

The tumor fades and shrinks. Improvement stopped at a median of 36 months in one study, and involution was complete at a mean of 3.5 years in another.

Show evidence (2 references)

PMID:22575857 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Kaplan-Meier analysis estimated that involution ceased at a median age of 36 months (interquartile range, 30 to 42 months), and 92 percent of tumors completed involution by 48 months."

Involution ceased at a median of 36 months; 92 per cent complete by 48 months.

PMID:27540637 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The average age at which hemangioma completed involution was 3.5 years."

Involution complete at 3.5 years on average.

Involuted phase

Age: After about three and a half years

What is left is normal skin or a lasting change: fine vessels, a pad of fibrofatty tissue, or slack thinned skin. Just over half of the hemangiomas in one study of tumors that had no systemic treatment left a significant sequela.

Show evidence (2 references)

PMID:27540637 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."

Significant sequelae in 101 of 184, with the three commonest kinds.

PMID:18535669 SUPPORT DIRECT BACKGROUND Human clinical

"It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum."

The opening of the stem cell study: the tumor regresses to a fibrofatty residuum.

📊

Prevalence

1

Infants born at one hospital in San Diego, California, and followed from birth to nine months

Period prevalence 4500.0 per 100,000 >1 in 1,000

27 of 594 infants had an infantile hemangioma, which the authors report as an incidence of 4.5 per cent. It is the proportion of a birth cohort that had the tumor at any time in the first nine months of life, so it is recorded as a period prevalence. Every tumor had appeared by three months. Follow-up at three months was available for 83 per cent of the infants, so the figure may be too low. A second paper reports the same cohort. A clinical practice guideline gives as many as 5 per cent of infants.

Show evidence (4 references)

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We evaluated 594 infants: 34 haemangiomas ... were identified in 29 infants, yielding an incidence of 4·5% for IH (27 infants)"

The birth cohort: 594 infants, of whom 27 had an infantile hemangioma (4.5 per cent). The words left out are a bracketed gloss that says the 34 lesions were infantile or congenital.

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Follow-up data at three months was available for 83% of infants."

The same study: follow-up at three months was available for 83 per cent of the infants.

PMID:22497908 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The most common vascular lesion was nevus simplex (83%), followed by infantile hemangioma (4.5% by age 3 months), capillary malformation (0.3%), and rapidly involuting congenital hemangioma (0.3%)."

An earlier report of the same cohort of 594 infants: infantile hemangioma in 4.5 per cent by the age of three months.

+ 1 more reference

🌍

Epidemiology

5

Sex and ethnicity

More girls than boys are affected. The excess is large in children referred to clinics or treated and small in children followed from birth. In a referral cohort of 1,058 children, those with hemangiomas were more often female and more often white non-Hispanic than births in general. In a cohort of twins the ratio of girls to boys among those with a hemangioma was 1.9 to 1, and 76 per cent of the 377 infants in a treatment trial were girls. In the cohort followed from birth, 53 per cent of the lesions were in girls, and no link with white race was found.

Show evidence (5 references)

PMID:17307549 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001)."

The referral cohort compared with United States birth data of 2002: children with hemangiomas were more likely to be female and white non-Hispanic.

PMID:26863906 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The female-to-male ratio was 1.7:1 in the entire cohort and 1.9:1 in those with IH."

A prospective cohort of 202 sets of twins: 1.9 girls for each boy among those with a hemangioma.

PMID:33856430 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Of 377 participants, 287 (76.1%) were female"

A randomized trial of treatment in China: 287 of 377 infants were girls.

+ 2 more references

Prematurity and low birth weight

The earlier and the smaller a child is born, the higher the risk. In the cohort followed from birth, 3.9 per cent of infants born at term had a hemangioma and 14.3 per cent of those born at 32 weeks or earlier. Among 64 pairs of twins whose weights differed by 10 per cent or more and of whom only one had a hemangioma, the smaller twin was the affected one in 62.5 per cent.

Show evidence (4 references)

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Only 3.9% of term infants were affected, while the incidence increased to 14.3% for extremely premature infants (Table 2), confirming the importance of gestational age as a risk factor for IH."

The birth cohort: 3.9 per cent of term infants and 14.3 per cent of extremely premature infants.

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Very low birth weight (p=0.028) and extreme prematurity (p=0.016) were found to be significant risk factors for the development of infantile hemangiomas."

The same cohort: very low birth weight and extreme prematurity were significant risk factors.

PMID:17307549 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001)."

The referral cohort: children with hemangiomas were more likely to have been born prematurely.

+ 1 more reference

Twin and multiple births

Twins are over-represented among children with hemangiomas: 10.6 per cent of the referral cohort came from a multiple pregnancy against 3.1 per cent of births in general. In the cohort followed from birth, 11 per cent of twins had a hemangioma, but the excess was not significant, and the authors put it down to the prematurity and low birth weight of twins.

Show evidence (3 references)

PMID:17307549 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001)."

The referral cohort: 10.6 per cent from a multiple gestation against 3.1 per cent of births.

PMID:26863906 SUPPORT DIRECT BACKGROUND Human clinical

"Twins have a higher-than-expected risk of infantile hemangiomas (IHs), but the exact reasons for this association are not clear."

The opening of the twin study states that twins have a higher risk than expected and that the reason is not clear.

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Although 11% of infants from twin gestations developed IH, statistical significance was not achieved due to confounding factors of prematurity and low birth weight in twins."

The birth cohort: 11 per cent of twins were affected, without statistical significance, which the authors attribute to confounding by prematurity and low birth weight.

Placental abnormalities and chorionic villus sampling

Abnormalities of the placenta are about twice as common in pregnancies that lead to a child with a hemangioma: 10 of 29 placentas in the birth cohort, against 16.9 per cent of the others. The commonest were pre-eclampsia and placenta previa, which were also more common in the referral cohort than in births in general. In a cohort of 375 children whose mothers had a prenatal test, a hemangioma was found in 27.2 per cent after transcervical chorionic villus sampling and in 9.4 per cent after amniocentesis.

Show evidence (4 references)

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Ten of 29 placentas (34.5%) from pregnancies with affected infants exhibited a placental or cord abnormality associated with abnormal placental perfusion."

The birth cohort: 10 of 29 placentas of affected infants had an abnormality of the placenta or cord.

PMID:24641194 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Placental anomalies were noted in almost 35% of haemangioma-related pregnancies, approximately twice the incidence noted in pregnancies with unaffected infants"

The abstract of the same study: about twice the rate seen in pregnancies with unaffected infants.

PMID:17307549 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Maternal age was significantly higher (P < .0001), and placenta previa (3.1%) and pre-eclampsia (11.8%) were more common."

The referral cohort: older mothers, and more placenta previa and pre-eclampsia, than in births in general.

+ 1 more reference

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Infantile Hemangioma:

Congenital Hemangioma Not Yet Curated MONDO:0018715

Overlapping Features A rarer vascular tumor that forms before birth and is fully grown at delivery. It does not grow afterwards: it shrinks within the first year or so (the rapidly involuting kind) or it stays (the non-involuting kind). The two tumors overlap in the clinic and under the microscope, and the authors of one pathology series suggested that they might be variations of one entity. The GLUT1 stain separates them, and congenital hemangiomas carry mutations of GNAQ or GNA11.

Distinguishing Features

Present and fully formed at birth, with no growth afterwards, where infantile hemangioma appears or grows after birth
GLUT1-negative endothelium, with one exception in a series of rapidly involuting congenital hemangiomas, where infantile hemangioma is GLUT1-positive
Somatic GNAQ or GNA11 mutations, found in all eight congenital hemangiomas sequenced in one study and in 4 of 8 archival ones (the study did not test infantile hemangiomas)
A single lesion when it is in the liver, where infantile hemangioma is usually multifocal or diffuse

Show evidence (8 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"CHs are rare benign vascular tumors that differ from IHs, are characteristically present at birth as fully developed hemangioma, do not show a proliferative phase or growth after birth, and are pathologically GLUT-1–negative"

A 2021 review: present at birth and fully developed, no growth after birth, GLUT1-negative.

PMID:27058448 SUPPORT DIRECT BACKGROUND Human clinical

"In contrast, congenital hemangiomas are GLUT1 negative and display one of two clinical patterns"

The introduction of a genetic study: congenital hemangiomas are GLUT1-negative.

PMID:15018449 SUPPORT DIRECT PRIMARY RESULT Human clinical

"With one exception, endothelial cells in RICH (as in NICH) did not express glucose transporter-1 protein, as does common infantile hemangioma."

A pathology series of rapidly involuting congenital hemangiomas: with one exception the endothelium did not express GLUT1.

+ 5 more references

Kaposiform Hemangioendothelioma Not Yet Curated MONDO:0016236

Overlapping Features A locally aggressive vascular tumor. It, and the related tufted angioma, cause the Kasabach-Merritt phenomenon, a life-threatening fall in platelets with consumption of clotting factors. Infantile hemangioma does not. The phenomenon is curated separately as Kasabach-Merritt Syndrome.

Distinguishing Features

The Kasabach-Merritt phenomenon (thrombocytopenia with consumptive coagulopathy), which infantile hemangioma does not cause
No endothelial GLUT1 staining in the five hemangioendotheliomas of one study, which were of the epithelioid or the kaposiform kind

Show evidence (3 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Tufted angioma or Kaposiform hemangioendothelioma, rather than IHs, cause KMP and require emergency referral"

A 2021 review: tufted angioma or kaposiform hemangioendothelioma, and not infantile hemangioma, cause the phenomenon.

PMID:32014025 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"KHEs are clinically heterogeneous and may develop into a life-threatening thrombocytopenia and consumptive coagulopathy, known as the Kasabach-Merritt phenomenon (KMP)."

A 2020 review of kaposiform hemangioendothelioma: it may develop into the Kasabach-Merritt phenomenon.

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Focal GLUT1 immunoreactivity was found in 3 of 12 angiosarcomas, but not in any of 5 hemangioendotheliomas (epithelioid or infantile kaposiform)."

The GLUT1 study: none of five hemangioendotheliomas stained.

Vascular Malformation Not Yet Curated MONDO:0024291

Overlapping Features A structural fault of vessels that is present at birth, grows in step with the child and does not involute. A flat hemangioma that hardly grows can be mistaken for a port-wine stain, which is a capillary malformation.

Distinguishing Features

Present at birth and growing in proportion with the child, with no phase of rapid growth and none of involution
No endothelial GLUT1 staining in any of the 66 malformations of one study or the 26 of another

Show evidence (4 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Vascular malformations are present at birth, may not be detectable clinically, and do not show a proliferative or involutive phase after birth; rather, they grow proportionately with the child or expand hemodynamically due to infection, trauma, or hormonal changes (puberty, pregnancy)"

A 2021 review: present at birth, no proliferative or involutive phase, growth in proportion with the child.

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."

No GLUT1 staining in 66 vascular malformations, of arteriovenous, venous, lymphatic and port-wine kinds.

PMID:11346333 SUPPORT DIRECT PRIMARY RESULT Human clinical

"No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin."

None of 26 vascular malformations stained for GLUT1 or the three other placental antigens.

+ 1 more reference

Pyogenic Granuloma Not Yet Curated MONDO:0022096

Overlapping Features A small, red, glistening papule on a stalk, on the face, arms or hands, also called lobular capillary hemangioma.

Distinguishing Features

A small pedunculated papule, where a hemangioma is a plaque or a mass
No endothelial GLUT1 staining in any of the 20 pyogenic granulomas of one study or the 13 of another

Show evidence (3 references)

PMID:34044479 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Pyogenic granuloma (lobular capillary hemangioma) ... GLUT-1 negative; WT-1, CD31 and CD34 positive; D2-40, LYVE-1 and Prox-1 negative ... Small (1 cm) red, glistening, pedunculated vascular papule on face, arms and hands."

The row for pyogenic granuloma in a table of a 2021 review: GLUT1-negative, and a small red pedunculated papule on the face, arms and hands. The dots stand for cell boundaries of the table.

PMID:10665907 SUPPORT DIRECT PRIMARY RESULT Human clinical

"No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."

No GLUT1 staining in 20 pyogenic granulomas.

PMID:11346333 SUPPORT DIRECT PRIMARY RESULT Human clinical

"No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin."

None of 13 pyogenic granulomas stained.

Neuroblastoma MONDO:0005072

Overlapping Features A malignant tumor that has been mistaken for hemangiomas. Neuroblastoma can spread to the liver and, rarely, to the skin, where it forms blue nodules; these are the two places where hemangiomas are also multiple. In one report a girl of four months who had a known hemangioma developed new nodules and a large liver and spleen, which were first put down to hemangioma and proved to be metastatic neuroblastoma. In another, a boy of nine months with nodules taken for deep hemangiomas had been started on propranolol before ultrasound showed nodules without increased blood flow and an adrenal mass. In an imaging series of liver lesions in infants of up to 100 days, one of the ten lesions that were not hemangiomas was a metastasis of neuroblastoma. It is curated separately as Neuroblastoma.

Distinguishing Features

Firm nodules that cannot be compressed, where a deep hemangioma is soft and compressible
No increased blood flow in the nodules on Doppler ultrasound
New lesions that appear after the first months of life
An adrenal mass on abdominal ultrasound, and neuroblastoma on biopsy of a nodule

Show evidence (8 references)

PMID:33644927 SUPPORT DIRECT BACKGROUND Human clinical

"Diffuse liver lesions in an infant have a differential diagnosis including infantile hemangioma (IH), which is common in the first year of life, and neuroblastoma (NBL) which presents at a median age of 18 months."

The introduction of a case report: diffuse liver lesions in an infant include infantile hemangioma and neuroblastoma.

PMID:33644927 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We describe the case of a 4-month-old girl with a known superficial/deep IH who presented with new axillary nodules and hepatosplenomegaly, initially suspected to reflect IH but later determined to be widely metastatic NBL."

The case: new nodules and hepatosplenomegaly in a girl with a known hemangioma were metastatic neuroblastoma.

PMID:33644927 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Hepatic IH and metastatic NBL can present similarly. Clinicians must maintain a broad differential when evaluating new findings in a patient with previously diagnosed IH."

Its conclusion: hepatic hemangioma and metastatic neuroblastoma can present alike.

+ 5 more references

Infantile Fibrosarcoma Not Yet Curated MONDO:0004557

Overlapping Features A rare sarcoma of soft tissue in the first year of life that can present as a highly vascular mass and has been diagnosed as a hemangioma or another benign vascular lesion. It differs in when it appears, in its shape and in how it grows, and the diagnosis is made on biopsy.

Distinguishing Features

A mass that is present at birth or enlarges from birth, where a hemangioma is absent or faint at birth
Closely packed fascicles of spindle cells on biopsy

Show evidence (4 references)

PMID:22474726 SUPPORT DIRECT BACKGROUND Human clinical

"Congenital infantile fibrosarcoma (CIFS) is a rare pediatric soft tissue tumor; clinically, it presents as a highly vascular mass and may simulate a hemangioma."

The opening of a case report: the tumor presents as a highly vascular mass and may simulate a hemangioma.

PMID:22474726 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We report a patient with CIFS who presented with a nonspecific ulcerated mass lesion over the right shoulder region that was clinically diagnosed as a benign vascular lesion. Histology revealed a highly cellular tumor with closely packed fascicles of spindle cells."

The case: an ulcerated mass over the shoulder, diagnosed clinically as a benign vascular lesion; histology showed a cellular spindle cell tumor.

PMID:27910123 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Clinically, these tumors differ from hemangiomas in the time of onset, morphology, and growth pattern and must be evaluated histologically for definitive diagnosis."

A case report and review: the tumors differ from hemangiomas in time of onset, shape and growth, and need histology.

+ 1 more reference

Hepatoblastoma MONDO:0018666

Overlapping Features A malignant tumor of the liver and, after hemangioma, the next most common liver tumor of the newborn. In an imaging series of 30 infants, alpha-fetoprotein, size, the number of lesions and bleeding into the lesion did not separate it from hemangioma; the way the lesion filled with contrast did. It is curated separately as Hepatoblastoma.

Distinguishing Features

Centripetal or flash filling on dynamic contrast-enhanced MRI, seen in 21 of 23 hemangiomas and in no other lesion of one series
Alpha-fetoprotein, size, multifocality and bleeding into the lesion did not differ significantly from hemangioma in that series

Show evidence (4 references)

PMID:39318559 SUPPORT DIRECT BACKGROUND Human clinical

"Hepatic hemangioma is the most common neonatal hepatic tumor ... This is followed by hepatoblastoma and mesenchymal hamartoma."

The introduction of the imaging study: hemangioma is the most common liver tumor of the newborn, followed by hepatoblastoma and mesenchymal hamartoma. The dots stand for a figure and a citation mark.

PMID:39318559 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Diagnoses in total 33 lesions included hemangiomas (23), hepatoblastoma (6), arteriovenous malformation (2), neuroblastoma metastases (1), and infarction (1)."

The lesions in the series: 23 hemangiomas and 6 hepatoblastomas among 33.

PMID:39318559 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Centripetal (16/23) or flash (5/23) filling were only seen with hemangioma."

Centripetal filling in 16 and flash filling in 5 of the 23 hemangiomas, and in no other lesion.

+ 1 more reference

🔬

Clinical Trials

1

NCT01056341 PHASE_III COMPLETED

The trial that established oral propranolol: a randomized, double-blind comparison of four regimens of propranolol with placebo in infants with a proliferating hemangioma that needed systemic treatment. It was registered as an adaptive phase II/III study; the phase field holds one value, and the later phase is recorded. Its results are quoted under Oral Propranolol.

Target Phenotypes: infantile hemangioma HP:0005306

Show evidence (2 references)

clinicaltrials:NCT01056341 SUPPORT DIRECT Human clinical

"The present study has been designed to confirm efficacy of propranolol in severe IH by demonstrating superiority over placebo and to document the safety profile of propranolol in this indication."

The registry record states the aim of the trial.

PMID:25693013 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy."

The published report of the trial, which gives the registration number NCT01056341 in its abstract.

🐁

Animal Models

1

Hemangioma stem cell implant in nude mice

Stem cells selected from human proliferating hemangiomas by the marker CD133, and grown from single cells, are suspended in Matrigel and injected under the skin of immunodeficient nu/nu mice. Within seven days they form human blood vessels that carry GLUT1; after two months the vessels thin out and human fat cells appear. The authors describe it as the first animal model of the tumor.

Species

Mouse

Genotype

nu/nu (immunodeficient)

Publication

PMID:18535669

Pathograph links

Hemangioma Stem Cell Vasculogenesis recapitulates fidelity: moderate observes: tissue Human hemangioma stem cells form GLUT1-positive human vessels in the implant.

Limitations: The host is an immunodeficient mouse and the cells are carried in Matrigel, so the implant lacks the skin, the immune system and the age of the infant in whom the tumor grows. What sets the stem cells off in a child is not modelled.

Show evidence (2 references)

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT Model organism

"The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice."

Human blood vessels seven days after implantation.

+ 1 more reference

Involution with Fibrofatty Replacement partially recapitulates fidelity: moderate observes: tissue The vessels of the implant diminish and human fat cells appear, as in the involuting tumor.

Limitations: The change takes two months in the implant and about three and a half years in a child, and the fibrous part of the residuum is not reported in the abstract. The limits of the host named for the first link apply here as well.

Show evidence (2 references)

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT Model organism

"Two months after implantation, the number of blood vessels diminished and human adipocytes became evident."

Two months after implantation, fewer vessels and human fat cells.

+ 1 more reference

Show evidence (3 references)

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT Model organism

"We tested to determine whether HemSCs would form hemangiomas in immunodeficient nu/nu mice."

The test: would the stem cells form hemangiomas in immunodeficient nu/nu mice.

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT Model organism

"Clonally expanded HemSCs or normal control cells were resuspended in Matrigel, a solubilized basement membrane preparation that has been shown to support angiogenesis and vasculogenesis"

The cells were implanted in Matrigel.

PMID:18535669 SUPPORT DIRECT PRIMARY RESULT Model organism

"In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy."

The authors describe it as the first animal model of the tumor.

{ }

Source YAML

click to show

name: Infantile Hemangioma
creation_date: '2026-11-11T02:55:07Z'
description: >-
  Infantile hemangioma is a benign tumor of the cells that line blood vessels
  and the most common tumor of infancy. A study that followed 594 newborns
  found one in 4.5 per cent of them by the age of three months. The tumor is
  absent or barely visible at birth, grows fast in the first weeks of life,
  reaches most of its final size by about three months and then shrinks
  slowly, until about three and a half years of age, often leaving changed
  skin behind. Its endothelial cells stain for the glucose transporter GLUT1
  at every stage, which separates it from congenital hemangioma, from other
  vascular tumors and from vascular malformations. Most lesions are small and
  need no treatment. A minority threaten the airway, the eye, the liver or the
  heart, ulcerate, or will disfigure, and for these oral propranolol is the
  first-line treatment, supported by a randomized trial of 456 infants. A
  large segmental hemangioma of the face can be part of PHACE syndrome, and
  one of the lower body part of LUMBAR syndrome. What starts the tumor is not
  known: stem cells isolated from it form GLUT1-positive vessels and later fat
  in mice, its endothelium shares markers and gene expression with the
  placenta, and prematurity, low birth weight and placental abnormalities go
  with a higher risk. Because the tumor is so common, rarer tumors of infancy
  that look like it have at first been diagnosed as hemangiomas, among them
  metastatic neuroblastoma and infantile fibrosarcoma.
categories:
- Vascular Tumor
- Benign Neoplasm
- Paediatric Vascular Anomaly
synonyms:
- capillary infantile hemangioma
- infantile haemangioma
- hemangioma of infancy
- juvenile hemangioma
- IH
parents:
- capillary hemangioma
notes: >-
  Name. The entry uses the name of the clinical literature and of the NCI
  Thesaurus (NCIT:C6645, Infantile Hemangioma). MONDO labels the term
  capillary infantile hemangioma. MONDO:0002407 capillary hemangioma carries
  infantile hemangioma as a synonym, though not as an exact one; it is the
  broader class and is not used.

  Heredity. MONDO places the term under hereditary disease, cross-references
  OMIM:602089 and lists hereditary capillary infantile hemangioma as a synonym
  (read through OLS on 11 November 2026). Most hemangiomas are sporadic. The
  families in which they run are recorded in the inheritance section.

  Scope. The entry covers infantile hemangioma of the skin and of the internal
  organs, of which the liver and the airway matter most. Congenital
  hemangioma, which is fully grown at birth and GLUT1-negative, is a different
  tumor and appears only as a differential diagnosis. PHACE syndrome
  (MONDO:0011676) and LUMBAR syndrome are the syndromes in which a segmental
  hemangioma comes with structural anomalies. They are not curated here beyond
  the imaging that looks for them.

  Subtypes. The hepatic form is the one subtype row. It has no MONDO term of
  its own: OLS searches of MONDO on 11 November 2026 for infantile hepatic
  hemangioma, hepatic infantile hemangioma and liver infantile hemangioma
  returned nothing, and MONDO:0002404 liver hemangioma covers every hemangioma
  of the liver at any age. The clinical classes by depth (superficial, deep,
  mixed) and by pattern (focal, segmental, indeterminate, multifocal) are
  described in the text and are not subtype rows.

  Sources. Many figures come from one prospective cohort of 1,058 to 1,096
  children seen at seven pediatric dermatology clinics in the United States
  (the Hemangioma Investigator Group). Children referred to such clinics have
  larger and more complicated tumors than children in general, so its rates of
  ulceration, complications and treatment are likely to be upper bounds. A
  cohort of 594 infants followed from birth gives the figures for unselected
  children. The studies of mechanism used cells cultured from the tumors of a
  few patients and implants in mice. The 2008 letter that reported propranolol
  for severe hemangiomas (PMID:18550886) and a 2000 report of hypothyroidism
  caused by the enzyme in the tumor (PMID:10900278) are not quoted, because no
  abstract or full text could be retrieved for either.
disease_term:
  preferred_term: infantile hemangioma
  term:
    id: MONDO:0011191
    label: capillary infantile hemangioma
has_subtypes:
- name: Hepatic
  display_name: Infantile hepatic hemangioma
  description: >-
    Infantile hemangioma of the liver. Its endothelium is GLUT1-positive, like
    that of the tumor in the skin. It is usually multifocal or diffuse; a
    single liver lesion present at birth is usually a congenital hemangioma.
    Most multifocal lesions cause no symptoms. The complications are heart
    failure from blood shunted through the tumors, hypothyroidism from an
    enzyme made by the tumor and, in diffuse disease, a liver large enough to
    compress the abdomen. In a prospective screening study, five or more
    hemangiomas of the skin was the best cut-off for examining the liver by
    ultrasound. The older name hepatic hemangioendothelioma should no longer
    be used for it.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C96840
        label: Liver Infantile Hemangioma
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: NCIT concept for infantile hemangioma of the liver.
  evidence:
  - reference: PMID:14991538
    reference_title: "GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that there are two fundamentally different hepatic vascular lesions in infants and young children: GLUT1-positive hepatic infantile hemangioma (HIH) and GLUT1-negative hepatic vascular malformation with capillary proliferation (HVMCP)."
    explanation: >-
      A pathology review of 19 liver vascular lesions of infants and young
      children: the infantile hemangioma of the liver is GLUT1-positive, and
      the lesion it was confused with, a vascular malformation with capillary
      proliferation, is GLUT1-negative.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic IHs usually present as a multifocal or diffuse hepatic distribution, whereas congenital hepatic hemangiomas present as a focal hepatic lesion"
    explanation: >-
      A 2021 review: infantile hemangiomas of the liver are usually multifocal
      or diffuse, and congenital ones focal.
  - reference: PMID:17208542
    reference_title: "Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that hepatic hemangiomas do not represent a single entity but, rather, 3 principle categories of lesions: focal, multifocal, and diffuse."
    explanation: >-
      The classification proposed in 2007 from radiology and pathology
      studies: focal, multifocal and diffuse lesions.
  - reference: PMID:17208542
    reference_title: "Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."
    explanation: >-
      The same paper gives the range of presentations, from no symptoms to
      heart failure, liver failure with hypothyroidism, abdominal compartment
      syndrome and death.
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH."
    explanation: >-
      A prospective screening study of 1,656 infants with hemangiomas of the
      skin: 31 had a hemangioma of the liver.
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Receiver operating characteristic curve analysis showed that 5 cutaneous IHs was the optimal cutoff point to screen for IHH, with an area under the curve of 0.872"
    explanation: >-
      The same study: five hemangiomas of the skin was the best cut-off for
      screening the liver.
  - reference: PMID:30244993
    reference_title: "Guidance Document for Hepatic Hemangioma (Infantile and Congenital) Evaluation and Monitoring."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend against using the term \"hemangioma\" for any vascular malformations affecting the liver or any hypervascular tumors that are not characterized by the approved definitions. We recommend against using the term \"hemangioendothelioma\" for infantile or congenital hemangioma."
    explanation: >-
      A consensus document of 2018 on naming: hemangioma is not to be used for
      vascular malformations of the liver, and hemangioendothelioma is not to
      be used for infantile or congenital hemangioma.
prevalence:
- population: Infants born at one hospital in San Diego, California, and followed from birth to nine months
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4500.0
  notes: >-
    27 of 594 infants had an infantile hemangioma, which the authors report as
    an incidence of 4.5 per cent. It is the proportion of a birth cohort that
    had the tumor at any time in the first nine months of life, so it is
    recorded as a period prevalence. Every tumor had appeared by three months.
    Follow-up at three months was available for 83 per cent of the infants, so
    the figure may be too low. A second paper reports the same cohort. A
    clinical practice guideline gives as many as 5 per cent of infants.
  evidence:
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We evaluated 594 infants: 34 haemangiomas ... were identified in 29 infants, yielding an incidence of 4·5% for IH (27 infants)"
    explanation: >-
      The birth cohort: 594 infants, of whom 27 had an infantile hemangioma
      (4.5 per cent). The words left out are a bracketed gloss that says the
      34 lesions were infantile or congenital.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow-up data at three months was available for 83% of infants."
    explanation: >-
      The same study: follow-up at three months was available for 83 per cent
      of the infants.
  - reference: PMID:22497908
    reference_title: "A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common vascular lesion was nevus simplex (83%), followed by infantile hemangioma (4.5% by age 3 months), capillary malformation (0.3%), and rapidly involuting congenital hemangioma (0.3%)."
    explanation: >-
      An earlier report of the same cohort of 594 infants: infantile
      hemangioma in 4.5 per cent by the age of three months.
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Infantile hemangiomas (IHs) occur in as many as 5% of infants, making them the most common benign tumor of infancy. Most IHs are small, innocuous, self-resolving, and require no treatment."
    explanation: >-
      The 2019 guideline of the American Academy of Pediatrics: as many as 5
      per cent of infants.
epidemiology:
- name: Sex and ethnicity
  description: >-
    More girls than boys are affected. The excess is large in children
    referred to clinics or treated and small in children followed from birth.
    In a referral cohort of 1,058 children, those with hemangiomas were more
    often female and more often white non-Hispanic than births in general. In
    a cohort of twins the ratio of girls to boys among those with a hemangioma
    was 1.9 to 1, and 76 per cent of the 377 infants in a treatment trial were
    girls. In the cohort followed from birth, 53 per cent of the lesions were
    in girls, and no link with white race was found.
  evidence:
  - reference: PMID:17307549
    reference_title: "Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001)."
    explanation: >-
      The referral cohort compared with United States birth data of 2002:
      children with hemangiomas were more likely to be female and white
      non-Hispanic.
  - reference: PMID:26863906
    reference_title: "Infantile Hemangiomas in Twins: A Prospective Cohort Study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The female-to-male ratio was 1.7:1 in the entire cohort and 1.9:1 in those with IH."
    explanation: >-
      A prospective cohort of 202 sets of twins: 1.9 girls for each boy among
      those with a hemangioma.
  - reference: PMID:33856430
    reference_title: "Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 377 participants, 287 (76.1%) were female"
    explanation: >-
      A randomized trial of treatment in China: 287 of 377 infants were girls.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A majority (53%) of lesions occurred in females, but not at the extreme F:M ratio of 4:1 that has been previously cited"
    explanation: >-
      The cohort followed from birth: 53 per cent of the lesions were in
      girls, a smaller excess than the ratio of 4 to 1 quoted before it.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not note a significant association with Caucasian race."
    explanation: >-
      The same cohort found no significant link with white race.
- name: Prematurity and low birth weight
  description: >-
    The earlier and the smaller a child is born, the higher the risk. In the
    cohort followed from birth, 3.9 per cent of infants born at term had a
    hemangioma and 14.3 per cent of those born at 32 weeks or earlier. Among
    64 pairs of twins whose weights differed by 10 per cent or more and of
    whom only one had a hemangioma, the smaller twin was the affected one in
    62.5 per cent.
  evidence:
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 3.9% of term infants were affected, while the incidence increased to 14.3% for extremely premature infants (Table 2), confirming the importance of gestational age as a risk factor for IH."
    explanation: >-
      The birth cohort: 3.9 per cent of term infants and 14.3 per cent of
      extremely premature infants.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Very low birth weight (p=0.028) and extreme prematurity (p=0.016) were found to be significant risk factors for the development of infantile hemangiomas."
    explanation: >-
      The same cohort: very low birth weight and extreme prematurity were
      significant risk factors.
  - reference: PMID:17307549
    reference_title: "Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001)."
    explanation: >-
      The referral cohort: children with hemangiomas were more likely to have
      been born prematurely.
  - reference: PMID:26863906
    reference_title: "Infantile Hemangiomas in Twins: A Prospective Cohort Study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "of the 64 sets of twins with 10% or greater difference in weight, the smaller twin had IH in 62.5% (n = 40) of cases, versus 37.5% (n = 24) of cases in which the higher-birthweight twin was affected"
    explanation: >-
      Twins whose weights differed by 10 per cent or more: the smaller twin
      was affected in 40 of 64 pairs and the larger in 24.
- name: Twin and multiple births
  description: >-
    Twins are over-represented among children with hemangiomas: 10.6 per cent
    of the referral cohort came from a multiple pregnancy against 3.1 per cent
    of births in general. In the cohort followed from birth, 11 per cent of
    twins had a hemangioma, but the excess was not significant, and the
    authors put it down to the prematurity and low birth weight of twins.
  evidence:
  - reference: PMID:17307549
    reference_title: "Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001)."
    explanation: >-
      The referral cohort: 10.6 per cent from a multiple gestation against 3.1
      per cent of births.
  - reference: PMID:26863906
    reference_title: "Infantile Hemangiomas in Twins: A Prospective Cohort Study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Twins have a higher-than-expected risk of infantile hemangiomas (IHs), but the exact reasons for this association are not clear."
    explanation: >-
      The opening of the twin study states that twins have a higher risk than
      expected and that the reason is not clear.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although 11% of infants from twin gestations developed IH, statistical significance was not achieved due to confounding factors of prematurity and low birth weight in twins."
    explanation: >-
      The birth cohort: 11 per cent of twins were affected, without
      statistical significance, which the authors attribute to confounding by
      prematurity and low birth weight.
- name: Placental abnormalities and chorionic villus sampling
  description: >-
    Abnormalities of the placenta are about twice as common in pregnancies
    that lead to a child with a hemangioma: 10 of 29 placentas in the birth
    cohort, against 16.9 per cent of the others. The commonest were
    pre-eclampsia and placenta previa, which were also more common in the
    referral cohort than in births in general. In a cohort of 375 children
    whose mothers had a prenatal test, a hemangioma was found in 27.2 per cent
    after transcervical chorionic villus sampling and in 9.4 per cent after
    amniocentesis.
  evidence:
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten of 29 placentas (34.5%) from pregnancies with affected infants exhibited a placental or cord abnormality associated with abnormal placental perfusion."
    explanation: >-
      The birth cohort: 10 of 29 placentas of affected infants had an
      abnormality of the placenta or cord.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Placental anomalies were noted in almost 35% of haemangioma-related pregnancies, approximately twice the incidence noted in pregnancies with unaffected infants"
    explanation: >-
      The abstract of the same study: about twice the rate seen in pregnancies
      with unaffected infants.
  - reference: PMID:17307549
    reference_title: "Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maternal age was significantly higher (P < .0001), and placenta previa (3.1%) and pre-eclampsia (11.8%) were more common."
    explanation: >-
      The referral cohort: older mothers, and more placenta previa and
      pre-eclampsia, than in births in general.
  - reference: PMID:20824891
    reference_title: "Hemangioma in the newborn: increased incidence after chorionic villus sampling."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more hemangiomas were present in 53 of 195 (27.2%) children in the CVS group versus 17 of 180 (9.4%) children in the amniocentesis group (odds ratio 3.6, 95% CI: 2.0-6.5)."
    explanation: >-
      A cohort study of 500 consecutive prenatal procedures: hemangiomas in 53
      of 195 children after chorionic villus sampling and in 17 of 180 after
      amniocentesis.
- name: Share of hemangiomas that need treatment
  description: >-
    The share depends on who is counted. In the cohort followed from birth,
    one of the 32 infantile hemangiomas needed treatment. Reviews and a
    consensus report put the share at about 10 to 12 per cent. In the referral
    cohort, 24 per cent of children had a complication and 38 per cent were
    treated, and segmental hemangiomas were 11 times more likely to have a
    complication than localized ones.
  evidence:
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, 20% of identified IHs were abortive or telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention."
    explanation: >-
      The birth cohort: only one hemangioma required intervention. A fifth
      were abortive or telangiectatic lesions that did not grow beyond three
      months.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of the spontaneous involution, most IHs do not require treatment, but about 10% of cases require early treatment due to size, location, and complications"
    explanation: >-
      A 2021 review: about 10 per cent of cases need early treatment.
  - reference: PMID:23266923
    reference_title: "Initiation and use of propranolol for infantile hemangioma: report of a consensus conference."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Although most are not worrisome, ∼12% of IHs are significantly complex, requiring referral to specialists for consideration of treatment."
    explanation: >-
      The introduction of a 2013 consensus report: about 12 per cent are
      complex enough to be referred.
  - reference: PMID:16950977
    reference_title: "Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-four percent of patients experienced complications related to their hemangioma(s), and 38% of our patients received some form of treatment during the study period."
    explanation: >-
      The referral cohort of 1,058 children: complications in 24 per cent and
      treatment in 38 per cent.
  - reference: PMID:16950977
    reference_title: "Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segmental hemangiomas were 11 times more likely to experience complications and 8 times more likely to receive treatment than localized hemangiomas, even when controlled for size."
    explanation: >-
      The same cohort: segmental hemangiomas had 11 times the complications
      and 8 times the treatment of localized ones.
inheritance:
- name: Sporadic
  inheritance_term:
    preferred_term: Sporadic
    term:
      id: HP:0003745
      label: Sporadic
  description: >-
    Most hemangiomas occur in a child with no affected relative. In a study of
    202 sets of twins, identical twins were not more often both affected than
    non-identical twins (18 of 42 pairs against 52 of 146), which argues
    against a strong inherited cause. The authors conclude that the origin is
    multifactorial.
  evidence:
  - reference: PMID:9916848
    reference_title: "Genetic mapping of a novel familial form of infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Although most hemangiomas occur sporadically and as single lesions, or in conjunction with pleiotropic genetic syndromes, we have previously identified six kindreds where hemangiomas appear to segregate as an autosomal dominant trait with high penetrance."
    explanation: >-
      The introduction of a linkage study: most hemangiomas occur
      sporadically.
  - reference: PMID:26863906
    reference_title: "Infantile Hemangiomas in Twins: A Prospective Cohort Study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no statistically significant difference in rates of concordance between monozygotic twins (43%, 18/42) and dizygotic twins (36%, 52/146) (p = 0.50)."
    explanation: >-
      The twin study: both twins were affected in 43 per cent of monozygotic
      and 36 per cent of dizygotic pairs, a difference that was not
      significant.
  - reference: PMID:26863906
    reference_title: "Infantile Hemangiomas in Twins: A Prospective Cohort Study."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that the origin of IHs is multifactorial and that predisposing factors such as birthweight, sex, and GA may interact with one another such that a threshold is reached for clinical expression."
    explanation: >-
      The authors' conclusion from the twin study: the origin is
      multifactorial.
- name: Autosomal dominant in rare families
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Six families have been described in which hemangiomas, and in some members
    vascular malformations, pass through two to four generations as an
    autosomal dominant trait with moderate to high penetrance. A genome-wide
    linkage search in five of them found linkage to chromosome 5q in three and
    evidence that the others map elsewhere. The papers cited name candidate
    genes in the region and identify no causal gene.
  evidence:
  - reference: PMID:9645641
    reference_title: "Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the rare familial occurrence of hemangiomas and/or vascular malformations in 6 kindreds, suggesting autosomal dominant inheritance."
    explanation: >-
      The report of the six kindreds.
  - reference: PMID:9645641
    reference_title: "Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The vascular lesions appeared to be transmitted in an autosomal dominant fashion with moderate to high penetrance."
    explanation: >-
      The same report: autosomal dominant transmission with moderate to high
      penetrance.
  - reference: PMID:9916848
    reference_title: "Genetic mapping of a novel familial form of infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We established evidence for linkage to 5q in three families, and evidence for locus heterogeneity."
    explanation: >-
      The linkage study in five of the families: linkage to 5q in three, and
      locus heterogeneity.
pathophysiology:
- name: Hemangioma Stem Cell Vasculogenesis
  description: >-
    The tumor contains multipotent stem cells, about 0.2 per cent of its
    cells, picked out by the marker CD133. Populations grown from single such
    cells formed human blood vessels within seven days of being implanted
    under the skin of immunodeficient mice, and the vessels carried GLUT1 and
    merosin, the markers of infantile hemangioma. The authors conclude that a
    stem cell, and not a mature endothelial cell, is the cell the tumor comes
    from. In culture, propranolol and its R enantiomer blocked the change of
    these stem cells into endothelial cells.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hemangioma stem cell
    term:
      id: CL:0000048
      label: multi fate stem cell
  biological_processes:
  - preferred_term: vasculogenesis
    term:
      id: GO:0001570
      label: vasculogenesis
    modifier: INCREASED
  evidence:
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we have reported the isolation of multipotential stem cells from hemangioma tissue that give rise to hemangioma-like lesions in immunodeficient mice."
    explanation: >-
      The stem cell study: stem cells isolated from hemangioma tissue gave
      rise to hemangioma-like lesions in immunodeficient mice.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "Cells were isolated based on expression of the stem cell marker CD133 and expanded from single cells as clonal populations."
    explanation: >-
      The cells were selected by CD133 and grown from single cells.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "approximately 0.2% of the hemangioma cells were selected with anti-CD133–coated beads"
    explanation: >-
      About 0.2 per cent of the cells of proliferating tumors were selected,
      in 28 specimens.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice."
    explanation: >-
      The selected cells formed human blood vessels seven days after
      implantation in the mice.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "The human vessels expressed GLUT-1 and merosin, immunodiagnostic markers for infantile hemangioma."
    explanation: >-
      The vessels formed in the mice carried the two markers used to diagnose
      infantile hemangioma.
  - reference: PMID:31358114
    reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "Propranolol significantly decreased VEGF-B induced expression of all five endothelial markers in HemSC to levels also achieved by Sm4 as compared to controls"
    explanation: >-
      A 2019 study of stem cells from four hemangiomas: propranolol reduced
      the endothelial markers that the growth factor VEGF-B induces in them,
      as did Sm4, an inhibitor of the transcription factor SOX18.
  downstream:
  - target: Proliferating GLUT1-Positive Endothelium
    causal_link_type: DIRECT
    hypothesis_groups:
    - stem_cell_origin
    description: >-
      The stem cells are proposed to give rise to the endothelium of the
      tumor. Shown for human cells implanted in mice; the step has not been
      observed in a child.
    evidence:
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "The human vessels expressed GLUT-1 and merosin, immunodiagnostic markers for infantile hemangioma."
      explanation: >-
        The vessels that the implanted stem cells formed in mice were
        GLUT1-positive, as the endothelium of the tumor is. Graded indirect
        because the observation was made in mice.
  - target: Involution with Fibrofatty Replacement
    causal_link_type: DIRECT
    hypothesis_groups:
    - stem_cell_origin
    description: >-
      The fat that replaces the tumor is proposed to come from the same stem
      cells. Shown for human cells implanted in mice.
    evidence:
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Two months after implantation, the number of blood vessels diminished and human adipocytes became evident."
      explanation: >-
        Two months after implantation the vessels had thinned out and human
        fat cells had appeared.
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Lentiviral expression of GFP was used to confirm that the hemangioma-derived cells formed the blood vessels and adipocytes in the immunodeficient mice."
      explanation: >-
        Labelling the implanted cells with green fluorescent protein showed
        that the vessels and the fat cells both came from them.
- name: Suppressed NFAT-Dependent VEGFR1 Expression
  description: >-
    Endothelial cells cultured from the hemangiomas of nine patients make
    little VEGFR1, the receptor that binds the growth factor VEGF without
    passing on a growth signal: its protein level was 10 to 20 per cent of
    that in control cells. The gene for VEGFR1 (FLT1) is switched on by the
    transcription factor NFAT, and NFAT is underactive in these cells because
    a pathway through beta-1 integrin, the integrin-like receptor TEM8
    (ANTXR1) and VEGFR2 is underactive. Hemangioma tissue in the proliferating
    phase showed the same low ratio of VEGFR1 to VEGFR2 transcripts;
    involuting tissue did not.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: hemangioma endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  genes:
  - preferred_term: FLT1
    term:
      id: hgnc:3763
      label: FLT1
  molecular_functions:
  - preferred_term: vascular endothelial growth factor binding
    term:
      id: GO:0038085
      label: vascular endothelial growth factor binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: calcineurin-NFAT signaling cascade
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: DECREASED
  evidence:
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "We show that expression of vascular endothelial growth factor receptor-1 (VEGFR1) in hemangioma endothelial cells (hemECs) and hemangioma tissue is markedly reduced compared to controls."
    explanation: >-
      The 2008 study: VEGFR1 expression is markedly reduced in hemangioma
      endothelial cells and in hemangioma tissue.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "The results showed that VEGFR1 protein levels in hemEC were only 10−20% of those in control cells"
    explanation: >-
      VEGFR1 protein in the cultured cells of all nine patients was 10 to 20
      per cent of control.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "In hemECs, transcription of the gene encoding VEGFR1 (FLT1) is dependent on nuclear factor of activated T cells (NFAT)."
    explanation: >-
      Transcription of the VEGFR1 gene depends on NFAT in these cells.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "Low VEGFR1 expression in hemECs is caused by reduced activity of a pathway involving beta1 integrin, the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGFR2 and NFAT."
    explanation: >-
      The low expression is traced to reduced activity of a pathway of beta-1
      integrin, TEM8, VEGFR2 and NFAT.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "real-time PCR showed COX-2/VEGFR2 and VEGFR1/VEGFR2 transcript ratios to be considerably lower in proliferating hemangioma tissue and hemEC than in HDMEC and other control endothelial cells, control tissues and involuting hemangioma tissue"
    explanation: >-
      The ratio of VEGFR1 to VEGFR2 transcripts was lower in proliferating
      hemangioma tissue and in the cultured cells than in control cells and
      tissues and in involuting hemangioma tissue.
  downstream:
  - target: Constitutive VEGFR2 Signaling
    causal_link_type: DIRECT
    description: >-
      With little VEGFR1 to hold VEGF back, VEGF reaches VEGFR2 and keeps it
      active.
    evidence:
    - reference: PMID:18931684
      reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: IN_VITRO
      snippet: "Low VEGFR1 expression in hemECs results in VEGF-dependent activation of VEGFR2 and downstream signaling pathways."
      explanation: >-
        The study's statement of the link, shown in the cultured cells.
- name: Constitutive VEGFR2 Signaling
  description: >-
    VEGF made by the tumor cells themselves keeps the receptor VEGFR2 switched
    on. The cultured hemangioma endothelial cells of all nine patients showed
    it, and they migrated and divided like normal endothelial cells that had
    been given VEGF. Soluble VEGFR1, or antibodies that neutralize VEGF,
    returned the signalling to normal. The finding rests on the cultured cells
    of nine patients in one study.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hemangioma endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  genes:
  - preferred_term: KDR
    term:
      id: hgnc:6307
      label: KDR
  molecular_functions:
  - preferred_term: vascular endothelial growth factor receptor activity
    term:
      id: GO:0005021
      label: vascular endothelial growth factor receptor activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: vascular endothelial growth factor receptor signaling pathway
    term:
      id: GO:0048010
      label: vascular endothelial growth factor receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "We report here that cultured hemEC from nine unrelated individuals with hemangioma (Supplementary Table 1 online) share a phenotype of constitutively active vascular endothelial growth factor receptor 2 (VEGFR2) signaling."
    explanation: >-
      Cultured hemangioma endothelial cells from nine unrelated patients
      shared constitutively active VEGFR2 signalling.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "Normalization of the constitutive VEGFR2 signaling in hemECs with soluble VEGFR1 or antibodies that neutralize VEGF or stimulate beta1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment."
    explanation: >-
      Soluble VEGFR1, or antibodies that neutralize VEGF or stimulate beta-1
      integrin, normalized the signalling in the cultured cells.
  downstream:
  - target: Proliferating GLUT1-Positive Endothelium
    causal_link_type: DIRECT
    description: >-
      Active VEGFR2 is proposed to drive the division and movement of the
      endothelial cells of the growing tumor. Shown in cultured cells.
    evidence:
    - reference: PMID:18931684
      reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: IN_VITRO
      snippet: "Migratory and proliferative activities in hemEC were almost identical to activities of VEGF-stimulated HDMEC"
      explanation: >-
        The cultured hemangioma cells migrated and proliferated like normal
        endothelial cells stimulated with VEGF. Graded indirect because the
        growth of the tumor itself was not measured.
- name: Proliferating GLUT1-Positive Endothelium
  description: >-
    In its growing phase the tumor is a dense mass of dividing endothelial
    cells that form capillaries. Endothelial cells cultured from growing
    hemangiomas are clonal, and they divide and move faster than normal
    endothelial cells. The endothelium stains strongly for the glucose
    transporter GLUT1 in every phase of the tumor, growing or shrinking: in a
    pathology study 139 of 143 hemangiomas were positive and none of 66
    vascular malformations. GLUT1 is otherwise found in endothelium that forms
    a barrier between blood and tissue, as in the brain and the placenta, and
    the hemangioma shares three further markers with the vessels of the
    placenta.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: hemangioma endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  locations:
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: subglottis
    term:
      id: UBERON:0036068
      label: subglottis
  biological_processes:
  - preferred_term: endothelial cell proliferation
    term:
      id: GO:0001935
      label: endothelial cell proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "These lesions enlarge rapidly through cellular hyperplasia during the first year of life and then involute over several years."
    explanation: >-
      The opening of the GLUT1 study: the tumors enlarge through cellular
      hyperplasia in the first year and then involute.
  - reference: PMID:11254674
    reference_title: "Clonality and altered behavior of endothelial cells from hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "We show, for the first time to our knowledge, that endothelial cells from proliferating hemangioma are clonal, and we demonstrate that these hemangioma-derived cells differ from normal endothelial cells in their rates of proliferation and migration in vitro."
    explanation: >-
      A 2001 study: endothelial cells from proliferating hemangiomas are
      clonal and differ from normal endothelial cells in how fast they
      proliferate and migrate in culture.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here that high endothelial immunoreactivity for the erythrocyte-type glucose transporter protein GLUT1 is a specific feature of juvenile hemangiomas during all phases of these lesions."
    explanation: >-
      High endothelial GLUT1 staining is a feature of the tumor in all its
      phases.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a retrospective study, we found intense endothelial GLUT1 immunoreactivity, involving more than 50% of lesional microvessels, in 97% (139 of 143) of juvenile hemangiomas from patients aged 1 month to 11 years."
    explanation: >-
      The count: 139 of 143 hemangiomas, from patients aged one month to 11
      years.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."
    explanation: >-
      None of 66 vascular malformations, 20 pyogenic granulomas or 7 specimens
      of granulation tissue stained.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because high levels of endothelial GLUT1 expression in normal tissue are restricted to microvessels with blood-tissue barrier function, these findings also have implications for the molecular and developmental pathogenic mechanisms of juvenile hemangiomas."
    explanation: >-
      In normal tissue, high endothelial GLUT1 is restricted to vessels with a
      blood-tissue barrier.
  - reference: PMID:11346333
    reference_title: "A unique microvascular phenotype shared by juvenile hemangiomas and human placenta."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of 66 hemangiomas (patients aged 22 days to 7 years) showed intense immunoreactivity for FcgammaRII, merosin, LeY, and GLUT1."
    explanation: >-
      A second study from the same group: all 66 hemangiomas stained for three
      further antigens of placental vessels as well as GLUT1.
  downstream:
  - target: Cutaneous Hemangioma
    causal_link_type: DIRECT
    description: >-
      The dividing endothelium is the growing tumor seen in the skin.
    evidence:
    - reference: PMID:10665907
      reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "These lesions enlarge rapidly through cellular hyperplasia during the first year of life and then involute over several years."
      explanation: >-
        The tumors enlarge through cellular hyperplasia.
  - target: Skin Ulcer
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ulcers form while the tumor is growing. Why the skin over a growing
      hemangioma breaks down is not established in the sources cited.
    evidence:
    - reference: PMID:18035154
      reference_title: "Multicenter prospective study of ulcerated hemangiomas."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ulceration occurred at a median age of 4 months, most often during the proliferative phase."
      explanation: >-
        Ulceration came at a median age of four months, most often in the
        proliferative phase. The timing links it to growth; the study does not
        show a cause.
  - target: Amblyopia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A tumor of the eyelid can press on the eye and distort it, producing
      astigmatism, or cover the pupil. Either can leave the eye with poor
      vision.
    evidence:
    - reference: PMID:29766557
      reference_title: "Risk factors for ocular complications in periocular infantile hemangiomas."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Although some children with periocular infantile hemangiomas do not require treatment, these lesions may result in amblyopia and visual impairment if not properly treated."
      explanation: >-
        The opening of a study of hemangiomas around the eye: they may cause
        amblyopia and visual impairment if not treated.
    - reference: PMID:29766557
      reference_title: "Risk factors for ocular complications in periocular infantile hemangiomas."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "Periocular infantile hemangiomas larger than 1 cm in diameter, with a deep component, and with involvement of the upper eyelid were significantly associated with astigmatism (P = .002, P = .02, and P = .003, respectively) and amblyopia (P = .002, P = .02, and P = .04, respectively)."
      explanation: >-
        In 96 patients, tumors larger than 1 cm, with a deep part, or on the
        upper eyelid were associated with astigmatism and with amblyopia. An
        association, so graded indirect.
  - target: Subglottic Hemangioma
    causal_link_type: DIRECT
    description: >-
      The same tumor can grow in the wall of the airway below the vocal cords.
    evidence:
    - reference: PMID:30174006
      reference_title: "Subglottic hemangioma: Understanding the association with facial segmental hemangioma in a beard distribution."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "A subglottic hemangioma (SGH) is a benign tumor of infancy that can cause severe obstruction of the airway."
      explanation: >-
        A subglottic hemangioma is a tumor of infancy that can obstruct the
        airway.
  - target: Hepatic Hemangioma
    causal_link_type: DIRECT
    description: >-
      The same tumor can grow in the liver.
    evidence:
    - reference: PMID:14991538
      reference_title: "GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The finding of consistent GLUT1 immunoreactivity of endothelial cells in HIH not only offers a powerful tool to distinguish HIH from HVMCP, but also provides immunophenotypic evidence of the similar biological origins of CJH and HIH."
      explanation: >-
        The liver tumor has the GLUT1-positive endothelium of the skin tumor,
        which the authors read as evidence of a shared origin. An inference
        from a shared marker.
  - target: High-Flow Shunting Through Hepatic Hemangiomas
    causal_link_type: DIRECT
    description: >-
      The vessels of large or numerous liver tumors can carry blood past the
      liver tissue.
    evidence:
    - reference: PMID:34044479
      reference_title: "Update on infantile hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure"
      explanation: >-
        A 2021 review: some multiple hepatic hemangiomas have high-flow
        shunting.
  - target: Type 3 Iodothyronine Deiodinase Activity in Tumor Tissue
    causal_link_type: DIRECT
    description: >-
      The tumor tissue itself makes the enzyme.
    evidence:
    - reference: PMID:34044479
      reference_title: "Update on infantile hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"
      explanation: >-
        A 2021 review: the enzyme is in the tissue of the hemangioma.
- name: Involution with Fibrofatty Replacement
  description: >-
    After the growing phase the vessels regress and the tumor is slowly
    replaced by fat and fibrous tissue. Two studies put the end of this
    process at about three and a half years: a median of 36 months in one,
    with 92 per cent of tumors finished by 48 months, and a mean of 3.5 years
    in the other. In mice, the vessels formed by implanted hemangioma stem
    cells thinned out after two months and human fat cells appeared in their
    place. What starts the regression is not known.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: fat cell differentiation
    term:
      id: GO:0045444
      label: fat cell differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum."
    explanation: >-
      The opening of the stem cell study: rapid growth after birth, then slow
      regression to a fibrofatty residuum.
  - reference: PMID:22575857
    reference_title: "Infantile hemangioma: clinical assessment of the involuting phase and implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kaplan-Meier analysis estimated that involution ceased at a median age of 36 months (interquartile range, 30 to 42 months), and 92 percent of tumors completed involution by 48 months."
    explanation: >-
      A study of 81 patients, most of whom later had reconstructive surgery:
      improvement stopped at a median of 36 months, and 92 per cent of tumors
      had finished involuting by 48 months.
  - reference: PMID:27540637
    reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average age at which hemangioma completed involution was 3.5 years."
    explanation: >-
      A study of 184 hemangiomas that had no systemic treatment: involution
      was complete at 3.5 years on average.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Two months after implantation, the number of blood vessels diminished and human adipocytes became evident."
    explanation: >-
      In the mouse implants, vessels diminished and human fat cells appeared
      after two months.
  downstream:
  - target: Residual Telangiectasia
    causal_link_type: DIRECT
    description: >-
      Fine dilated vessels are the commonest change left in the skin when the
      tumor has gone.
    evidence:
    - reference: PMID:27540637
      reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."
      explanation: >-
        After involution of untreated hemangiomas, telangiectasia was the
        commonest sequela.
  - target: Anetoderma
    causal_link_type: DIRECT
    description: >-
      The skin over the former tumor can be left slack and thinned.
    evidence:
    - reference: PMID:27540637
      reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."
      explanation: >-
        Anetodermic skin was among the three commonest sequelae, with
        telangiectasia and fibrofatty tissue.
- name: High-Flow Shunting Through Hepatic Hemangiomas
  description: >-
    Multifocal and diffuse hemangiomas of the liver can carry so much blood
    through large shunting vessels that the heart has to pump more than it can
    sustain.
  biological_scale: TISSUE
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:17208542
    reference_title: "Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."
    explanation: >-
      The paper that classified hepatic hemangiomas: heart failure goes with
      high-volume shunting.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure"
    explanation: >-
      A 2021 review: high-flow shunting through multiple hepatic hemangiomas
      causes high-output cardiac failure.
  downstream:
  - target: High-Output Heart Failure
    causal_link_type: DIRECT
    description: >-
      The shunted blood returns to the heart at once, so the heart must raise
      its output.
    evidence:
    - reference: PMID:34044479
      reference_title: "Update on infantile hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure"
      explanation: >-
        The review states the link.
    - reference: PMID:17208542
      reference_title: "Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."
      explanation: >-
        Congestive heart failure is listed with high-volume vascular shunting.
- name: Type 3 Iodothyronine Deiodinase Activity in Tumor Tissue
  description: >-
    Hemangioma tissue can make large amounts of type 3 iodothyronine
    deiodinase, the enzyme that inactivates thyroid hormone. When there is
    much tumor, as in multifocal or diffuse disease of the liver, the hormone
    is broken down faster than the thyroid gland can replace it. The condition
    is called consumptive hypothyroidism.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DIO3
    term:
      id: hgnc:2885
      label: DIO3
  molecular_functions:
  - preferred_term: type 3 iodothyronine deiodinase activity
    term:
      id: GO:0033798
      label: thyroxine 5-deiodinase activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: thyroid hormone catabolic process
    term:
      id: GO:0042404
      label: thyroid hormone catabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:32508067
    reference_title: "A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Consumptive hypothyroidism is a rare paraneoplastic syndrome characterized by excessive inactivation of the thyroid hormones due to increased type 3 iodothyronine deiodinase activity of tumors."
    explanation: >-
      The opening of a case report of 2020 defines the condition: thyroid
      hormone is inactivated by the type 3 deiodinase activity of a tumor.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"
    explanation: >-
      A 2021 review: in multiple or diffuse hepatic hemangiomas the enzyme in
      the tumor tissue inactivates thyroid hormone.
  - reference: PMID:21382982
    reference_title: "Consumptive hypothyroidism: a case report and review of the literature."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic haemangioendotheliomata is capable of producing an excess of the thyroid hormone inactivating enzyme, type 3 iodothyronine deiodinase. The increased enzyme activity leads to rapid degradation of thyroid hormones, resulting in frank hypothyroidism."
    explanation: >-
      A case report and review of 2011 states the mechanism. It uses the older
      name hepatic haemangioendothelioma. The case, an infant of three months
      with multiple liver tumors, fits infantile hepatic hemangioma, but the
      abstract reports no GLUT1 staining, so the item is graded indirect.
  downstream:
  - target: Hypothyroidism
    causal_link_type: DIRECT
    description: >-
      Thyroid hormone is destroyed in the tumor faster than it is made.
    evidence:
    - reference: PMID:32508067
      reference_title: "A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."
      explanation: >-
        A boy of one month with diffuse infantile hepatic hemangiomas and
        severe consumptive hypothyroidism. One case.
    - reference: PMID:21382982
      reference_title: "Consumptive hypothyroidism: a case report and review of the literature."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Hepatic haemangioendotheliomata is capable of producing an excess of the thyroid hormone inactivating enzyme, type 3 iodothyronine deiodinase. The increased enzyme activity leads to rapid degradation of thyroid hormones, resulting in frank hypothyroidism."
      explanation: >-
        The increased enzyme activity degrades thyroid hormone and produces
        hypothyroidism. The abstract uses the older name for the tumor, as
        noted above.
mechanistic_hypotheses:
- hypothesis_group_id: stem_cell_origin
  hypothesis_label: The tumor grows from a multipotent stem cell that forms its vessels and later its fat
  status: ALTERNATIVE
  description: >-
    Proposed in 2008. In favour: stem cells from the tumor form GLUT1-positive
    human vessels in mice and later fat, which is the course the tumor takes
    in a child; and the endothelial cells of the tumor are clonal, as cells
    that descend from one cell would be. Against a settled answer: the
    experiments were done with cultured cells and with implants in
    immunodeficient mice, the studies cited identify no mutation that would
    make such a cell grow, and the hypothesis does not say what sets the cell
    off. Reviews list it beside the placental and hypoxia hypotheses, which
    are not exclusive of it, so none of the three is marked CANONICAL. Its two
    edges run from Hemangioma Stem Cell Vasculogenesis to Proliferating
    GLUT1-Positive Endothelium and to Involution with Fibrofatty Replacement.
  evidence:
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy."
    explanation: >-
      The authors' conclusion: a stem cell is the cell of origin. An inference
      from cultured cells and from implants in mice.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, when transplanted into immunodeficient mice, hemangioma-derived cells recapitulated the unique evolution of infantile hemangioma"
    explanation: >-
      The implanted cells went through the course of the tumor, vessels first
      and fat later.
  - reference: PMID:11254674
    reference_title: "Clonality and altered behavior of endothelial cells from hemangiomas."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "We conclude that hemangiomas constitute clonal expansions of endothelial cells. This is consistent with the possibility that these tumors are caused by somatic mutations in one or more genes regulating endothelial cell proliferation."
    explanation: >-
      The 2001 clonality study: hemangiomas are clonal expansions of
      endothelial cells, which the authors call consistent with a somatic
      mutation. No mutation was shown.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Many mechanisms have been proposed to explain the pathogenesis of infantile hemangiomas, but the exact etiology of these lesions remains unclear. Significant evidence suggests that they are derived from endothelial stem or progenitor cells"
    explanation: >-
      The discussion of the birth-cohort paper: the cause is unclear, and much
      evidence points to endothelial stem or progenitor cells.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenesis of IH has not yet been completely defined, and current studies support several hypotheses."
    explanation: >-
      A 2021 review: the pathogenesis is not fully defined and several
      hypotheses are supported. This is why the hypothesis is not marked
      CANONICAL.
- hypothesis_group_id: placental_origin
  hypothesis_label: The tumor cells come from the placenta or are programmed like placental vessels
  status: ALTERNATIVE
  description: >-
    Proposed in 2001, when the endothelium of the tumor was found to share
    four markers with the vessels of the placenta that the vessels of normal
    skin lack. In favour: the pattern of gene expression of the tumor is
    closer to that of the placenta than to that of any other tissue compared;
    abnormalities of the placenta are about twice as common in affected
    pregnancies; and hemangiomas were about three times as common after
    chorionic villus sampling, which disturbs the placenta, as after
    amniocentesis. The hypothesis exists in two forms, cells carried from the
    placenta to the child and cells of the child that take on a placental
    program, and the evidence does not separate them. No edge of the graph
    belongs to it, because no step of it has been observed.
  evidence:
  - reference: PMID:11346333
    reference_title: "A unique microvascular phenotype shared by juvenile hemangiomas and human placenta."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of 66 hemangiomas (patients aged 22 days to 7 years) showed intense immunoreactivity for FcgammaRII, merosin, LeY, and GLUT1."
    explanation: >-
      All 66 hemangiomas stained for the four antigens.
  - reference: PMID:11346333
    reference_title: "A unique microvascular phenotype shared by juvenile hemangiomas and human placenta."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microvascular immunoreactivity for all 4 markers was observed in placental chorionic villi, but was absent in microvessels of normal skin and subcutis."
    explanation: >-
      The vessels of placental villi carried all four; the vessels of normal
      skin carried none.
  - reference: PMID:11346333
    reference_title: "A unique microvascular phenotype shared by juvenile hemangiomas and human placenta."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinct constellation of tissue-specific markers is uniquely coexpressed by hemangiomas and placental microvessels. These findings imply a unique relationship between hemangioma and the placenta and suggest new hypotheses concerning the origin of these tumors."
    explanation: >-
      The authors' conclusion: a relationship between hemangioma and placenta
      that suggests new hypotheses of origin.
  - reference: PMID:16365311
    reference_title: "Evidence by molecular profiling for a placental origin of infantile hemangioma."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show here that the transcriptomes of human placenta and infantile hemangioma are sufficiently similar to suggest a placental origin for this tumor"
    explanation: >-
      A 2005 comparison of gene expression: similar enough to suggest a
      placental origin.
  - reference: PMID:16365311
    reference_title: "Evidence by molecular profiling for a placental origin of infantile hemangioma."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that the level of transcriptome similarity between placenta and hemangioma exceeded that of any other tissue compared and paralleled that observed between a given tissue and its derived tumor, such as normal and cancerous lung."
    explanation: >-
      The similarity between placenta and hemangioma exceeded that of any
      other tissue compared.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Placental anomalies were noted in almost 35% of haemangioma-related pregnancies, approximately twice the incidence noted in pregnancies with unaffected infants"
    explanation: >-
      The birth cohort: placental anomalies in almost 35 per cent of affected
      pregnancies, about twice the rate of the others. An association.
  - reference: PMID:20824891
    reference_title: "Hemangioma in the newborn: increased incidence after chorionic villus sampling."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more hemangiomas were present in 53 of 195 (27.2%) children in the CVS group versus 17 of 180 (9.4%) children in the amniocentesis group (odds ratio 3.6, 95% CI: 2.0-6.5)."
    explanation: >-
      Hemangiomas in 27.2 per cent of children after chorionic villus sampling
      and 9.4 per cent after amniocentesis. An association.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The second hypothesis is the placental theory, which suggests that IH is derived from embolized placental cells"
    explanation: >-
      A 2021 review states the hypothesis in its embolization form.
- hypothesis_group_id: hypoxia_trigger
  hypothesis_label: Low oxygen in the tissue starts or drives the growth of the tumor
  status: ALTERNATIVE
  description: >-
    Low oxygen makes tissues release signals that call in and expand
    vessel-forming progenitor cells. In favour: these signals were raised in
    the blood and the tumors of ten children with growing hemangiomas; low
    oxygen and estrogen together made hemangioma endothelial cells divide
    faster in culture; and the conditions that raise the risk, among them
    prematurity, low birth weight, pre-eclampsia and placenta previa, are ones
    in which the fetus or the placenta is short of oxygen. The evidence is of
    association. The hypothesis can be combined with either of the other two.
    No edge of the graph belongs to it.
  evidence:
  - reference: PMID:17872454
    reference_title: "Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical specimens and blood samples were obtained from children with proliferating hemangioma and age-matched controls (n=10, each group)."
    explanation: >-
      A 2007 study: specimens and blood from ten children with proliferating
      hemangiomas and ten controls.
  - reference: PMID:17872454
    reference_title: "Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that all these mediators of EPC trafficking are elevated in blood and specimens from children with proliferating infantile hemangioma."
    explanation: >-
      The mediators measured, which low oxygen induces, were raised in the
      blood and the tumors of the children with hemangiomas.
  - reference: PMID:17872454
    reference_title: "Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "In vitro, the combination of hypoxia and estrogen demonstrated a synergistic effect on hemangioma endothelial cell proliferation."
    explanation: >-
      In culture, hypoxia and estrogen together increased the proliferation of
      hemangioma endothelial cells.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our study the development of IH was significantly associated with a history of disorders often related to placental hypoxia, such as pre-eclampsia and placenta previa (Table 3)."
    explanation: >-
      The birth cohort: hemangiomas went with pre-eclampsia and placenta
      previa, conditions the authors relate to placental hypoxia.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The third hypothesis is the tissue hypoxia-induced vascular proliferation theory, which suggests that the induction and proliferation of EPCs are stimulated by hypoxic conditions (preterm, low birth weight, increased maternal age, placental anomalies) mediated by HIF-1α"
    explanation: >-
      A 2021 review states the hypothesis and the conditions it draws on.
phenotypes:
- category: Dermatologic
  name: Cutaneous Hemangioma
  description: >-
    The tumor of the skin. A precursor mark was present at birth in 65 per
    cent of a series of 30 infants with tumors of the face, and every tumor
    had appeared by three months in the cohort followed from birth. A
    superficial tumor is bright red; a deep one lies under skin of normal or
    bluish color and is soft enough to compress; a mixed one is both. Growth
    is fastest between five and a half and seven and a half weeks of age. The
    tumor reaches 80 per cent of its final size at about three months and has
    stopped growing by about five months in most children, although deep and
    segmental tumors grow for longer. In a review, 60 per cent of tumors are
    on the head and neck; in the cohort followed from birth most were on the
    trunk, and a fifth were small flat lesions that hardly grew.
  phenotype_term:
    preferred_term: infantile hemangioma of the skin
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: PMID:22826568
    reference_title: "Early growth of infantile hemangiomas: what parents' photographs tell us."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemangioma precursors were present at birth in 65% of patients."
    explanation: >-
      A study of parents' photographs of 30 infants with facial hemangiomas: a
      precursor was present at birth in 65 per cent.
  - reference: PMID:22826568
    reference_title: "Early growth of infantile hemangiomas: what parents' photographs tell us."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age."
    explanation: >-
      The same study: growth was fastest between 5.5 and 7.5 weeks of age.
  - reference: PMID:18676554
    reference_title: "Growth characteristics of infantile hemangiomas: implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty percent of hemangioma size was reached during the early proliferative stage at a mean age of 3 months."
    explanation: >-
      A referral cohort with growth data on 526 hemangiomas: 80 per cent of
      the final size was reached at a mean age of three months.
  - reference: PMID:18676554
    reference_title: "Growth characteristics of infantile hemangiomas: implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differences in growth between hemangioma subtypes included that deep hemangiomas tend to grow later and longer than superficial hemangiomas and that segmental hemangiomas tended to exhibit more continued growth after 3 months of age."
    explanation: >-
      The same cohort: deep hemangiomas grow later and longer, and segmental
      ones go on growing after three months.
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "the most rapid and significant growth occurs between 1 and 3 months of age and that growth is completed by 5 months of age in most cases"
    explanation: >-
      The 2019 guideline: growth is fastest between one and three months and
      complete by five months in most cases.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "All IHs were present by 3 months of age, and cessation of growth had occurred in all by 9 months of age. Most occurred on the trunk."
    explanation: >-
      The cohort followed from birth: all tumors present by three months,
      growth over in all by nine months, and most on the trunk.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighteen lesions (53%) were noted on the trunk and 12 (35%) on the extremities, while only 4 lesions (12%) were present on the head or neck"
    explanation: >-
      The sites in that cohort: 18 of 34 lesions on the trunk, 12 on the limbs
      and 4 on the head or neck. The 34 lesions include two congenital
      hemangiomas.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "IHs are most frequently located in the head and neck region (60%), followed by the trunk (25%) and the extremities (15%)"
    explanation: >-
      A 2021 review gives the distribution seen in clinic series: head and
      neck first.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, 20% of identified IHs were abortive or telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention."
    explanation: >-
      The cohort followed from birth: a fifth of the tumors were abortive or
      telangiectatic lesions that did not grow beyond three months.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Superficial IHs are usually located in the epidermis and dermis with little or no involvement of the subcutaneous fat, bright red in color"
    explanation: >-
      The review's description of the superficial type.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, the skin overlying the deep hemangiomas may appear skin-colored or blue, and the lesions are generally less defined but are still compressible"
    explanation: >-
      The introduction of a case report describes the deep type: skin-colored
      or blue, less well defined, and still compressible.
- category: Dermatologic
  name: Skin Ulcer
  description: >-
    The skin over the tumor breaks down in about one child in six seen at a
    specialist clinic: 173 of 1,096 children in the largest series. Ulcers
    form at a median age of four months, while the tumor is growing, and are
    commoner in large, mixed and segmental tumors and on the lower lip, the
    neck and the anogenital area. They can be painful and can scar. About two
    fifths of ulcerated tumors bled, rarely to a degree that mattered, and
    about one in six became infected.
  phenotype_term:
    preferred_term: ulceration of the hemangioma
    term:
      id: HP:0200042
      label: Skin ulcer
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:18035154
    reference_title: "Multicenter prospective study of ulcerated hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "One thousand ninety-six patients were enrolled, and 173 (15.8%) patients experienced ulceration."
    explanation: >-
      The referral cohort: 173 of 1,096 children, which is 15.8 per cent and
      falls in the OCCASIONAL band of 5 to 29 per cent. Children seen at
      specialist clinics have larger tumors than children in general, so the
      figure is an upper bound.
  - reference: PMID:18035154
    reference_title: "Multicenter prospective study of ulcerated hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ulceration occurred at a median age of 4 months, most often during the proliferative phase."
    explanation: >-
      Ulceration came at a median age of four months, most often in the
      proliferative phase.
  - reference: PMID:18035154
    reference_title: "Multicenter prospective study of ulcerated hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemangiomas with ulcerations were more likely large, mixed clinical type, segmental morphologic type, and located on the lower lip, neck, or anogenital region."
    explanation: >-
      The tumors that ulcerated were more often large, mixed, segmental, or on
      the lower lip, neck or anogenital region.
  - reference: PMID:18035154
    reference_title: "Multicenter prospective study of ulcerated hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bleeding occurred in 41% of ulcerated lesions but was rarely of clinical significance. Infection occurred in 16%."
    explanation: >-
      Bleeding in 41 per cent of ulcerated lesions, rarely significant, and
      infection in 16 per cent.
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "These include IHs that may cause permanent scarring and disfigurement (eg, facial IHs), hepatic or airway IHs, and IHs with the potential for functional impairment (eg, periorbital IHs), ulceration (that may cause pain or scarring), and associated underlying abnormalities (eg, intracranial and aortic arch vascular abnormalities accompanying a large facial IH)."
    explanation: >-
      The guideline lists ulceration among the reasons a hemangioma is a
      problem, because it may cause pain or scarring.
- category: Ophthalmologic
  name: Amblyopia
  description: >-
    Poor vision in an eye that was not used properly in infancy. A hemangioma
    of the eyelid can cause it by distorting the eye, which produces
    astigmatism, or by covering the pupil. In a series of 96 children with a
    hemangioma around the eye, a tumor larger than 1 cm, a deep component and
    a site on the upper eyelid were each associated with astigmatism and with
    amblyopia. The abstract gives no rate, so no frequency is set.
  phenotype_term:
    preferred_term: amblyopia from a hemangioma around the eye
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: PMID:29766557
    reference_title: "Risk factors for ocular complications in periocular infantile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Although some children with periocular infantile hemangiomas do not require treatment, these lesions may result in amblyopia and visual impairment if not properly treated."
    explanation: >-
      The opening of the study: these lesions may result in amblyopia and
      visual impairment if not treated.
  - reference: PMID:29766557
    reference_title: "Risk factors for ocular complications in periocular infantile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-six patients (74% female, median age of onset 0.48 months) were included."
    explanation: >-
      The series: 96 patients seen by a dermatologist and an ophthalmologist.
  - reference: PMID:29766557
    reference_title: "Risk factors for ocular complications in periocular infantile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periocular infantile hemangiomas larger than 1 cm in diameter, with a deep component, and with involvement of the upper eyelid were significantly associated with astigmatism (P = .002, P = .02, and P = .003, respectively) and amblyopia (P = .002, P = .02, and P = .04, respectively)."
    explanation: >-
      Size above 1 cm, a deep component and upper eyelid involvement were each
      associated with astigmatism and with amblyopia.
  - reference: PMID:28089471
    reference_title: "Infantile haemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The main indications for treatment are life-threatening infantile haemangioma (causing heart failure or respiratory distress), tumours posing functional risks (eg, visual obstruction, amblyopia, or feeding difficulties), ulceration, and severe anatomic distortion, especially on the face."
    explanation: >-
      A 2017 review lists visual obstruction and amblyopia among the reasons
      to treat.
- category: Respiratory
  name: Subglottic Hemangioma
  description: >-
    A hemangioma in the airway, typically below the vocal cords. It is rare:
    13 of 761 children with hemangiomas at one vascular anomaly center had a
    subglottic one, and 1.6 per cent of 798 at another had a hemangioma of the
    airway. It is diagnosed at about four months, with noisy breathing in and
    out, a barking cough and breathlessness, and can be taken for croup. A
    segmental hemangioma of the lower face and neck, the beard area, is the
    warning sign: a third of the children who had one in the second series had
    a tumor of the airway. But in the first series more than half of the
    children with a subglottic tumor had no hemangioma of the skin at all.
  phenotype_term:
    preferred_term: hemangioma of the airway
    term:
      id: HP:0410264
      label: Subglottic hemangioma
  frequency: VERY_RARE
  evidence:
  - reference: PMID:30174006
    reference_title: "Subglottic hemangioma: Understanding the association with facial segmental hemangioma in a beard distribution."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of 761 cases of infantile hemangiomas demonstrated only 13 patients with subglottic hemangiomas (1.7%)."
    explanation: >-
      One center, 2013 to 2017: 13 of 761, which is 1.7 per cent and falls in
      the VERY_RARE band, below 5 per cent.
  - reference: PMID:41860115
    reference_title: "Risk Factors for Airway Infantile Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study included 798 children with an IH visiting our paediatric vascular anomaly unit between 1.1.2008 and 31.12.2017."
    explanation: >-
      A second center: 798 children seen between 2008 and 2017.
  - reference: PMID:41860115
    reference_title: "Risk Factors for Airway Infantile Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "An airway IH was diagnosed in 1.6% of the cohort. When a segmental beard distribution hemangioma was present, the risk for an airway IH was 33.3%, and when a non-beard distribution segmental hemangioma on the face or neck was observed, the risk was 11.5%."
    explanation: >-
      In that series an airway hemangioma was diagnosed in 1.6 per cent, also
      in the VERY_RARE band. The risk was 33.3 per cent with a segmental
      hemangioma in the beard distribution. The figure counts hemangiomas
      anywhere in the airway.
  - reference: PMID:30174006
    reference_title: "Subglottic hemangioma: Understanding the association with facial segmental hemangioma in a beard distribution."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of those 13 patients, only 4 patients (30%) had BD while 2 patients (15%) had other cutaneous hemangiomas and 7 patients (55%) had no cutaneous hemangiomas."
    explanation: >-
      Of the 13 children, 4 had a hemangioma in the beard distribution, 2 had
      other skin hemangiomas and 7 had none.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Subglottic hemangiomas are diagnosed at mean age of 4 months, and patients present with progressive biphasic stridor, a barking cough, and dyspnea, and they may be misdiagnosed with congenital laryngeal stridor or infectious croup"
    explanation: >-
      A 2021 review: diagnosis at a mean of four months, with biphasic
      stridor, a barking cough and dyspnea, and confusion with croup.
- category: Hepatic
  name: Hepatic Hemangioma
  description: >-
    The tumor in the liver, usually several or many. In a screening study of
    1,656 infants with hemangiomas of the skin, 31 had one, and the risk rose
    with the number of skin tumors. Most cause no symptoms.
  phenotype_term:
    preferred_term: infantile hepatic hemangioma
    term:
      id: HP:0031207
      label: Hepatic hemangioma
  subtype: Hepatic
  sequelae:
  - target: Hepatomegaly
    causal_link_type: DIRECT
    description: >-
      When the tumors are diffuse the liver becomes very large.
    evidence:
    - reference: PMID:34044479
      reference_title: "Update on infantile hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Diffuse hepatic IHs are rare but present as severe hepatomegaly leading to abdominal compartment syndrome causing abnormal ventilation and renal failure due to renal vein compression"
      explanation: >-
        A 2021 review: diffuse hepatic hemangiomas present as severe
        hepatomegaly.
  evidence:
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH."
    explanation: >-
      The screening study: 31 infants with a hepatic hemangioma among 676 with
      three or more skin hemangiomas and 980 with one or two.
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for IHH is recommended in patients younger than 9 months who present with 5 or more cutaneous IHs."
    explanation: >-
      Its conclusion: screen infants younger than nine months who have five or
      more skin hemangiomas.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic IHs usually present as a multifocal or diffuse hepatic distribution, whereas congenital hepatic hemangiomas present as a focal hepatic lesion"
    explanation: >-
      A 2021 review: usually multifocal or diffuse.
- category: Hepatic
  name: Hepatomegaly
  description: >-
    In diffuse disease the tumors take up much of the liver, which becomes
    very large. It can raise the pressure in the abdomen enough to hinder
    breathing and to compress the veins of the kidneys, a state called
    abdominal compartment syndrome.
  phenotype_term:
    preferred_term: massive enlargement of the liver
    term:
      id: HP:0002240
      label: Hepatomegaly
  subtype: Hepatic
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse hepatic IHs are rare but present as severe hepatomegaly leading to abdominal compartment syndrome causing abnormal ventilation and renal failure due to renal vein compression"
    explanation: >-
      A 2021 review: severe hepatomegaly leading to abdominal compartment
      syndrome, with abnormal ventilation and renal failure from compression
      of the renal veins.
  - reference: PMID:17208542
    reference_title: "Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."
    explanation: >-
      The paper that classified hepatic hemangiomas lists abdominal
      compartment syndrome among the presentations.
- category: Cardiovascular
  name: High-Output Heart Failure
  description: >-
    Heart failure in an infant whose heart is pumping more than normal,
    because blood is shunted through the liver tumors. A 2017 review names
    heart failure and respiratory distress as the life-threatening forms of
    the disease.
  phenotype_term:
    preferred_term: high-output heart failure
    term:
      id: HP:0001722
      label: High-output congestive heart failure
  subtype: Hepatic
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple IHs are usually asymptomatic, but some are associated with high-flow macrovascular shunting causing high-output cardiac failure"
    explanation: >-
      A 2021 review: high-flow shunting through multiple hepatic hemangiomas
      causes high-output cardiac failure.
  - reference: PMID:17208542
    reference_title: "Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death."
    explanation: >-
      Congestive heart failure with high-volume shunting is among the
      presentations of hepatic hemangioma.
  - reference: PMID:32508067
    reference_title: "A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."
    explanation: >-
      A boy of one month with diffuse infantile hepatic hemangiomas presented
      with cardiac failure. One case.
  - reference: PMID:28089471
    reference_title: "Infantile haemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The main indications for treatment are life-threatening infantile haemangioma (causing heart failure or respiratory distress), tumours posing functional risks (eg, visual obstruction, amblyopia, or feeding difficulties), ulceration, and severe anatomic distortion, especially on the face."
    explanation: >-
      A 2017 review names heart failure and respiratory distress as the
      life-threatening forms.
- category: Endocrine
  name: Hypothyroidism
  description: >-
    Hypothyroidism caused by the tumor destroying thyroid hormone, and not by
    a fault of the thyroid gland. It is seen with multifocal or diffuse tumors
    of the liver and can need more thyroid hormone than usual to correct.
  phenotype_term:
    preferred_term: consumptive hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  subtype: Hepatic
  evidence:
  - reference: PMID:32508067
    reference_title: "A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."
    explanation: >-
      A boy of one month with diffuse infantile hepatic hemangiomas and severe
      consumptive hypothyroidism. One case.
  - reference: PMID:32508067
    reference_title: "A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was successfully treated with propranolol, prednisolone, and levothyroxine, and he showed normal thyroid function at 3 months of age and normal neurodevelopment at 9 months of age."
    explanation: >-
      The same boy was treated with propranolol, prednisolone and
      levothyroxine and had normal thyroid function at three months and normal
      development at nine.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"
    explanation: >-
      A 2021 review: hypothyroidism can occur in multiple or diffuse hepatic
      hemangiomas, so thyroid function is tested.
  - reference: PMID:21382982
    reference_title: "Consumptive hypothyroidism: a case report and review of the literature."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic haemangioendotheliomata is capable of producing an excess of the thyroid hormone inactivating enzyme, type 3 iodothyronine deiodinase. The increased enzyme activity leads to rapid degradation of thyroid hormones, resulting in frank hypothyroidism."
    explanation: >-
      A case report and review of 2011 that uses the older name hepatic
      haemangioendothelioma for the tumor; graded indirect for that reason.
- category: Dermatologic
  name: Residual Telangiectasia
  description: >-
    Fine red vessels left in the skin where the tumor was. It was the
    commonest lasting change in a study of photographs of 184 hemangiomas that
    had no systemic treatment, 101 of which left a significant sequela of some
    kind. Across 17 studies in a systematic review, the reported rate of any
    sequela ranged from about 5 to over 90 per cent.
  phenotype_term:
    preferred_term: telangiectasia left after involution
    term:
      id: HP:0001009
      label: Telangiectasia
  notes: >-
    No frequency band is set. The abstract reports telangiectasia in 145
    hemangiomas, which it gives as 84.3 per cent. That percentage corresponds
    to 172 hemangiomas and not to the 184 included, and the abstract does not
    say what the 172 are.
  evidence:
  - reference: PMID:27540637
    reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multicentric retrospective cohort study of images from 187 infantile hemangiomas that had not received systemic treatment and had follow-up pictures until regression"
    explanation: >-
      The study: photographs of hemangiomas that had no systemic treatment,
      followed until regression, from four hospitals in three countries.
  - reference: PMID:27540637
    reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."
    explanation: >-
      Significant sequelae in 101 of 184; telangiectasia the commonest kind.
  - reference: PMID:36434402
    reference_title: "Skin sequelae in patients with infantile hemangioma: a systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 4448 articles initially identified, 62 underwent full-text review, and 17 met inclusion criteria. The overall rate of sequelae ranged from 5.3 to 93.5%."
    explanation: >-
      A systematic review of 17 studies: overall rates of sequelae from 5.3 to
      93.5 per cent.
- category: Dermatologic
  name: Anetoderma
  description: >-
    Slack, thinned skin over the site of the former tumor. It was the third
    commonest lasting change in the same study, after telangiectasia and
    fibrofatty tissue.
  phenotype_term:
    preferred_term: slack skin left after involution
    term:
      id: HP:0032026
      label: Anetoderma
  evidence:
  - reference: PMID:27540637
    reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."
    explanation: >-
      Anetodermic skin in 56 hemangiomas, given as 32.6 per cent. As for
      telangiectasia, the denominator is not stated, so no frequency band is
      set.
genetic:
- name: KDR
  association: Germline missense variant C482R of VEGFR2
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  gene_term:
    preferred_term: KDR
    term:
      id: hgnc:6307
      label: KDR
  notes: >-
    KDR encodes VEGFR2. One study found the variant in the cultured tumor
    cells of two of nine patients and then in blood: 10 of 114 people with a
    history of hemangioma carried it, against 12 of 295 controls (P = 0.02).
    The authors call it a risk-factor mutation and a relatively common
    variant. The controls included people with hemangioma at the population
    frequency, the variant did not change the expression of the receptor or
    its phosphorylation by VEGF in a cell line, and the sources cited contain
    no replication. No gene-disease validity assertion is recorded.
  evidence:
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a subset of individuals with hemangioma, we found missense mutations in the genes encoding VEGFR2 (KDR) and TEM8 (ANTXR1)."
    explanation: >-
      The 2008 study: missense changes in KDR and ANTXR1 in a subset of
      patients.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allele-specific PCR identified heterozygosity for the same change in 8 blood genomic DNA samples collected from an additional 105 individuals with a history of hemangioma (10 total out of 114 individuals) and in 12 DNA samples from 295 “controls” (all Caucasian)."
    explanation: >-
      The count in blood samples: 10 of 114 people with a history of
      hemangioma and 12 of 295 controls.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The controls include individuals with hemangioma at the population frequency (10%) (see Methods)."
    explanation: >-
      The controls include people who had a hemangioma, at the frequency of
      the general population.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "On that basis, the difference in the frequency of the C482R change among individuals with a history of hemangioma and controls is statistically significant (P = 0.02, Fisher's exact two-tailed test)."
    explanation: >-
      The difference in frequency was significant at P = 0.02.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "No difference in receptor expression and VEGF-induced phosphorylation was apparent between wild-type and C482R mutant receptor transiently expressed in 293-EBNA cells"
    explanation: >-
      Expressed in a cell line, the variant receptor did not differ from the
      normal one in expression or in phosphorylation induced by VEGF.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering all these data together, we conclude that the TEM8 and VEGFR2 amino acid sequence changes represent risk factor mutations for infantile hemangioma."
    explanation: >-
      The authors' conclusion: the changes are risk factors for infantile
      hemangioma.
- name: ANTXR1
  association: Germline missense variant A326T of TEM8, found in one patient
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  gene_term:
    preferred_term: ANTXR1
    term:
      id: hgnc:21014
      label: ANTXR1
  notes: >-
    ANTXR1 encodes TEM8, an integrin-like receptor. The variant was found in
    one of the nine patients whose tumor cells were studied and in none of 110
    other people with a history of hemangioma or 295 controls. Expressed in
    normal endothelial cells in culture, the variant reduced the binding of
    NFAT to the promoter of the VEGFR1 gene, which is the mechanism described
    under Suppressed NFAT-Dependent VEGFR1 Expression. One carrier is too few
    to say what the variant does to risk, so the relationship is recorded as
    UNKNOWN. The gene is not wired to a mechanism node.
  evidence:
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A germline G-to-A transition replaces alanine with threonine in the transmembrane domain of the integrin-like molecule TEM8 in hemEC4"
    explanation: >-
      A germline change in TEM8 in the cells of one patient.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using allele-specific PCR, we screened for the A allele in blood genomic DNA samples collected from 110 individuals with a history of hemangioma and 295 “controls” (all Caucasian; see below). No other individual carrying the A allele was found."
    explanation: >-
      No other carrier among 110 people with a history of hemangioma and 295
      controls.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found heterozygosity for nucleotide changes resulting in potential disease-associated amino acid substitutions in three of the nine individuals with hemangioma"
    explanation: >-
      Three of the nine patients carried a change in one of the two genes.
  - reference: PMID:18931684
    reference_title: "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "Expression of mutant TEM8 significantly reduced association of NFATc2 with the VEGFR1 promoter"
    explanation: >-
      Expressed in cultured endothelial cells, the variant TEM8 reduced the
      binding of NFATc2 to the VEGFR1 promoter.
diagnosis:
- name: Clinical Examination
  description: >-
    Most hemangiomas are diagnosed from the history and the look of the
    lesion: a mark that was absent or faint at birth, grew in the first weeks,
    and is soft. Features that do not fit call for imaging or a biopsy. They
    include a mass that is fully formed at birth, a firm mass that cannot be
    compressed, and new lesions after the first months of life.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Most IHs can be diagnosed clinically through history taking and physical examinations."
    explanation: >-
      A 2021 review: most are diagnosed clinically.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report demonstrates that atypical features include lesions that are noncompressible or appear after the first few months of a child’s life."
    explanation: >-
      A case report of neuroblastoma taken for hemangiomas names the atypical
      features: lesions that cannot be compressed or that appear after the
      first few months.
  - reference: PMID:27910123
    reference_title: "Congenital infantile fibrosarcoma mimicking a cutaneous vascular lesion: a case report and review of the literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, these tumors differ from hemangiomas in the time of onset, morphology, and growth pattern and must be evaluated histologically for definitive diagnosis."
    explanation: >-
      A case report and review of infantile fibrosarcoma: it differs from
      hemangioma in time of onset, shape and growth, and needs histology.
- name: Doppler Ultrasonography
  description: >-
    The first imaging test. It is advised when the diagnosis is uncertain,
    when the tumor grows explosively or for too long, when there are five or
    more tumors of the skin, and when an associated anomaly is suspected. A
    hemangioma is a well-defined solid mass with high blood flow and no
    arteriovenous shunting. In a reported case, nodules that had been taken
    for deep hemangiomas showed no increase in blood flow, and the examination
    went on to find an adrenal mass.
  diagnosis_term:
    preferred_term: Doppler ultrasonography
    term:
      id: NCIT:C62781
      label: Doppler Ultrasound
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "US with Doppler is the imaging modality of choice for IH assessment and is recommended when the diagnosis of IH is uncertain, when IHs show explosive or prolonged growth without involution, to differentiate IHs from malignant vascular tumors or vascular malformations, when there are 5 or more cutaneous IHs, or when the association with anatomic abnormalities such as PHACE syndrome or LUMBAR syndrome is suspected"
    explanation: >-
      A 2021 review: Doppler ultrasound is the imaging method of choice, with
      its indications.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "On US with Doppler, IHs appear as well-defined solid masses with high-flow vascularity but without arteriovenous shunting"
    explanation: >-
      The appearance of a hemangioma on Doppler ultrasound.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ultrasound revealed a lack of increased vascularity of the masses and an adrenal mass, leading to a biopsy and diagnosis of a neuroblastoma involving the adrenal gland, liver, and skin."
    explanation: >-
      The case report: no increased vascularity in the nodules, and an adrenal
      mass.
- name: GLUT1 Immunohistochemistry
  description: >-
    A biopsy is seldom needed. When one is taken, staining of the endothelium
    for GLUT1 identifies infantile hemangioma at any stage, in the skin and in
    the liver, and separates it from congenital hemangioma, vascular
    malformations and pyogenic granuloma. The stain is not specific in an
    absolute sense: 3 of 12 angiosarcomas showed focal staining in the same
    study.
  diagnosis_term:
    preferred_term: GLUT1 immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  evidence:
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings establish GLUT1 immunoreactivity as a highly selective and diagnostically useful marker for juvenile hemangiomas."
    explanation: >-
      The study that introduced the stain: a highly selective and
      diagnostically useful marker.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a retrospective study, we found intense endothelial GLUT1 immunoreactivity, involving more than 50% of lesional microvessels, in 97% (139 of 143) of juvenile hemangiomas from patients aged 1 month to 11 years."
    explanation: >-
      Positive in 139 of 143 hemangiomas.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."
    explanation: >-
      Negative in all 66 vascular malformations and all 20 pyogenic
      granulomas.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal GLUT1 immunoreactivity was found in 3 of 12 angiosarcomas, but not in any of 5 hemangioendotheliomas (epithelioid or infantile kaposiform)."
    explanation: >-
      Focal staining in 3 of 12 angiosarcomas; none in 5
      hemangioendotheliomas.
  - reference: PMID:14991538
    reference_title: "GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that there are two fundamentally different hepatic vascular lesions in infants and young children: GLUT1-positive hepatic infantile hemangioma (HIH) and GLUT1-negative hepatic vascular malformation with capillary proliferation (HVMCP)."
    explanation: >-
      In the liver, GLUT1 separates infantile hemangioma from a vascular
      malformation with capillary proliferation.
- name: MRI and MRA for Associated Anomalies
  description: >-
    A segmental hemangioma, or one larger than 5 cm, on the face or scalp can
    be part of PHACE syndrome, in which the hemangioma comes with anomalies of
    the brain, the arteries of the head and neck, the heart and aorta, and the
    eyes. In a prospective study of 108 infants with large facial hemangiomas,
    33 had the syndrome; anomalies of the arteries of the brain were found in
    91 per cent of them and of the heart in 67 per cent. Magnetic resonance
    imaging and angiography of the head and neck, with echocardiography, look
    for them. A segmental hemangioma over the lower spine or pelvis calls for
    imaging of the spine, because it can be part of LUMBAR syndrome.
  diagnosis_term:
    preferred_term: magnetic resonance imaging and angiography
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:19858157
    reference_title: "Consensus Statement on Diagnostic Criteria for PHACE Syndrome."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "A subgroup of patients with infantile hemangiomas have associated structural anomalies of the brain, cerebral vasculature, eyes, sternum, and/or aorta in the neurocutaneous disorder known as PHACE syndrome."
    explanation: >-
      The opening of the 2009 consensus statement: a subgroup of patients have
      the associated anomalies.
  - reference: PMID:19858157
    reference_title: "Consensus Statement on Diagnostic Criteria for PHACE Syndrome."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Definite PHACE requires the presence of a characteristic segmental hemangioma or hemangioma >5 cm on the face or scalp plus 1 major criterion or 2 minor criteria."
    explanation: >-
      The consensus criteria: definite PHACE needs a segmental hemangioma, or
      one larger than 5 cm, on the face or scalp plus one major or two minor
      criteria.
  - reference: PMID:20643720
    reference_title: "Risk for PHACE syndrome in infants with large facial hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-three (31%) of 108 had PHACE."
    explanation: >-
      The prospective study: 33 of 108 infants with large facial hemangiomas.
  - reference: PMID:20643720
    reference_title: "Risk for PHACE syndrome in infants with large facial hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common extracutaneous anomalies observed in infants with PHACE were of the arteries of the cerebrovasculature (91%) and cardiac anomalies (67%)."
    explanation: >-
      The commonest anomalies in those 33: cerebrovascular arteries and the
      heart.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with a large (>5 cm in diameter) segmentally patterned facial or scalp IHs are at risk for PHACE syndrome, and MRI and/or MRA of the head and neck (including the aortic arch and brachiocephalic origin) and echocardiography are recommended for further evaluation"
    explanation: >-
      A 2021 review: MRI or MRA of the head and neck and echocardiography for
      a large segmental hemangioma of the face or scalp.
  - reference: PMID:38759778
    reference_title: "Delphi Consensus on Diagnostic Criteria for LUMBAR Syndrome."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of LUMBAR requires the presence of a segmental, or patterned, infantile hemangioma of the lumbosacral, sacrococcygeal, or pelvic cutaneous regions plus one additional criterion of the urogenital, spinal, bony, anorectal, arterial, or renal organ systems."
    explanation: >-
      The 2024 consensus criteria for LUMBAR syndrome.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with large segmental IHs on the lower half of the body are at risk for LUMBAR syndrome, for which spine MRI is recommended, especially in the presence of sacral dimples, skin appendages, hair tufts, or lipomas."
    explanation: >-
      The review: spine MRI for large segmental hemangiomas of the lower half
      of the body.
- name: Ultrasound Screening of the Liver
  description: >-
    Infants with many hemangiomas of the skin are screened for hemangiomas of
    the liver by abdominal ultrasound. A prospective study of 1,656 infants
    found that five skin tumors was the best cut-off and recommends screening
    infants younger than nine months who have five or more.
  diagnosis_term:
    preferred_term: abdominal ultrasonography
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 676 patients with at least 3 cutaneous IHs and 980 patients with 1 or 2 focal cutaneous IHs were enrolled. Thirty-one patients were found to have IHH."
    explanation: >-
      The study: 31 hepatic hemangiomas among 1,656 infants.
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Receiver operating characteristic curve analysis showed that 5 cutaneous IHs was the optimal cutoff point to screen for IHH, with an area under the curve of 0.872"
    explanation: >-
      Five skin hemangiomas was the optimal cut-off, with an area under the
      curve of 0.872.
  - reference: PMID:33285272
    reference_title: "Screening for infantile hepatic hemangioma in patients with cutaneous infantile hemangioma: A multicenter prospective study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for IHH is recommended in patients younger than 9 months who present with 5 or more cutaneous IHs."
    explanation: >-
      The recommendation.
- name: Thyroid Function Testing
  description: >-
    Infants with multifocal or diffuse hemangiomas of the liver have their
    thyroid function tested, because the tumor can destroy thyroid hormone.
  notes: >-
    No diagnosis term is bound. A label search of the local NCIT build on 11
    November 2026 for Thyroid Function returned 15 terms, all of them grades
    of adverse events. NCIT:C64813 Thyrotropin Measurement and NCIT:C81295
    Thyroid Stimulating Hormone Measurement name one analyte each and are
    narrower than the test meant here.
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In cases of multiple or diffuse hepatic IHs, hypothyroidism can occur due to inactivation of the thyroid hormones by type 3 iodothyronine deiodinase in the IH tissue; therefore, thyroid function testing is required"
    explanation: >-
      A 2021 review: thyroid function testing is required in multiple or
      diffuse hepatic hemangiomas.
  - reference: PMID:32508067
    reference_title: "A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis."
    explanation: >-
      A case in which screening of thyroid function found severe
      hypothyroidism.
differential_diagnoses:
- name: Congenital Hemangioma
  description: >-
    A rarer vascular tumor that forms before birth and is fully grown at
    delivery. It does not grow afterwards: it shrinks within the first year or
    so (the rapidly involuting kind) or it stays (the non-involuting kind).
    The two tumors overlap in the clinic and under the microscope, and the
    authors of one pathology series suggested that they might be variations of
    one entity. The GLUT1 stain separates them, and congenital hemangiomas
    carry mutations of GNAQ or GNA11.
  distinguishing_features:
  - Present and fully formed at birth, with no growth afterwards, where infantile hemangioma appears or grows after birth
  - GLUT1-negative endothelium, with one exception in a series of rapidly involuting congenital hemangiomas, where infantile hemangioma is GLUT1-positive
  - Somatic GNAQ or GNA11 mutations, found in all eight congenital hemangiomas sequenced in one study and in 4 of 8 archival ones (the study did not test infantile hemangiomas)
  - A single lesion when it is in the liver, where infantile hemangioma is usually multifocal or diffuse
  disease_term:
    preferred_term: congenital hemangioma
    term:
      id: MONDO:0018715
      label: congenital hemangioma
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "CHs are rare benign vascular tumors that differ from IHs, are characteristically present at birth as fully developed hemangioma, do not show a proliferative phase or growth after birth, and are pathologically GLUT-1–negative"
    explanation: >-
      A 2021 review: present at birth and fully developed, no growth after
      birth, GLUT1-negative.
  - reference: PMID:27058448
    reference_title: "Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, congenital hemangiomas are GLUT1 negative and display one of two clinical patterns"
    explanation: >-
      The introduction of a genetic study: congenital hemangiomas are
      GLUT1-negative.
  - reference: PMID:15018449
    reference_title: "Rapidly involuting congenital hemangioma: clinical and histopathologic features."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "With one exception, endothelial cells in RICH (as in NICH) did not express glucose transporter-1 protein, as does common infantile hemangioma."
    explanation: >-
      A pathology series of rapidly involuting congenital hemangiomas: with
      one exception the endothelium did not express GLUT1.
  - reference: PMID:15018449
    reference_title: "Rapidly involuting congenital hemangioma: clinical and histopathologic features."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that RICH, NICH, and common infantile hemangioma have overlapping clinical and pathologic features."
    explanation: >-
      The same series: the congenital tumors and infantile hemangioma overlap
      clinically and pathologically.
  - reference: PMID:27058448
    reference_title: "Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants."
    explanation: >-
      The genetic study sequenced tissue from eight participants.
  - reference: PMID:27058448
    reference_title: "Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%."
    explanation: >-
      Mosaic GNAQ or GNA11 mutations in all the samples tested.
  - reference: PMID:27058448
    reference_title: "Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants."
    explanation: >-
      Four of eight archival congenital hemangiomas of the skin and liver
      carried one.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic IHs usually present as a multifocal or diffuse hepatic distribution, whereas congenital hepatic hemangiomas present as a focal hepatic lesion"
    explanation: >-
      In the liver, congenital hemangiomas are focal and infantile ones
      multifocal or diffuse.
- name: Kaposiform Hemangioendothelioma
  description: >-
    A locally aggressive vascular tumor. It, and the related tufted angioma,
    cause the Kasabach-Merritt phenomenon, a life-threatening fall in
    platelets with consumption of clotting factors. Infantile hemangioma does
    not. The phenomenon is curated separately as Kasabach-Merritt Syndrome.
  distinguishing_features:
  - The Kasabach-Merritt phenomenon (thrombocytopenia with consumptive coagulopathy), which infantile hemangioma does not cause
  - No endothelial GLUT1 staining in the five hemangioendotheliomas of one study, which were of the epithelioid or the kaposiform kind
  disease_term:
    preferred_term: kaposiform hemangioendothelioma
    term:
      id: MONDO:0016236
      label: kaposiform hemangioendothelioma
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Tufted angioma or Kaposiform hemangioendothelioma, rather than IHs, cause KMP and require emergency referral"
    explanation: >-
      A 2021 review: tufted angioma or kaposiform hemangioendothelioma, and
      not infantile hemangioma, cause the phenomenon.
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "KHEs are clinically heterogeneous and may develop into a life-threatening thrombocytopenia and consumptive coagulopathy, known as the Kasabach-Merritt phenomenon (KMP)."
    explanation: >-
      A 2020 review of kaposiform hemangioendothelioma: it may develop into
      the Kasabach-Merritt phenomenon.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal GLUT1 immunoreactivity was found in 3 of 12 angiosarcomas, but not in any of 5 hemangioendotheliomas (epithelioid or infantile kaposiform)."
    explanation: >-
      The GLUT1 study: none of five hemangioendotheliomas stained.
- name: Vascular Malformation
  description: >-
    A structural fault of vessels that is present at birth, grows in step with
    the child and does not involute. A flat hemangioma that hardly grows can
    be mistaken for a port-wine stain, which is a capillary malformation.
  distinguishing_features:
  - Present at birth and growing in proportion with the child, with no phase of rapid growth and none of involution
  - No endothelial GLUT1 staining in any of the 66 malformations of one study or the 26 of another
  disease_term:
    preferred_term: vascular malformation
    term:
      id: MONDO:0024291
      label: vascular malformation
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular malformations are present at birth, may not be detectable clinically, and do not show a proliferative or involutive phase after birth; rather, they grow proportionately with the child or expand hemodynamically due to infection, trauma, or hormonal changes (puberty, pregnancy)"
    explanation: >-
      A 2021 review: present at birth, no proliferative or involutive phase,
      growth in proportion with the child.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."
    explanation: >-
      No GLUT1 staining in 66 vascular malformations, of arteriovenous,
      venous, lymphatic and port-wine kinds.
  - reference: PMID:11346333
    reference_title: "A unique microvascular phenotype shared by juvenile hemangiomas and human placenta."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin."
    explanation: >-
      None of 26 vascular malformations stained for GLUT1 or the three other
      placental antigens.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a subset of IHs with minimal or arrested growth (IH-MAGs) that typically present as a patch of reticulated telangiectasia and can be misdiagnosed as a port-wine stain or other vascular birthmark"
    explanation: >-
      Hemangiomas with minimal or arrested growth can be misdiagnosed as a
      port-wine stain.
- name: Pyogenic Granuloma
  description: >-
    A small, red, glistening papule on a stalk, on the face, arms or hands,
    also called lobular capillary hemangioma.
  distinguishing_features:
  - A small pedunculated papule, where a hemangioma is a plaque or a mass
  - No endothelial GLUT1 staining in any of the 20 pyogenic granulomas of one study or the 13 of another
  disease_term:
    preferred_term: pyogenic granuloma
    term:
      id: MONDO:0022096
      label: pyogenic granuloma
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyogenic granuloma (lobular capillary hemangioma) ... GLUT-1 negative; WT-1, CD31 and CD34 positive; D2-40, LYVE-1 and Prox-1 negative ... Small (1 cm) red, glistening, pedunculated vascular papule on face, arms and hands."
    explanation: >-
      The row for pyogenic granuloma in a table of a 2021 review:
      GLUT1-negative, and a small red pedunculated papule on the face, arms
      and hands. The dots stand for cell boundaries of the table.
  - reference: PMID:10665907
    reference_title: "GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens."
    explanation: >-
      No GLUT1 staining in 20 pyogenic granulomas.
  - reference: PMID:11346333
    reference_title: "A unique microvascular phenotype shared by juvenile hemangiomas and human placenta."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin."
    explanation: >-
      None of 13 pyogenic granulomas stained.
- name: Neuroblastoma
  description: >-
    A malignant tumor that has been mistaken for hemangiomas. Neuroblastoma
    can spread to the liver and, rarely, to the skin, where it forms blue
    nodules; these are the two places where hemangiomas are also multiple. In
    one report a girl of four months who had a known hemangioma developed new
    nodules and a large liver and spleen, which were first put down to
    hemangioma and proved to be metastatic neuroblastoma. In another, a boy of
    nine months with nodules taken for deep hemangiomas had been started on
    propranolol before ultrasound showed nodules without increased blood flow
    and an adrenal mass. In an imaging series of liver lesions in infants of
    up to 100 days, one of the ten lesions that were not hemangiomas was a
    metastasis of neuroblastoma. It is curated separately as Neuroblastoma.
  distinguishing_features:
  - Firm nodules that cannot be compressed, where a deep hemangioma is soft and compressible
  - No increased blood flow in the nodules on Doppler ultrasound
  - New lesions that appear after the first months of life
  - An adrenal mass on abdominal ultrasound, and neuroblastoma on biopsy of a nodule
  disease_term:
    preferred_term: neuroblastoma
    term:
      id: MONDO:0005072
      label: neuroblastoma
  evidence:
  - reference: PMID:33644927
    reference_title: "Metastatic neuroblastoma masquerading as infantile hemangioma in a 4-month-old child."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse liver lesions in an infant have a differential diagnosis including infantile hemangioma (IH), which is common in the first year of life, and neuroblastoma (NBL) which presents at a median age of 18 months."
    explanation: >-
      The introduction of a case report: diffuse liver lesions in an infant
      include infantile hemangioma and neuroblastoma.
  - reference: PMID:33644927
    reference_title: "Metastatic neuroblastoma masquerading as infantile hemangioma in a 4-month-old child."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the case of a 4-month-old girl with a known superficial/deep IH who presented with new axillary nodules and hepatosplenomegaly, initially suspected to reflect IH but later determined to be widely metastatic NBL."
    explanation: >-
      The case: new nodules and hepatosplenomegaly in a girl with a known
      hemangioma were metastatic neuroblastoma.
  - reference: PMID:33644927
    reference_title: "Metastatic neuroblastoma masquerading as infantile hemangioma in a 4-month-old child."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic IH and metastatic NBL can present similarly. Clinicians must maintain a broad differential when evaluating new findings in a patient with previously diagnosed IH."
    explanation: >-
      Its conclusion: hepatic hemangioma and metastatic neuroblastoma can
      present alike.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present a case of a nine-month-old male infant who presented with multiple noncompressible blue-purple subcutaneous nodules, initially suggestive of atypical deep hemangiomas."
    explanation: >-
      A second case: multiple blue-purple nodules that could not be
      compressed, first read as atypical deep hemangiomas.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the presumptive diagnosis of infantile hemangiomas, propranolol therapy was initiated."
    explanation: >-
      Propranolol had been started on the presumptive diagnosis.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ultrasound revealed a lack of increased vascularity of the masses and an adrenal mass, leading to a biopsy and diagnosis of a neuroblastoma involving the adrenal gland, liver, and skin."
    explanation: >-
      Ultrasound showed no increased vascularity and an adrenal mass, and
      biopsy gave the diagnosis.
  - reference: PMID:39640139
    reference_title: "Metastatic Neuroblastoma Mimicking Multiple Infantile Hemangiomas Diagnosed With Ultrasound."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report demonstrates that atypical features include lesions that are noncompressible or appear after the first few months of a child’s life."
    explanation: >-
      The features the authors call atypical for a hemangioma.
  - reference: PMID:39318559
    reference_title: "Can Dynamic Contrast-Enhanced MRI Be Used to Differentiate Hepatic Hemangioma from Other Lesions in Early Infancy?"
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnoses in total 33 lesions included hemangiomas (23), hepatoblastoma (6), arteriovenous malformation (2), neuroblastoma metastases (1), and infarction (1)."
    explanation: >-
      An MRI series of 33 liver lesions in 30 infants: 23 hemangiomas, 6
      hepatoblastomas, 2 arteriovenous malformations, 1 metastasis of
      neuroblastoma and 1 infarction.
- name: Infantile Fibrosarcoma
  description: >-
    A rare sarcoma of soft tissue in the first year of life that can present
    as a highly vascular mass and has been diagnosed as a hemangioma or
    another benign vascular lesion. It differs in when it appears, in its
    shape and in how it grows, and the diagnosis is made on biopsy.
  distinguishing_features:
  - A mass that is present at birth or enlarges from birth, where a hemangioma is absent or faint at birth
  - Closely packed fascicles of spindle cells on biopsy
  disease_term:
    preferred_term: infantile fibrosarcoma
    term:
      id: MONDO:0004557
      label: congenital fibrosarcoma
  evidence:
  - reference: PMID:22474726
    reference_title: "Congenital infantile fibrosarcoma: a clinical mimicker of hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital infantile fibrosarcoma (CIFS) is a rare pediatric soft tissue tumor; clinically, it presents as a highly vascular mass and may simulate a hemangioma."
    explanation: >-
      The opening of a case report: the tumor presents as a highly vascular
      mass and may simulate a hemangioma.
  - reference: PMID:22474726
    reference_title: "Congenital infantile fibrosarcoma: a clinical mimicker of hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a patient with CIFS who presented with a nonspecific ulcerated mass lesion over the right shoulder region that was clinically diagnosed as a benign vascular lesion. Histology revealed a highly cellular tumor with closely packed fascicles of spindle cells."
    explanation: >-
      The case: an ulcerated mass over the shoulder, diagnosed clinically as a
      benign vascular lesion; histology showed a cellular spindle cell tumor.
  - reference: PMID:27910123
    reference_title: "Congenital infantile fibrosarcoma mimicking a cutaneous vascular lesion: a case report and review of the literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, these tumors differ from hemangiomas in the time of onset, morphology, and growth pattern and must be evaluated histologically for definitive diagnosis."
    explanation: >-
      A case report and review: the tumors differ from hemangiomas in time of
      onset, shape and growth, and need histology.
  - reference: PMID:27910123
    reference_title: "Congenital infantile fibrosarcoma mimicking a cutaneous vascular lesion: a case report and review of the literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented at seven weeks of life with a multinodular lesion that had enlarged significantly since birth, and the skin biopsy revealed a fibrosarcoma."
    explanation: >-
      Its case: a lesion that had enlarged since birth, presumed vascular on
      two ultrasound studies, and a fibrosarcoma on biopsy.
- name: Hepatoblastoma
  description: >-
    A malignant tumor of the liver and, after hemangioma, the next most common
    liver tumor of the newborn. In an imaging series of 30 infants,
    alpha-fetoprotein, size, the number of lesions and bleeding into the
    lesion did not separate it from hemangioma; the way the lesion filled with
    contrast did. It is curated separately as Hepatoblastoma.
  distinguishing_features:
  - Centripetal or flash filling on dynamic contrast-enhanced MRI, seen in 21 of 23 hemangiomas and in no other lesion of one series
  - Alpha-fetoprotein, size, multifocality and bleeding into the lesion did not differ significantly from hemangioma in that series
  disease_term:
    preferred_term: hepatoblastoma
    term:
      id: MONDO:0018666
      label: hepatoblastoma
  evidence:
  - reference: PMID:39318559
    reference_title: "Can Dynamic Contrast-Enhanced MRI Be Used to Differentiate Hepatic Hemangioma from Other Lesions in Early Infancy?"
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic hemangioma is the most common neonatal hepatic tumor ... This is followed by hepatoblastoma and mesenchymal hamartoma."
    explanation: >-
      The introduction of the imaging study: hemangioma is the most common
      liver tumor of the newborn, followed by hepatoblastoma and mesenchymal
      hamartoma. The dots stand for a figure and a citation mark.
  - reference: PMID:39318559
    reference_title: "Can Dynamic Contrast-Enhanced MRI Be Used to Differentiate Hepatic Hemangioma from Other Lesions in Early Infancy?"
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnoses in total 33 lesions included hemangiomas (23), hepatoblastoma (6), arteriovenous malformation (2), neuroblastoma metastases (1), and infarction (1)."
    explanation: >-
      The lesions in the series: 23 hemangiomas and 6 hepatoblastomas among
      33.
  - reference: PMID:39318559
    reference_title: "Can Dynamic Contrast-Enhanced MRI Be Used to Differentiate Hepatic Hemangioma from Other Lesions in Early Infancy?"
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Centripetal (16/23) or flash (5/23) filling were only seen with hemangioma."
    explanation: >-
      Centripetal filling in 16 and flash filling in 5 of the 23 hemangiomas,
      and in no other lesion.
  - reference: PMID:39318559
    reference_title: "Can Dynamic Contrast-Enhanced MRI Be Used to Differentiate Hepatic Hemangioma from Other Lesions in Early Infancy?"
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no significant difference in alpha-fetoprotein elevation ( p 0.08), average size ( p 0.35), multifocality ( p 0.38), and intralesional hemorrhage ( p 1) between hemangioma and hepatoblastoma."
    explanation: >-
      No significant difference between hemangioma and hepatoblastoma in
      alpha-fetoprotein, size, multifocality or bleeding.
treatments:
- name: Active Observation
  description: >-
    Most hemangiomas are left to run their course. The family is told what to
    expect, and the child is seen often in the first weeks and months, which
    is when a tumor that will cause trouble shows itself. In a randomized
    trial of 121 infants with early uncomplicated hemangiomas, those who were
    only observed did as well at one year as those treated with a pulsed dye
    laser.
  action_category: MONITORING
  treatment_term:
    preferred_term: active observation
    term:
      id: NCIT:C25598
      label: Observation Activity
  evidence:
  - reference: PMID:28089471
    reference_title: "Infantile haemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Most infantile haemangiomas do not require therapy. However, to identify at-risk haemangiomas, close follow-up is crucial in the first weeks of life; 80% of all haemangiomas reach their final size by 3 months of age."
    explanation: >-
      A 2017 review: most need no therapy, and close follow-up in the first
      weeks finds those at risk.
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Infantile hemangiomas (IHs) occur in as many as 5% of infants, making them the most common benign tumor of infancy. Most IHs are small, innocuous, self-resolving, and require no treatment."
    explanation: >-
      The 2019 guideline: most are small, harmless and resolve without
      treatment.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, 20% of identified IHs were abortive or telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention."
    explanation: >-
      In the cohort followed from birth, only one hemangioma required
      intervention.
  - reference: PMID:12241656
    reference_title: "Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did a prospective, randomised controlled trial in which we enrolled 121 infants aged 1-14 weeks with early haemangiomas."
    explanation: >-
      The randomized trial of laser against observation: 121 infants aged 1 to
      14 weeks.
  - reference: PMID:12241656
    reference_title: "Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "PDL treatment in uncomplicated haemangiomas is no better than a wait-and-see policy."
    explanation: >-
      Its conclusion: laser treatment of uncomplicated hemangiomas is no
      better than waiting.
- name: Oral Propranolol
  description: >-
    A beta-blocker taken by mouth, and the first-line treatment for a
    hemangioma that needs one. In the randomized trial of 456 infants, 3 mg
    per kg per day for six months cleared or nearly cleared the tumor in 60
    per cent, against 4 per cent on placebo, and 88 per cent had improved by
    the fifth week. One in ten of those who responded needed treatment again.
    A meta-analysis of 18 studies estimated clearance at 95 per cent with
    propranolol, 43 per cent with oral corticosteroids and 6 per cent without
    treatment. The guideline dose is 2 to 3 mg per kg per day for at least six
    months. Low blood sugar, low blood pressure, a slow heart rate and
    bronchospasm are the known harms; in the trial they were infrequent. How
    the drug works is not settled (see the discussions).
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: propranolol
      term:
        id: CHEBI:8499
        label: propranolol
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  target_mechanisms:
  - target: Hemangioma Stem Cell Vasculogenesis
    treatment_effect: INHIBITS
    description: >-
      In culture, propranolol stops hemangioma stem cells from turning into
      endothelial cells. The R enantiomer, which has little beta-blocking
      activity, does the same, and the authors attribute the effect to
      inhibition of the transcription factor SOX18. Whether this is how the
      drug shrinks a tumor in a child is not known.
    evidence:
    - reference: PMID:31358114
      reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: IN_VITRO
      snippet: "Propranolol significantly decreased VEGF-B induced expression of all five endothelial markers in HemSC to levels also achieved by Sm4 as compared to controls"
      explanation: >-
        Propranolol reduced the endothelial markers induced in hemangioma stem
        cells, as did an inhibitor of SOX18.
    - reference: PMID:31358114
      reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: IN_VITRO
      snippet: "The R(+) enantiomer recapitulated propranolol and Sm4-induced inhibition on all markers, whereas the S(-) enantiomer showed only weak or no inhibition on hemangioma markers"
      explanation: >-
        The R enantiomer had the effect and the S enantiomer little or none.
    - reference: PMID:31358114
      reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: IN_VITRO
      snippet: "These results are consistent with a SOX18-dependent, β-adrenergic receptor independent blockade of hemangioma endothelial differentiation, which strongly suggests that blockade of SOX18 activity is the main mode of action of propranolol in this setting."
      explanation: >-
        The authors' reading: a blockade of endothelial differentiation that
        depends on SOX18 and not on the beta-adrenergic receptor. An inference
        from cultured cells.
  evidence:
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy."
    explanation: >-
      The trial: randomized, double-blind, in infants of one to five months
      with a proliferating hemangioma that needed systemic treatment.
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 460 infants who underwent randomization, 456 received treatment."
    explanation: >-
      460 infants were randomized and 456 treated.
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001)."
    explanation: >-
      Success at week 24 in 60 per cent on 3 mg per kg per day for six months
      and 4 per cent on placebo.
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo."
    explanation: >-
      Improvement by week 5 in 88 per cent against 5 per cent.
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up."
    explanation: >-
      Ten per cent of those treated successfully needed systemic treatment
      again.
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol."
    explanation: >-
      The known adverse events were infrequent and no more frequent than on
      placebo.
  - reference: PMID:26772662
    reference_title: "Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral propranolol had the largest mean estimate of expected clearance (95%; 95% Bayesian credible interval [BCI]: 88%-99%) relative to oral corticosteroids (43%, 95% BCI: 21%-66%) and control (6%, 95% BCI: 1%-11%)."
    explanation: >-
      A network meta-analysis of 18 studies: expected clearance of 95 per cent
      with oral propranolol, 43 per cent with oral corticosteroids and 6 per
      cent in controls.
  - reference: PMID:26772662
    reference_title: "Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strength of evidence (SOE) was high for propranolol's effects on reducing lesion size compared with observation/placebo."
    explanation: >-
      The same analysis rated the strength of evidence for propranolol as
      high.
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "When systemic treatment is indicated, propranolol is the drug of choice at a dose of 2 to 3 mg/kg per day. Treatment typically is continued for at least 6 months and often is maintained until 12 months of age (occasionally longer)."
    explanation: >-
      The 2019 guideline: the drug of choice, with dose and duration.
  - reference: PMID:28089471
    reference_title: "Infantile haemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral propranolol is now the first-line treatment, which should be administered as early as possible to avoid potential complications."
    explanation: >-
      A 2017 review: first-line, and to be given early.
  - reference: PMID:41860115
    reference_title: "Risk Factors for Airway Infantile Hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Propranolol was sufficient treatment for 80.0% of infants with an airway IH."
    explanation: >-
      In a series of airway hemangiomas, propranolol alone was enough for 80
      per cent of the infants.
- name: Atenolol
  description: >-
    A cardioselective beta-blocker. A randomized trial of 377 infants in China
    found it as effective as propranolol at six months (a response in 92.5
    against 93.7 per cent), with fewer adverse events (44.4 against 70.0 per
    cent). An earlier trial of 23 patients found no significant difference in
    complete response.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atenolol
      term:
        id: CHEBI:2904
        label: atenolol
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: PMID:24656727
    reference_title: "Atenolol versus propranolol for the treatment of infantile hemangiomas: a randomized controlled study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Atenolol is a cardioselective beta-blocker that may have fewer adverse events."
    explanation: >-
      The background of the first trial: atenolol is cardioselective and may
      have fewer adverse events.
  - reference: PMID:33856430
    reference_title: "Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 377 patients met the criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187 [49.6%]) groups."
    explanation: >-
      The larger trial: 377 infants randomized to propranolol or atenolol.
  - reference: PMID:33856430
    reference_title: "Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%)."
    explanation: >-
      Response at six months in 93.7 per cent on propranolol and 92.5 per cent
      on atenolol.
  - reference: PMID:33856430
    reference_title: "Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adverse events were more common in the propranolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI, 15.7%-34.8%), but the frequency of severe adverse events did not differ meaningfully between the groups."
    explanation: >-
      Adverse events in 70.0 per cent on propranolol and 44.4 per cent on
      atenolol; severe events did not differ.
  - reference: PMID:24656727
    reference_title: "Atenolol versus propranolol for the treatment of infantile hemangiomas: a randomized controlled study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirteen patients were treated with atenolol and 10 with propranolol."
    explanation: >-
      The first trial: 13 patients on atenolol and 10 on propranolol.
  - reference: PMID:24656727
    reference_title: "Atenolol versus propranolol for the treatment of infantile hemangiomas: a randomized controlled study."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients treated with atenolol had a complete response of 53.8% and 60% with propranolol, respectively. These results were nonsignificant (P = .68)."
    explanation: >-
      Complete response in 53.8 per cent on atenolol and 60 per cent on
      propranolol, not a significant difference.
- name: Topical Timolol
  description: >-
    A beta-blocker applied to the skin. The guideline allows it for selected
    small, thin, superficial hemangiomas. A placebo-controlled trial of 69
    infants younger than 60 days found no significant difference in clearance
    at 24 weeks, 11 infants in each group, and concluded that the benefit is
    limited when the drug is given that early.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: timolol
      term:
        id: CHEBI:39465
        label: timolol
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical timolol may be used to treat select small, thin, superficial IHs."
    explanation: >-
      The 2019 guideline: it may be used for selected small, thin, superficial
      hemangiomas.
  - reference: PMID:33825828
    reference_title: "Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days"
    explanation: >-
      The trial: 69 infants with a mean age of 48 days.
  - reference: PMID:33825828
    reference_title: "Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial."
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37)."
    explanation: >-
      Complete or nearly complete resolution at 24 weeks in 11 infants on
      timolol and 11 on placebo. The trial enrolled fewer infants than
      planned.
  - reference: PMID:33825828
    reference_title: "Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial."
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this randomized clinical trial, results demonstrated that topical timolol is well tolerated for the treatment of early proliferative IH but provides limited benefit in lesion resolution when given during the early proliferative stage."
    explanation: >-
      Its conclusion: well tolerated, with limited benefit for resolution in
      the early proliferative stage.
- name: Systemic Corticosteroids
  description: >-
    Corticosteroids by mouth were used before propranolol and are now kept for
    children who cannot take propranolol or do not respond to it. A randomized
    trial of 19 infants found prednisolone and propranolol similarly
    effective, but six of the eight infants on prednisolone left the trial
    early because of adverse events, and none of the 11 on propranolol. The
    meta-analysis estimated clearance at 43 per cent with oral
    corticosteroids.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic corticosteroid therapy may be considered in IH patients in whom propranolol is contraindicated or ineffective"
    explanation: >-
      A 2021 review: considered when propranolol is contraindicated or
      ineffective.
  - reference: PMID:24526257
    reference_title: "Propranolol vs prednisolone for symptomatic proliferating infantile hemangiomas: a randomized clinical trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phase 2, investigator-blinded, multi-institutional RCT conducted in 3 academic vascular anomalies clinics on 19 of 44 eligible infants aged between 2 weeks and 6 months."
    explanation: >-
      The trial: 19 infants in three vascular anomaly clinics.
  - reference: PMID:24526257
    reference_title: "Propranolol vs prednisolone for symptomatic proliferating infantile hemangiomas: a randomized clinical trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both medications show similar efficacy for reducing the area of symptomatic, proliferating IH. Although prednisolone showed a faster response rate, propranolol was better tolerated with significantly fewer severe AEs."
    explanation: >-
      Similar efficacy; propranolol was better tolerated, with fewer severe
      adverse events.
  - reference: PMID:24526257
    reference_title: "Propranolol vs prednisolone for symptomatic proliferating infantile hemangiomas: a randomized clinical trial."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early study withdrawal owing to AEs occurred in 6 (75%) of 8 patients in the prednisolone group but 0 of 11 propranolol-treated participants."
    explanation: >-
      Early withdrawal for adverse events in 6 of 8 on prednisolone and 0 of
      11 on propranolol.
  - reference: PMID:26772662
    reference_title: "Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral propranolol had the largest mean estimate of expected clearance (95%; 95% Bayesian credible interval [BCI]: 88%-99%) relative to oral corticosteroids (43%, 95% BCI: 21%-66%) and control (6%, 95% BCI: 1%-11%)."
    explanation: >-
      The meta-analysis: expected clearance of 43 per cent with oral
      corticosteroids.
- name: Pulsed Dye Laser
  description: >-
    Laser treatment of the surface of the tumor. A randomized trial of 121
    infants found that treating early uncomplicated hemangiomas with it was no
    better than waiting: 42 per cent of treated and 44 per cent of observed
    children had clear or nearly clear skin at one year, and the treated
    children had more skin atrophy and more loss of pigment. Its accepted use
    is for the changes left in the skin after involution.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: pulsed dye laser treatment
    term:
      id: NCIT:C15466
      label: Laser Therapy
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery and/or laser treatment are most useful for the treatment of residual skin changes after involution and, less commonly, may be considered earlier to treat some IHs."
    explanation: >-
      The 2019 guideline: laser and surgery are most useful for residual skin
      changes after involution.
  - reference: PMID:12241656
    reference_title: "Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis."
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The number of children whose lesions showed complete clearance or minimum residual signs at 1 year was not significantly different in the PDL treated and observation groups (25, 42%, vs 27, 44%; p=0.92)."
    explanation: >-
      The trial: clearance or minimal residual signs at one year in 25 treated
      and 27 observed infants.
  - reference: PMID:12241656
    reference_title: "Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis."
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, PDL treated infants were more likely to have skin atrophy (17, 28%, vs 5, 8%; p=0.008) and hypopigmentation (27, 45%, vs 9, 15%; p=0.001)."
    explanation: >-
      Skin atrophy and hypopigmentation were more frequent after laser
      treatment.
  - reference: PMID:12241656
    reference_title: "Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis."
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "PDL treatment in uncomplicated haemangiomas is no better than a wait-and-see policy."
    explanation: >-
      Its conclusion for uncomplicated hemangiomas.
- name: Surgical Excision
  description: >-
    Surgery is rarely the first treatment. It is used mainly to remove or
    reshape what the involuted tumor leaves behind. One study suggests
    considering it at about three and a half years of age, when most tumors
    have stopped improving.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical excision
    term:
      id: NCIT:C15232
      label: Excision
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: PMID:30584062
    reference_title: "Clinical Practice Guideline for the Management of Infantile Hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery and/or laser treatment are most useful for the treatment of residual skin changes after involution and, less commonly, may be considered earlier to treat some IHs."
    explanation: >-
      The 2019 guideline: surgery is most useful for residual changes and is
      less often considered earlier.
  - reference: PMID:22575857
    reference_title: "Infantile hemangioma: clinical assessment of the involuting phase and implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most infantile hemangiomas do not improve significantly after 3.5 years of age."
    explanation: >-
      A study of the involuting phase: most hemangiomas do not improve
      significantly after 3.5 years of age.
  - reference: PMID:22575857
    reference_title: "Infantile hemangioma: clinical assessment of the involuting phase and implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-six percent of the cohort was treated with a corticosteroid during the proliferative phase and 87.6 percent underwent reconstruction for a residual deformity."
    explanation: >-
      In that series, 87.6 per cent had reconstruction for a residual
      deformity. Most of the series had surgery, so the figure does not
      describe hemangiomas in general.
animal_models:
- name: Hemangioma stem cell implant in nude mice
  species: Mouse
  genotype: nu/nu (immunodeficient)
  publication: PMID:18535669
  description: >-
    Stem cells selected from human proliferating hemangiomas by the marker
    CD133, and grown from single cells, are suspended in Matrigel and injected
    under the skin of immunodeficient nu/nu mice. Within seven days they form
    human blood vessels that carry GLUT1; after two months the vessels thin
    out and human fat cells appear. The authors describe it as the first
    animal model of the tumor.
  evidence:
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "We tested to determine whether HemSCs would form hemangiomas in immunodeficient nu/nu mice."
    explanation: >-
      The test: would the stem cells form hemangiomas in immunodeficient nu/nu
      mice.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Clonally expanded HemSCs or normal control cells were resuspended in Matrigel, a solubilized basement membrane preparation that has been shown to support angiogenesis and vasculogenesis"
    explanation: >-
      The cells were implanted in Matrigel.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy."
    explanation: >-
      The authors describe it as the first animal model of the tumor.
  modeled_mechanisms:
  - target: Hemangioma Stem Cell Vasculogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Human hemangioma stem cells form GLUT1-positive human vessels in the
      implant.
    limitations: >-
      The host is an immunodeficient mouse and the cells are carried in
      Matrigel, so the implant lacks the skin, the immune system and the age
      of the infant in whom the tumor grows. What sets the stem cells off in a
      child is not modelled.
    evidence:
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice."
      explanation: >-
        Human blood vessels seven days after implantation.
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "The human vessels expressed GLUT-1 and merosin, immunodiagnostic markers for infantile hemangioma."
      explanation: >-
        The vessels carried GLUT1 and merosin.
  - target: Involution with Fibrofatty Replacement
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The vessels of the implant diminish and human fat cells appear, as in
      the involuting tumor.
    limitations: >-
      The change takes two months in the implant and about three and a half
      years in a child, and the fibrous part of the residuum is not reported
      in the abstract. The limits of the host named for the first link apply
      here as well.
    evidence:
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Two months after implantation, the number of blood vessels diminished and human adipocytes became evident."
      explanation: >-
        Two months after implantation, fewer vessels and human fat cells.
    - reference: PMID:18535669
      reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, when transplanted into immunodeficient mice, hemangioma-derived cells recapitulated the unique evolution of infantile hemangioma"
      explanation: >-
        The authors' summary: the implanted cells went through the course of
        the tumor.
progression:
- phase: Precursor mark
  age_range: At birth
  notes: >-
    Many tumors are announced by a faint mark that is present at birth. One
    was present in 65 per cent of 30 infants whose facial tumors were followed
    in their parents' photographs. In the cohort examined within 48 hours of
    birth, 3 of 34 lesions were seen at birth.
  evidence:
  - reference: PMID:22826568
    reference_title: "Early growth of infantile hemangiomas: what parents' photographs tell us."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemangioma precursors were present at birth in 65% of patients."
    explanation: >-
      Precursors at birth in 65 per cent of the photographed series.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three hemangiomas (9%) were noted on examination immediately after birth, 13 (38%) were present by 1 month and 18 (53%) were noted between 1 and 3 months of age."
    explanation: >-
      The cohort followed from birth: 3 lesions seen at birth, 13 by one month
      and 18 between one and three months. The 34 lesions include two
      congenital hemangiomas.
- phase: Proliferative phase
  age_range: From the first weeks to about five months, up to nine months
  notes: >-
    The tumor grows fastest between five and a half and seven and a half
    weeks, reaches 80 per cent of its size at about three months and has
    stopped growing by five months in most children and by nine months in all
    of the cohort followed from birth. Deep tumors grow later and longer, and
    segmental tumors go on growing after three months. Ulceration, obstruction
    of the airway or of vision, and heart failure belong to this phase.
  evidence:
  - reference: PMID:22826568
    reference_title: "Early growth of infantile hemangiomas: what parents' photographs tell us."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age."
    explanation: >-
      Fastest growth between 5.5 and 7.5 weeks.
  - reference: PMID:18676554
    reference_title: "Growth characteristics of infantile hemangiomas: implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty percent of hemangioma size was reached during the early proliferative stage at a mean age of 3 months."
    explanation: >-
      Eighty per cent of the size at a mean age of three months.
  - reference: PMID:18676554
    reference_title: "Growth characteristics of infantile hemangiomas: implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differences in growth between hemangioma subtypes included that deep hemangiomas tend to grow later and longer than superficial hemangiomas and that segmental hemangiomas tended to exhibit more continued growth after 3 months of age."
    explanation: >-
      Deep and segmental tumors grow for longer.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "All IHs were present by 3 months of age, and cessation of growth had occurred in all by 9 months of age. Most occurred on the trunk."
    explanation: >-
      Growth had stopped in all by nine months.
  - reference: PMID:18035154
    reference_title: "Multicenter prospective study of ulcerated hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ulceration occurred at a median age of 4 months, most often during the proliferative phase."
    explanation: >-
      Ulceration at a median of four months, in the proliferative phase.
- phase: Involuting phase
  age_range: From the end of growth to about three and a half years
  notes: >-
    The tumor fades and shrinks. Improvement stopped at a median of 36 months
    in one study, and involution was complete at a mean of 3.5 years in
    another.
  evidence:
  - reference: PMID:22575857
    reference_title: "Infantile hemangioma: clinical assessment of the involuting phase and implications for management."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kaplan-Meier analysis estimated that involution ceased at a median age of 36 months (interquartile range, 30 to 42 months), and 92 percent of tumors completed involution by 48 months."
    explanation: >-
      Involution ceased at a median of 36 months; 92 per cent complete by 48
      months.
  - reference: PMID:27540637
    reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average age at which hemangioma completed involution was 3.5 years."
    explanation: >-
      Involution complete at 3.5 years on average.
- phase: Involuted phase
  age_range: After about three and a half years
  notes: >-
    What is left is normal skin or a lasting change: fine vessels, a pad of
    fibrofatty tissue, or slack thinned skin. Just over half of the
    hemangiomas in one study of tumors that had no systemic treatment left a
    significant sequela.
  evidence:
  - reference: PMID:27540637
    reference_title: "Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%)."
    explanation: >-
      Significant sequelae in 101 of 184, with the three commonest kinds.
  - reference: PMID:18535669
    reference_title: "Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum."
    explanation: >-
      The opening of the stem cell study: the tumor regresses to a fibrofatty
      residuum.
clinical_trials:
- name: NCT01056341
  phase: PHASE_III
  status: COMPLETED
  description: >-
    The trial that established oral propranolol: a randomized, double-blind
    comparison of four regimens of propranolol with placebo in infants with a
    proliferating hemangioma that needed systemic treatment. It was registered
    as an adaptive phase II/III study; the phase field holds one value, and
    the later phase is recorded. Its results are quoted under Oral
    Propranolol.
  target_phenotypes:
  - preferred_term: infantile hemangioma
    term:
      id: HP:0005306
      label: Capillary hemangioma
  evidence:
  - reference: clinicaltrials:NCT01056341
    reference_title: "A Randomised, Controlled, Multidose, Multicentre, Adaptive Phase II/III Study in Infants With Proliferating Infantile Hemangiomas (IHs) Requiring Systemic Therapy to Compare 4 Regimens of Propranolol (1 or 3 mg/kg/Day for 3 or 6 Months) to Placebo (Double Blind)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present study has been designed to confirm efficacy of propranolol in severe IH by demonstrating superiority over placebo and to document the safety profile of propranolol in this indication."
    explanation: >-
      The registry record states the aim of the trial.
  - reference: PMID:25693013
    reference_title: "A randomized, controlled trial of oral propranolol in infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy."
    explanation: >-
      The published report of the trial, which gives the registration number
      NCT01056341 in its abstract.
discussions:
- discussion_id: ih_origin_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What starts an infantile hemangioma: a stem cell that has gone wrong,
    cells from the placenta, a lack of oxygen, or a combination?
  attaches_to:
  - mechanistic_hypotheses#stem_cell_origin
  - mechanistic_hypotheses#placental_origin
  - mechanistic_hypotheses#hypoxia_trigger
  - pathophysiology#Hemangioma Stem Cell Vasculogenesis
  rationale: >-
    The three hypotheses answer different questions and are not exclusive. The
    stem cell work shows which cell can build the tumor, in mice, and not why
    it starts to. The placental and hypoxia hypotheses rest on shared markers
    and on associations with events of pregnancy. No study cited follows a
    tumor from its first cell in a child, and none identifies a genetic change
    in the tumor. Until one of these is done, the first step of the disease
    cannot be drawn.
  evidence:
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenesis of IH has not yet been completely defined, and current studies support several hypotheses."
    explanation: >-
      A 2021 review: the pathogenesis is not completely defined.
  - reference: PMID:16365311
    reference_title: "Evidence by molecular profiling for a placental origin of infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The origin of the pathogenic endothelial cells in common infantile hemangioma is unknown."
    explanation: >-
      The opening of the 2005 transcriptome study: the origin of the
      endothelial cells is unknown.
  - reference: PMID:11254674
    reference_title: "Clonality and altered behavior of endothelial cells from hemangiomas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemangioma, the most common tumor of infancy, is a benign vascular neoplasm of unknown etiology."
    explanation: >-
      The opening of the 2001 clonality study: a neoplasm of unknown etiology.
  - reference: PMID:24641194
    reference_title: "Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Many mechanisms have been proposed to explain the pathogenesis of infantile hemangiomas, but the exact etiology of these lesions remains unclear. Significant evidence suggests that they are derived from endothelial stem or progenitor cells"
    explanation: >-
      The discussion of the 2014 birth-cohort study: the exact etiology
      remains unclear.
- discussion_id: ih_propranolol_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does propranolol shrink an infantile hemangioma: by blocking
    beta-adrenergic receptors, by inhibiting the transcription factor SOX18,
    or both?
  attaches_to:
  - treatments#Oral Propranolol
  - pathophysiology#Hemangioma Stem Cell Vasculogenesis
  rationale: >-
    The effect of the drug on hemangiomas was noticed in infants treated for a
    heart condition, and it was adopted before its action was understood. A
    review lists five proposed actions. A laboratory study found that the R
    enantiomer, which has little beta-blocking activity, stops hemangioma stem
    cells from becoming endothelial cells as well as the mixture does, and
    attributes this to SOX18. If that is the action that matters in children,
    the R enantiomer alone might treat the tumor without the harms of
    beta-blockade, which the authors propose. Atenolol, which blocks beta-1
    receptors selectively, worked as well as propranolol in a trial, which any
    account has to explain.
  evidence:
  - reference: PMID:31358114
    reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Propranolol use in obstructive hypertrophic cardiomyopathy revealed its beneficial effects in infantile hemangioma"
    explanation: >-
      The 2019 study recalls how the effect was found: in the use of
      propranolol for obstructive hypertrophic cardiomyopathy.
  - reference: PMID:31358114
    reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited."
    explanation: >-
      The same study: the mechanism behind the clinical benefit is poorly
      understood.
  - reference: PMID:34044479
    reference_title: "Update on infantile hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of action of propranolol on IHs is unclear; however, the hypothesized mechanisms are the induction of vasoconstriction, angiogenesis inhibition by decreased VEGF and bFGF levels, induction of endothelial cell apoptosis, inhibition of nitric oxide production, and suppression of the renin-angiotensin system"
    explanation: >-
      A 2021 review: the mechanism is unclear, with the hypothesized actions
      listed.
  - reference: PMID:31358114
    reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect."
    explanation: >-
      The R enantiomer inhibits SOX18 independently of any anti-adrenergic
      effect.
  - reference: PMID:31358114
    reference_title: "R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "These results are consistent with a SOX18-dependent, β-adrenergic receptor independent blockade of hemangioma endothelial differentiation, which strongly suggests that blockade of SOX18 activity is the main mode of action of propranolol in this setting."
    explanation: >-
      The authors' reading of the experiments on hemangioma stem cells.
  - reference: PMID:33856430
    reference_title: "Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%)."
    explanation: >-
      Atenolol and propranolol gave the same response rate at six months in a
      randomized trial.
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:D18.0
      label: Hemangioma
    mapping_predicate: skos:broadMatch
    mapping_source: ICD-10-CM
    mapping_justification: The ICD-10-CM codes whose labels name hemangioma are D18 and its children, which are divided by site. None is specific to infantile hemangioma, and D18.0 covers hemangioma of any kind and at any age.
  mondo_mappings:
  - term:
      id: MONDO:0011191
      label: capillary infantile hemangioma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this entry.
  ncit_mappings:
  - term:
      id: NCIT:C6645
      label: Infantile Hemangioma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT concept for the same tumor, which MONDO lists as a cross-reference of MONDO:0011191.

Infantile Hemangioma

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