OBSERVATION

Familial Segregation of Hemangiomas and Vascular

Malformations as an Autosomal Dominant Trait
Francine Blei, MD; Jeffrey Walter, BS; Seth J. Orlow, MD, PhD; Douglas A. Marchuk, PhD

Background: The pathogenesis of infantile hemangio-
mas is not yet understood. Growth factors and hor-
monal and mechanical influences have been thought to
affect the focal abnormal growth of endothelial cells in
these lesions. However, these influences may represent
secondary responses to an underlying primary molecu-
lar event leading to the development of hemangiomas.
Observations: We report the rare familial occurrence
of hemangiomas and/or vascular malformations in 6 kin-
dreds, suggesting autosomal dominant inheritance. In
these families, multiple generations (2-4) were affected
by hemangiomas or vascular malformations. In contrast
to the generally accepted female-male ratio of 3:1 to 4:1
associated with sporadic hemangiomas, the families with
hemangiomas in our study demonstrated a 2:1 ratio. Ad-
ditionally, vascular malformations and hemangiomas were
present in different members of the same family. The vas-
cular lesions appeared to be transmitted in an autoso-
mal dominant fashion with moderate to high pen-
etrance.
Conclusions: We have identified 6 families demonstrat-
ing autosomal dominant segregation of childhood hem-
angiomas. Additionally, family members with vascular
malformations were identified in these kindreds. Physi-
cians caring for children with hemangiomas and vascu-
lar malformations should include in their medical his-
tories inquiries about vascular lesions in other family
members, even when obvious lesions are not present in
the parents. The identification of the mutation(s) un-
derlying vascular lesions will provide insight into the
pathogenesis of these familial hemangiomas and, poten-
tially, common sporadic hemangiomas. In addition, such
research would shed light on the regulation of angio-
genic processes during development.
Arch Dermatol. 1998;134:718-722

From the Departments of
Pediatrics (Drs Blei and Orlow)
and Dermatology (Dr Orlow),
New York University Medical
Center, New York, NY, and the
Department of Genetics, Duke
University, Durham, NC (Mr
Walter and Dr Marchuk).
H
EMANGIOMAS, the most
common type of tumor in
infants,1 are benign local-
ized growths of proliferat-
ing blood vessels that con-
sist primarily of endothelial cells.
Hemangiomas may be superficial, deep, or
both and are most commonly located in the
head and neck region. Although most in-
fants exhibit only 1 hemangioma, 20% may
develop multiple hemangiomas. A subset of
these children with multiple hemangio-
mas have “diffuse neonatal hemangioma-
tosis” and are at risk of developing internal
hemangiomas. Hemangiomas occur more
frequently in females (female-male ratio, 3:1
to 4:1). They are usually self-limiting and
go through a characteristic 2-staged pro-
cess of growth and regression. The prolif-
eration phase corresponds with a rapid pe-
riod of growth of endothelial cells forming
syncytial masses with and without lu-
mens. This phase usually lasts from 6 to 12
months. Later, in the involution phase, fi-
brosis of the tissue increases, with a de-
creasing endothelial cell component and
deposition of fibroadipose tissue. The in-
volution phase usually begins spontane-
ously and can last for months or often years.
Despite this clinical course, hemangiomas
nonetheless may be the source of psycho-
social morbidity (although this has not been
well studied) and can compromise critical
organ functions (eg, the airway and vi-
sion), requiring medical intervention.1
The separation of vascular anoma-
lies into proliferative lesions and static mal-
formations represents an important ad-
vance, because the management of these
2 types of anomalies is very different.1
Whereas hemangiomas are proliferative
vascular lesions that occur abruptly and
exhibit the clinical course described above,
vascular malformations are present at birth
and grow proportionately with the rate of
growth of the child, with no tendency for
spontaneous involution. Vascular malfor-
mations may change in size in response to
infection, trauma, or hormonal changes,
but they are not proliferative.
For editorial comment
see page 740
The pathogenesis of infantile heman-
giomas is not yet understood. Recent im-
munohistochemical analyses of hemangio-
mas document a number of biochemical
markers for the different phases of the de-
velopment of hemangiomas.2,3 Proliferat-
ing cell nuclear antigen, vascular endothe-
lial growth factor, and type IV collagenase

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 Family 121
I
1 2
METHODS II
1 2 3 4 5 6 7 8 9

III ?
When documenting the medical histories of our pedi- 1 2 3 4 5 6 7 8
atric patients with vascular anomalies, we inquired if Family 129
other family members were affected by vascular le- I
sions. Our categorization of the patients followed the 1 2

classification scheme proposed by Mulliken and II

1 2 3 4 5 6
Glowacki.13 We defined as hemangiomas lesions that
grew after birth or were present at birth and showed III
1 2 3 4
evidence of regression subsequent to infancy. Lesions
IV
that had been treated with liquid nitrogen (a treat- 1 2 3
ment used on hemangiomas in the 1950s and 1960s) V
were also classified as hemangiomas. By contrast, vas- 1 2

cular malformations were defined as lesions that were Family 130

I
present at birth (or presumed to be so in the case of 1 2
cerebral lesions) and did not undergo the progression II Normal Male
and regression of hemangiomas or have the typical ra- 1 2
Normal Female
diological appearance of vascular malformations. III
For families with multiple members (from 2 or 1 2 3 4 5 6 Male With Childhood
Hemangioma
more generations) affected by hemangiomas, we ob- Female With Childhood
Family 132
tained a thorough medical history from available fam- Hemangioma
I
ily members to document the most accurate clinical 1 2 Male With Vascular
history and description of their vascular lesions. All Malformation
II
Female With Vascular
probands and immediate family members were also 1 2 3 4
Malformation
examined, and when possible, second- and third- III
? Female With Uncertain
1 2
generation family members also underwent exami- Diagnosis
nations. When possible, photographs were ob- Family 133
tained from the families or taken of the family I
members at the time of their medical examinations. 1 2

For family members affected by hemangiomas, we II

1 2 3 4 5 6
noted the type and distribution of their vascular le-
sions. The family pedigrees are shown in the Figure. III
1 2 3 4 5 6 7

Family 136
I
1 2

were detected solely in the proliferating phase, whereas II

basic fibroblast growth factor and plasminogen activator
were detected in both the proliferating and involution
stages, but much less so in the involution phase. Tissue
inhibitor of metalloproteinase was observed only in the
involution phase. CD31, von Willebrand factor, and smooth
muscle cell actin staining were present during the prolif-
eration phase but increased during the involution phase.
Fully involuted lesions showed markedly lower levels of
staining for all 3 antigens. Martin-Padura et al4 demon-
strated by immunohistochemical analysis the presence of
normal endothelial and basement membrane markers in
hemangioma tissue, suggesting that the abnormal growth
seen in proliferating hemangiomas is related more to the
local release of growth factors than to an altered endothe-
lial phenotype. More recently, Berard and colleagues5 re-
ported that human neonatal stromal hemangioma cells ex-
press vascular endothelial growth factor, which functions
in an autocrine loop and as a paracrine factor for endo-
thelial cells. These data provide some insight into the patho-
genesis of hemangiomas, but the expression of growth fac-
tors and enzymes may be secondary responses to an
underlying primary molecular event leading to the devel-
opment of hemangiomas.
One approach to the identification of an underlying
molecular event is to search for genetic alterations that may
lead to the development of hemangiomas. However, there
1 2 3 4
III
1 2 3 4 5
IV
1 2 3
Pedigree drawings of the kindreds described in the “Results” section.
Standard symbols are used for males, females, and their relationships.
Deceased family members are marked with a slash.
is a paucity of literature on the molecular genetic analysis
of hemangioma tissue, and we are not aware of published
descriptions of familial inheritance that might suggest pre-
disposing genetic mutations. A recent review of the lit-
erature on genetics by Burns et al6 revealed that dysmor-
phic syndromes are more commonly associated with
vascular malformations than with hemangiomas. Ex-
amples of these disorders are Sturge-Weber syndrome (as-
sociated with capillary malformation), Turner and Noonan
syndromes (associated with lymphatic malformation), Klip-
pel-Trenaunay syndrome (associated with capillary,
venous, and lymphatic malformations), and blue rubber–
bleb nevus syndrome (associated with venous malforma-
tions). On the other hand, dysmorphic syndromes asso-
ciated with hemangiomas seem to be limited to variable
forms of expression, including posterior fossa brain mal-
formations, hemangiomas, arterial abnormalities, coarc-
tation of the aorta, other cardiac defects, eye abnormali-
ties, sternal clefting, and supraumbilical raphe (PHACES

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 syndrome).7-11 In contrast to several heritable vascular mal-
formation syndromes (eg, hereditary hemorrhagic telan-
giectasia, cerebral vascular malformations, and mucocu-
taneous venous vascular malformations), syndromes
associated with hemangiomas do not appear to be inher-
ited. Interestingly, Gorlin et al12 observed a marked fe-
male predilection in syndromes associated with facial
hemangiomas that far exceeded the expected 3:1 to 4:1
female-male ratio.
We describe herein kindreds in which multiple mem-
bers are affected by hemangiomas, apparently through
autosomal dominant inheritance. Furthermore, we iden-
tify patients with hemangioma(s) who have relatives with
vascular malformations.
RESULTS
We identified several families with multiple generations
with infantile hemangiomas. Representative pedigrees and
clinical descriptions of 6 of these families are listed be-
low in more detail. The pedigrees are illustrated in the
Figure. The appearance, location, and clinical courses of
the hemangiomas in these families were indistinguish-
able from sporadic hemangiomas. Interestingly, in our
families, the distribution of hemangiomas between sexes
differed from the generally accepted female-male ratio of
3:1 to 4:1. In the pedigrees presented, the female-male
ratio was 2:1. In addition to these families, we have iden-
tified several other families in which several members were
affected by hemangiomas but not clearly with autoso-
mal dominant segregation. This could be due to re-
duced penetrance in some of the family members. When
we considered these families, the overall female-male ra-
tio of family members with hemangiomas was 1.4:1.
FAMILY 121
A woman (I-2) had 6 hemangiomas (on her head, leg, and
trunk). Four of her 5 children had hemangiomas. One of
her daughters (II-2) had a large hemangioma on her fore-
arm. That daughter had 1 son (III-1) who had a heman-
gioma on his cheek. Another daughter (II-4) of the pro-
positus (I-2) had hemangiomas on her lip and groin. That
daughter (II-4) gave birth to 2 children, one of whom (her
son [III-3]) had a hemangioma. Another daughter (II-5)
of the propositus had a hemangioma on her buttocks. She
had no offspring. The propositus had 2 identical twin boys,
one (II-7) who had a capillary malformation on his fore-
arm (extending from just above the wrist to just below the
elbow) and another (II-8) who had a hemangioma on his
face and shoulder. One of these sons (II-7) had 3 chil-
dren, one of whom (a daughter [III-6]) had hemangio-
mas on her head. The other twin son (II-8) had 2 sons,
one of whom (III-8) had a hemangioma.
Thus, in this kindred, 3 successive generations were
affected by vascular lesions, including both hemangio-
mas and vascular malformations. All 5 children of the pro-
positus (I-2) had vascular lesions: 4 had hemangiomas,
and 1 (an identical twin) had a capillary malformation.
Four of the propositus’ 8 grandchildren had hemangio-
mas. The female-male ratio of hemangiomas in this kin-
dred was 1.25:1.
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FAMILY 129
A woman (II-3) had a hemangioma on her back. Her niece
(III-3) had a vascular lesion on her scalp. That niece (III-3)
had 2 sons, one of whom (IV-1) had a hemangioma on his
head.Theunaffectedson(IV-2)had2daughters,oneofwhom
(V-2) had an extensive hemangioma on her buttocks, peri-
neum, and leg. Thus, we were able to identify 4 generations
of family members with hemangiomas in this kindred.
FAMILY 130
A man (II-1) had a port-wine stain (capillary malformation)
on his hand. His wife (II-2) had a hemangioma on her head.
Three of their 6 children had vascular lesions. One daugh-
ter(III-1)hadahemangiomaontheanteriorpartofherchest;
another daughter (III-2) had a lymphatic vascular malfor-
mation (cystic hygroma) on her neck; and another daugh-
ter (III-6) had a hemangioma behind her ear lobe.
FAMILY 132
A woman (I-2) had 2 or more small hemangiomas on her
trunk. Of her 3 children, one son (II-3) had 3 or 4 hem-
angiomas on his chest and back. This son had 2 chil-
dren with hemangiomas: a daughter (III-1) who had a
single hemangioma on her nose, and a son (III-2) who
had 1 large hemangioma on his back and 3 smaller hem-
angiomas on his chest, shoulder, and foot.
Thus, in this kindred, there were hemangiomas in
3 successive generations. Most of the affected individu-
als in this kindred exhibited multiple hemangiomas.
FAMILY 133
A man (I-1) had a capillary malformation on his neck. He
had 3 children, 2 of whom (II-2 and II-5) had capillary mal-
formations, and 1 of whom (II-3) had a hemangioma on her
calf. One daughter (II-2) had 3 children, 1 of whom (III-2)
had a hemangioma on her scalp. The man’s other daughter
(II-3) had 2 sons, 1 of whom (III-4) had a hemangioma on
his eyelid. The other son (III-5) had a capillary malforma-
tion on his neck. One of the sons of I-1 (II-5) had 2 daugh-
ters (III-6 and III-7), both of whom had hemangiomas. One
ofthosedaughters(III-6)hadahemangiomaonherbackand
neck, while the other (III-7) had a subglottic hemangioma.
FAMILY 136
A man (II-2) had a capillary malformation on his abdo-
men. He had a set of fraternal twins, one of whom (III-3)
had a large capillary malformation over her lower face
and neck. The twin brother (II-2) was unaffected. A fe-
male cousin (III-5) had a hemangioma on her forehead.
III-3 had 2 offspring, a son (IV-3) who had a heman-
gioma on his cheek, and a daughter (IV-2) who had a
hemangioma on her abdomen.
ADDITIONAL KINDREDS
We also identified families (not reported in this series)
in which multiple members of 1 generation were af-
 fected by similar vascular lesions. One girl had a large
venous malformation on her knee. Her brother had a le-
sion similar in appearance on his chest wall. Similarly, a
brother and sister in another family both had hemangio-
mas on their right cheeks. In some families, it appears
that clear segregation of the same or similar phenotype
(eg, hemangioma) is a dominant trait. However, per-
haps most interestingly, we noted that it was not uncom-
mon for our patients with hemangiomas to have sib-
lings and other relatives with vascular malformations (eg,
port-wine stains, lymphatic vascular malformations, or
cerebral arteriovenous malformations). In addition to
those described in the above pedigrees, we identified 2
children with hemangiomas who had relatives with vas-
cular malformations: one child’s mother had a cranial vas-
cular malformation, and the other child’s maternal aunt
had a large port-wine stain on her face and neck. Fur-
thermore, the parents of 2 patients with vascular mal-
formations that resembled those related to Klippel-
Trenaunay syndrome also had vascular malformations (the
mother had a cerebral arteriovenous malformation, and
the father had a port-wine stain on his face).
COMMENT
Although most hemangiomas occur sporadically or as part
of pleiotropic syndromes, we identified a number of kin-
dreds in which clear autosomal dominant segregation of
hemangiomas and/or vascular malformations was evi-
dent. For other families, reduced penetrance may mask
autosomal dominant segregation. Both males and fe-
males were affected in approximately equal numbers, with
the trait passing through at least 3 generations. There was
not sufficient documented medical history to determine
if these lesions occurred in earlier generations. Both hem-
angiomas and vascular malformations were observed in
the same kindreds in some cases (Figure) and some-
times in the same individual (data not shown), suggest-
ing that although these lesions have different patho-
logic features and clinical courses, an underlying genetic
influence may be common to both. In family 121, an ob-
ligate carrier of the predisposing gene had a vascular mal-
formation (capillary malformation), yet his children and
his mother had hemangiomas. Furthermore, his identi-
cal twin brother developed a hemangioma in infancy.
In our 6 family pedigrees, the female-male ratio of
individuals with hemangiomas was 2:1. At least 1 case
of male-to-male transmission was demonstrated. These
data suggest that the genes predisposing to hemangio-
mas in these kindreds are not sex linked. Furthermore,
although a female-male ratio of 3:1 to 4:1 has been re-
ported for cases of sporadic hemangiomas, that ratio ap-
parently did not apply to the families in our study. If we
assume that the skewed sex ratio with respect to spo-
radic hemangiomas is the result of hormonal influ-
ences, it appears that in these families such an influence
is less relevant than or at least partially overridden by a
predisposing genetic mutation. There are apparently 2
cases of a skipped generation in these kindreds, suggest-
ing that the predisposing mutation has a high but in-
complete penetrance and exerts a major influence on the
development of the lesions. In 2 individuals in family 121,
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multiple hemangiomas were present in the same indi-
vidual, suggesting that the predisposing genetic factor has
a strong influence on the formation of vascular lesions.
Cheung et al14 studied the genetic factors involved in
hemangiomas in a cohort of 118 pairs of twins. There was
no significant difference between the number of monozy-
gotic and dizygotic twins with hemangiomas. These data
indicate that for sporadic hemangiomas, germ line muta-
tions are not significant predisposing factors. Findings from
our examination of kindreds affected by hemangiomas and
results from the twin study by Cheung et al14 suggest that
familial forms of hemangiomas are rare. One explanation
for this low population frequency may be that only spe-
cific germ line mutations in a small number of genes are
capable of creating the hemangioma phenotype. There is
a precedent for this hypothesis in the rare case of families
with autosomal dominant venous malformations who har-
bor a specific kinase-activating arginine-to-tryptophan mu-
tation in the Tie-2 receptor tyrosine kinase.15 Presumably,
most other possible mutations in this gene would lower or
destroy the function of kinases or proteins, which would
therefore not lead to the phenotype for venous malforma-
tions. In support of this hypothesis, the inactivation of the
Tie-2 receptor in mice leads to embryonic lethality in the
homozygous state and an apparent lack of any discernible
phenotype in the heterozygous state.16,17
The apparent rarity of the families described herein
may also be due in part to insufficient data, since it is not
routine to ask about familial tendencies for hemangio-
mas or vascular malformations. In addition, hemangio-
mas disappear with age, so some individuals may not know
or may never have been told that they had a lesion as an
infant. Although we do believe that families with autoso-
mal dominant vascular anomalies are uncommon, it is likely
that other such families will be identified through careful
patient inquiry. Therefore, physicians caring for children
with hemangiomas and vascular malformations should in-
clude in their medical history inquiries about vascular
lesions in other family members, even when obvious
lesions are not present in the parents (their hemangio-
mas would have long since resolved).
Other vascular lesions that are considered nonhe-
reditary show familial segregation in rare instances. For
example, Pasyk et al18 describe 6 families with medial tel-
angiectatic nevi affecting multiple generations, suggest-
ing autosomal dominant inheritance, even though these
lesions are not normally considered to be heritable. Cebal-
los-Quintal et al19 describe a patient with Klippel-
Trenaunay-Weber syndrome whose mother had a large
cutaneous vascular lesion on her back and whose ma-
ternal grandmother had early venous varicosities of the
legs. These authors suggest that the relatives of the pa-
tient had phenotypes of milder vascular malformations.
They propose that Klippel-Trenaunay-Weber syn-
drome may be transmitted via autosomal dominant in-
heritance with variable expressivity.
Although sporadic hemangiomas are undoubtedly
caused by multiple factors (including environmental, hor-
monal, and/or mechanical influences), we believe that the
identification of the gene(s) underlying the hemangioma
phenotype in these families will shed light on the patho-
genesis of sporadic hemangiomas and these rare familial
 forms of autosomal dominant vascular anomalies. Muta-
tions that pass through the germ line and predispose fam-
ily members to develop hemangiomas may also contrib-
ute to the formation of sporadic hemangiomas. These
somatic mutations, which occur during fetal develop-
ment, may lead to clonal expansion of affected vascular tis-
sue. Rapid proliferation may be due to release from growth
inhibition by hormonal, immunological, and other changes
shortly after birth. Alternatively, the gene products them-
selves may be deregulated or may otherwise play a role in
the formation of lesions in sporadic hemangiomas. The iden-
tification of these genes and their gene products would there-
fore be invaluable to our understanding of the develop-
ment of hemangiomas in particular, and more generally,
the regulation of angiogenesis.
Venous malformations and hemangiomas have dis-
tinctly different clinical courses and a number of differ-
ent pathologic characteristics.1 Thus, it is surprising that
in some of our families, both types of vascular lesions were
present in different individuals. This might indicate that
although different, the development of both types of le-
sions may involve the deregulation of a common regu-
latory pathway. A number of tyrosine kinases and other
growth regulatory molecules have been implicated in the
processes of angiogenesis and vasculogenesis.20,21 A ge-
netic linkage analysis of the families in our study and a
candidate gene approach that considers these gene prod-
ucts might indicate whether any of these gene products
play a role in the pathogenesis of venous malformations
and hemangiomas.
Within the past several years, a genetic linkage ap-
proach has been successful in identifying specific ge-
netic defects associated with certain inherited vascular
anomalies. Two genes have been isolated that are mu-
tated in hereditary hemorrhagic telangiectasia, an auto-
somal dominant disorder of vascular dysplasia that in-
cludes the development of arteriovenous malformations.
Endoglin is the gene for hereditary hemorrhagic telan-
giectasia 1 and a transforming growth factor b–binding
protein found on endothelial cells.22 The activin receptor-
like kinase-1 gene is mutated in a second form of heredi-
tary hemorrhagic telangiectasia.23 Both gene products may
be involved in vascular remodeling associated with trans-
forming growth factor b. A mutation causing an activat-
ing mutation in the kinase domain of Tie-2 was recently
reported in 2 families with multiple members that have
mucosal venous vascular malformations.15 This muta-
tion is thought to cause an abnormal interaction be-
tween endothelial cells and smooth muscle cells, lead-
ing to dilated venous channels surrounded by few smooth
muscle cells. An inherited form of a cerebral cavernous
malformation has been mapped to chromosome 7q,24-26
although the gene has yet to be identified. It is hoped that
molecular analyses of these and other kindreds with mem-
bers affected by hemangiomas will lead to the identifi-
cation of the predisposing genetic factors related to the
development of hemangiomas and the role of their gene
products in the more common sporadic lesions.
Accepted for publication November 28, 1997.
Douglas A. Marchuk, PhD, is an Established Investi-
gator of the American Heart Association.
ARCH DERMATOL / VOL 134, JUNE 1998
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We are grateful to Mary Robyn Tudor, BA, for her as-
sistance with family contact and assessment and to family
members for their cooperation. We also thank Linda Shan-
non, MS, for referring some of the families to us.
Reprints: Francine Blei, MD, Department of Pediat-
rics, Section on Pediatric Hematology/Oncology, New York
University Medical Center, 550 First Ave, New York, NY
10016.
REFERENCES
1. Mulliken JB, Young AE, eds. Vascular Birthmarks: Hemangiomas and Vascular
Malformations. Philadelphia, Pa: WB Saunders Co; 1988.
2. Takahashi K, Mulliken J, Kozakewich H, Rogers R, Folkman J, Ezekowitz RAB.
Cellular markers that distinguish the phases of hemangiomas during infancy and
childhood. J Clin Invest. 1994;93:2357-2364.
3. Kraling B, Razon MJ, Boon LM, et al. E-selectin is present in proliferating endo-
thelial cells in human hemangiomas. Am J Pathol. 1996;148:1181-1191.
4. Martin-Padura I, DeCastellarnau C, Uccini S, et al. Expression of VE (vascular
endothelial)-cadherin and other endothelial-specific markers in hemangiomas.
J Pathol. 1995;175:51-57.
5. Berard M, Sordello S, Ortega N, et al. Vascular endothelial growth factor confers
a growth advantage in vitro and in vivo to stromal cells cultured from neonatal
hemangiomas. Am J Pathol. 1997;150:1315-1326.
6. Burns AJ, Kaplan LC, Mulliken JB. Is there an association between hemangio-
mas and syndromes with dysmorphic features? Pediatrics. 1991;88:1257-
1267.
7. Reese V, Frieden I, Paller AS, et al. Association of facial hemangiomas with Dandy-
Walker and other posterior fossa malformations. J Pediatr. 1993;122:379-384.
8. Goh WHS, Lo R. A new 3C syndrome: cerebellar hypoplasia, cavernous heman-
gioma and coarctation of the aorta. Dev Med Child Neurol. 1993;35:631-641.
9. Frieden IJ, Reese V, Cohen D. PHACE syndrome: the association of posterior fossa
brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta
and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132:307-311.
10. Pascual-Castroviejo I, Viano J, Palencia R, et al. Hemangiomas of the head, neck,
and chest with associated vascular and brain abnormalities: a complex neuro-
cutaneous syndrome. AJNR Am J Neuroradiol. 1996;17:461-471.
11. Schieken LS, Brenner JI, Baker KR, Ringel RE, Pacifico A. Aneurysm of the as-
cending aorta associated with sternal cleft, cutaneous hemangioma, and occlu-
sion of the right innominate artery in a neonate. Am Heart J. 1987;113:202-204.
12. Gorlin RJ, Kantaputra P, Aughton FJ, Mulliken JB. Marked female predilection in
some syndromes associated with facial hemangiomas. Am J Med Genet. 1994;
52:130-135.
13. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants
and children: a classification based on endothelial characteristics. Plast Recon-
str Surg. 1982;69:412-420.
14. Cheung DS, Warman ML, Mulliken JB. Hemangioma in twins. Ann Plast Surg.
1997;38:269-274.
15. Vikkula M, Boon LM, Carraway KL, et al. Vascular dysmorphogenesis caused by
an activating mutation in the receptor tyrosine kinase tie-2. Cell. 1996;87:1181-
1190.
16. Dumont DJ, Gradwohl G, Fong GH, et al. Dominant-negative and targeted null
mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in
vasculogenesis of the embryo. Genes Dev. 1994;8:1897-1909.
17. Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of receptor tyrosine kinases
Tie-1 and Tie-2 in blood vessel formation. Nature. 1995;376:70-74.
18. Pasyk KA, Wlodarczyk SR, Jakobzak MM, Kurek M, Aughton DJ. Familial medial
telangiectatic nevus: variant of nevus flammeus—port wine stain. Plast Reconstr
Surg. 1993;91:1032-1041.
19. Ceballos-Quintal JM, Pinto-Escalante D, Castillo-Zapata I. A new case of Klippel-
Trenaunay-Weber (KTW) syndrome: evidence of autosomal dominant inherit-
ance. Am J Med Genet. 1996;63:426-427.
20. Mustonen T, Alitalo K. Endothelial receptor tyrosine kinases involved in angio-
genesis [review]. J Cell Biol. 1995;129:895-898.
21. Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis?
Cell. 1996;87:1153-1155.
22. McAllister KA, Grogg KM, Johnson DW. Endoglin, a TGF-b binding protein for
endothelial cells, is the gene for hereditary hemorrhagic telangiectasia. Nat Genet.
1994;8:345-351.
23. Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like
kinase-1 gene in hereditary hemorrhagic telangiectasia type 2. Nat Genet. 1996;
13:189-195.
24. Dubovsky J, Zabramski JM, Kurth J, et al. A gene responsible for cavernous mal-
formations of the brain maps to chromosome 7q. Hum Mol Genet. 1995;4:453-
458.
25. Gunel M, Awad IA, Anson J, Lifton RP. Mapping a gene causing cerebral cav-
ernous malformation to 7q11.2-q21. Proc Natl Acad Sci U S A. 1995;92:6620-
6624.
26. Marchuk DA, Gallione CJ, Morrison LA, et al. A locus for cerebral cavernous mal-
formations maps to chromosome 7q in two families. Genomics. 1995;28:311-
314.
 nervous system and the immune system. Lancet. 1995;345:99-102.
14. Cohen N, Moynihan JA, Ader R. Pavlovian conditioning of the immune system.
Int Arch Allergy Immunol. 1994;105:101-106. 27.
15. Russell M, Dark KA, Cummins RW, Ellman G, Callaway E, Peeke HVS. Learned
histamine release. Science. 1984;225:733-734. 28.
16. MacQueen G, Marshall J, Perdue M, Siegel S, Bienenstock J. Pavlovian condi-
tioning of rat mucosal mast cells to secrete rat mast cell protease II. Science. 29.
1989;243:83-84.
17. Kelley KW, Dantzer R, Mormede P, Salmon H, Aynaud JM. Conditioned taste aver- 30.
sion suppresses induction of delayed-type hypersensitivity immune reactions.
Physiol Behav. 1984;34:189-193. 31.
18. Stockhorst U, Klosterhalfen S, Klosterhalfen W, Winkelmann M, Steingrueber HJ.
Anticipatory nausea in cancer patients receiving chemotherapy: classical condi- 32.
tioning, etiology and therapeutical implications. Integr Physiol Behav Sci. 1993;
28:177-181. 33.
19. Kiecolt-Glaser J, Glaser R. Psychoneuroimmunology and health consequences:
data and shared mechanisms. Psychosom Med. 1995;57:269-274. 34.
20. Cohen S, Tyrrell DA, Smith AP. Psychological stress and susceptibility to the com-
mon cold. N Engl J Med. 1991;325:606-612. 35.
21. Spiegel D, Kraemer HC, Bloom J, Gottheil E. Effect of psychosocial treatment on
survival of patients with metastatic breast cancer. Lancet. 1989;2:888-891. 36.
22. Fawzy FI, Fawzy NW, Hyun CS, et al. Malignant melanoma: effects of an early
structured psychiatric intervention, coping, and affective state on recurrence and 37.
survival 6 years later. Arch Gen Psychiatry. 1993;50:681-689.
23. Black S. Inhibition of immediate-type hypersensitivity response by direct sug- 38.
gestion under hypnosis. BMJ. 1963;6:925-929.
24. Black S. Shift in dose-response curve of Prausnitz-Kustner reaction by direct sug-
gestion under hypnosis. BMJ. 1963;6:990-992. 39.
25. Black S, Humphrey JH, Niven JSF. Inhibition of Mantoux reaction by direct sug-
gestion under hypnosis. BMJ. 1963;6:1649-1652. 40.
26. Zachariae R, Bjerring P, Arendt-Nielsen L. Modulation of type I immediate and
Correction
Error in Figure. In the observation titled “Familial Segre-
gation of Hemangiomas and Vascular Malformations as an I 1
Autosomal Dominant Trait,” published in the June issue of
the ARCHIVES (1998;134:718-722), one of the elements of II
the Figure was incorrectly presented; subject I-2 in family 1 2
121, who was affected, should have been represented with
III
a darkened circle. The portion of the Figure concerning this
family is reprinted correctly here. We regret the error.
Pedigree drawings of the kindreds described in the “Results” section.
Standard symbols are used for males, females, and their relationships.
ARCH DERMATOL / VOL 134, NOV 1998
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type IV delayed immunoreactivity using direct suggestion and guided imagery
during hypnosis. Allergy. 1989;44:537-542.
Zachariae R, Bjerring P. The effect of hypnotically induced analgesia on flare re-
action of cutaneous histamine prick test. Arch Dermatol Res. 1990;282:539-543.
Wyler-Harper J, Bircher AJ, Langewitz W, Kiss A. Hypnosis and the allergic re-
sponse. Schweiz Med Wochenschr. 1994;124(suppl):67-76.
Frankel FH. Hypnosis as a treatment method in psychosomatic medicine. Int J
Psychiatry Med. 1975;6:75-85.
Stewart AC, Thomas SE. Hypnotherapy as a treatment for atopic dermatitis in
adults and children. Br J Dermatol. 1995;132:778-783.
Shertzer CL, Lookingbill DP. Effects of relaxation therapy and hypnotizability in
chronic urticaria. Arch Dermatol. 1987;123:913-916.
Surman OS, Gottlieb SK, Hackett TP, Silverberg EL. Hypnosis in the treatment
of warts. Arch Gen Psychiatry. 1973;28:439-441.
Ewin DM. Hypnotherapy for warts (verruca vulgaris): 41 consecutive cases with
33 cures. Am J Clin Hypn. 1992;1:1-10.
Frankel FH, Misch RC. Hypnosis in a case of long standing psoriasis in a person
with character problems. Int J Clin Exp Hypn. 1973;21:121-130.
Tausk FA, Whitmore SE. A controlled study of hypnosis in the treatment of pa-
tients with psoriasis. Psychother Psychosom. In press.
Kirsch I. APA definition and description of hypnosis: defining hypnosis for the
public. Contemp Hypn. 1994;11:142-143.
Fredriksson T, Petterson U. Severe psoriasis: oral therapy with a new retinoid.
Dermatologica. 1978;157:238-244.
Kirsch I. Specifying nonspecifics: psychological mechanisms of placebo ef-
fects. In: Harrington A, ed. The Placebo Effect. Cambridge, Mass: Harvard Uni-
versity Press; 1997.
Nickel JC. Placebo therapy in benign prostatic hyperplasia: a 25-month study—
Canadian PROSPECT Study Group. Br J Urol. 1998;81:383-387.
Kirsch I. Clinical hypnosis as a nondeceptive placebo: empirically derived tech-
niques. Am J Clin Hypn. 1994;37:95-106.
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