DOI: 10.1111/pde.

13930

Pediatric
ORIGINAL ARTICLE Dermatology

Atypical presentations of congenital hemangiomas: Extending

the clinical phenotype

Emily S. West MD1 | Kristin Totoraitis MD2 | Bhupender Yadav MD3 |

Anna Yasmine Kirkorian MD4,5 | Beth A. Drolet MD6 | Joyce M. Teng MD, PhD7 |
Aimee C. Smidt MD8 | Jeffrey L. Sugarman MD, PhD1 | Ilona J. Frieden MD1

1
Department of Dermatology, University of
California at San Francisco, San Francisco, Abstract
California Background/Objectives: Congenital hemangiomas (CH) are a group of benign vas‐
2
Department of Dermatology, University of
cular tumors that are present at birth and exhibit variable involution during infancy.
Minnesota, Minneapolis, Minnesota
3
Department of Radiology, Children's
Congenital hemangiomas that do not involute are typically solitary patch or plaque‐
National Health Network, Washington, type tumors that grow proportionally with somatic growth. We report a case series
District of Columbia
4
of 9 patients with persistent CH, which exhibited uncommon features including seg‐
Division of Dermatology, Children's
National Health Network, Washington, mental involvement, recurrent or severe pain, or growth via volumetric increase in
District of Columbia size or apparent increased extent of anatomic involvement over time.
5
Department of Dermatology, George
Methods: Via retrospective chart review, we included patients with persistent CH
Washington University School of Medicine
& Health Sciences, Washington, District of and atypical presentations. Available data regarding clinical characteristics, natural
Columbia
6
history, histopathology, imaging, and genetic tests were collected.
Department of Dermatology, Medical
College of Wisconsin, Milwaukee, Wisconsin Results: Data on 9 patients were collected, including 7 noninvoluting CH and 2 par‐
7
Department of Dermatology, Stanford tially involuting CH. Three of the 9 cases had segmental distribution, 6 had apparent
University, Palo Alto, California
growth or clinical evolution, and 4 were symptomatic with pain. One also had marked
8
Department of Dermatology, University
of New Mexico School of Medicine,
localized intravascular coagulopathy.
Albuquerque, New Mexico Conclusions: Ongoing or recurrent pain and large extent of anatomic involvement can

Correspondence
be features of CH, albeit uncommon ones, and can pose both diagnostic and manage‐
Emily S. West, MD, Department of ment challenges. Tissue genomic studies can offer a novel tool for CH diagnosis.
Dermatology, University of California at San
Francisco, 1701 Divisadero Street, 3rd floor,
KEYWORDS
San Francisco, CA 94115.
Email: Emily.west@ucsf.edu genetic diseases, hemangiomas, mechanisms, vascular malformation, vascular tumors

1 | I NTRO D U C TI O N
Congenital hemangiomas (CH), historically believed to represent
atypical infantile hemangiomas (IH), are now recognized as a distinct
clinical entity. They are characterized by their presence at birth, ab‐
sence of postnatal proliferation, and lack of immunohistochemical
staining with GLUT1, which is characteristic of IH.1 Three subtypes
have been defined: rapidly involuting CH (RICH), noninvoluting CH
Institutional board approval waived per institutional requirements for case reports/
retrospective chart review
(NICH), and partially involuting CH (PICH). NICH are often described
as solitary localized tumors that do not expand or involute over
time, but a minority of reports note clinical evolution and pain. 2,3
Most NICH are round or oval and well circumscribed, but segmental
cases have been described. Recently, postzygotic somatic activat‐
ing missense mutations in GNAQ and GNA11 codon 209 have been
reported to underlie NICH and RICH and likely also cause PICH.4
We now report 9 cases of CH, including 7 cases of NICH and 2 of
PICH, with atypical presentations including segmental distribution,
severe or persistent pain, or apparent increased extent of anatomic
involvement over time, and discuss these findings in the context

Pediatric Dermatology. 2019;00:1–8. wileyonlinelibrary.com/journal/pde

© 2019 Wiley Periodicals, Inc. | 1
2 | Pediatric WEST et al.
Dermatology
(A) (B) F I G U R E 1 Patient 1 with segmental
NICH. A, Initial presentation with
faintly raised blue plaque with central
telangiectases and peripheral rim of
pallor involving the right neck, scalp, and
upper trunk. B, Follow‐up 3 years later,
showing increased density of central
telangiectases, increased blue‐purple hue,
and increased prominence of adjacent
veins

of previous reports of CH to extend understanding of their clinical At last follow‐up at age 9, she continued to have intermittent swell‐
characteristics. ing and prominence of the involved area. Surgical intervention was
not recommended due to size, and sirolimus was deferred given un‐
certain efficacy.
2 | CASE SERIES

2.1 | Patient 1 2.2 | Patient 2

A 6‐year‐old girl presented for evaluation of a vascular birthmark A previously healthy 13‐year‐old boy presented with acute onset
involving her right neck and shoulder. At birth, she had a flat red‐blue pain and swelling within a congenital vascular anomaly of his left
patch involving the postauricular neck, which per mother's history thigh. He was born with a blue tumor involving the medial aspect of
extended to involve the ipsilateral chest, shoulder, and upper back. his left thigh that partially involuted by age 2, leaving an asympto‐
She also had intermittent unprovoked swelling, which appeared to matic blue patch with telangiectases (Figure 2). He had no trauma or
be associated with further growth. She intermittently experienced injury to the area preceding presentation. Physical examination of
localized discomfort, neck pain, and headaches. Prior evaluations the left thigh revealed a 20 × 17 cm blue patch with central telan‐
including echocardiogram, head and neck magnetic resonance imag‐ giectases and a rim of pallor. The patch was tender to palpation but
ing (MRI), and ophthalmologic examination did not support diagnosis without a bruit or thrill.
of PHACE syndrome. Chromosomal screen and RASA1 testing were Laboratory studies were notable for an elevated D‐dimer (798 ng/
normal. Lesional skin biopsy showed irregular vascular spaces with mL; normal range 0‐543 ng/mL). Complete blood count, metabolic
walls of varying thickness in the dermis and subcutaneous fat. Some panel, prothrombin time, activated partial thromboplastin time, and
channels contained smooth muscle cells within their walls and WT‐1 fibrinogen level were within normal limits. Ultrasound demonstrated
immunoperoxidase stain labeled small constituent blood vessels, but
not larger thicker‐walled vessels. Histopathology was thought to be
compatible with either an arteriovenous malformation or a GLUT1
negative hemangioma. Treatments including propranolol initiation at
age 4 and arterial embolization did not result in clinical improvement.
Examination revealed an otherwise healthy appearing girl with
a minimally elevated plaque extending over her right neck, inferior
face, upper trunk, and chest with a faint blue hue, coarse telangiec‐
tases, and rim of pallor (Figure 1). Over the following 3 years, the
clinical appearance remained relatively stable; however, at times
swelling and prominent veins were noted. Laboratories including
complete blood count, fibrin D‐dimers, and fibrinogen were within
normal limits. Propranolol was discontinued at age 8 due to lack of
efficacy. Repeated head and neck MRI showed a stable T2‐weighted
hyperintense lesion involving the right neck and thorax; review of
the angiography confirmed a high‐flow vascular anomaly with small
areas of puddling and no true arteriovenous shunting. Lesional test‐
ing of archival tissue using next‐generation sequencing with the
F I G U R E 2 Patient 2 with PICH of right thigh. Right thigh with
UCSF 500 panel was performed and revealed a somatic activating bluish vascular patch with slight halo of vasoconstriction and
missense mutation in GNAQ p.Q209H, confirming a diagnosis of CH. central telangiectases
TA B L E 1 Patient summaries of atypical presentations of congenital hemangiomas

Age
WEST et al.

at last
evalu-
ation/ Anatomic site Symptoms and
Patient Sex Diagnosis and size atypical features Treatments and outcomes Imaging Histopathology and additional tests

1 10 y/F NICH (Figure Right neck Segmental Propranolol and arterial embo‐ MRI: T2W hyperintense enhanc‐ Dermis and subcutaneous fat with irregu‐
1) and shoulder, Pain lization with no effect ing lesion with flow voids; high lar vascular spaces with walls of varying
back Episodic swell‐ flow with no true arteriovenous thickness, some containing smooth muscle
ing, lateral shunting cells within their walls. WT1 positive small
growth, venous constituent blood vessels, but not larger
prominence thicker‐walled vessels.
Somatic activating missense mutation in
GNAQ p.Q209H
2 13 y/M PICH (Figure Left thigh Pain, tenderness to Aspirin with slight improve‐ US: heterogeneous hyperechoic Several large and irregularly muscularized
2) 20 × 17 cm palpation, local‐ ment in pain, sclerotherapy vascular mass with venous and dermal veins with a minimal increase in small
ized intravascular with resolution of pain arterial waveforms veins throughout. Several small clusters of
coagulopathy MRI: 8.2 × 8.8 × 1.2 cm vascular small caliber vessels, some with thick hyalin‐
Involution of mass, communicating with the ized basement membranes and some with
congenital tumor superficial and left common hobnailed endothelium. Cellular clusters
by age 2 y, lateral femoral veins; no discrete arterial within the lumens of multiple small ves‐
growth, increased feeding vessel sels, no thrombus. GLUT1 negative, D2‐40
varicosities highlighted a few slightly dilated dermal
lymphatic channels.
3 28 y/F NICH (Figure Left scalp, Segmental Partial excision of 7 × 7 cm MRI: poorly delineated high‐flow Excisional specimen interpreted as
3) neck, upper Asymptomatic exophytic tumor during in‐ vascular lesion “hemangioma”
back and Proportional fancy without recurrence
shoulder growth
22 × 18 cm
4 9 y/M NICH (Figure Left scalp, Segmental No treatment MRI: enhancing vascular subcu‐ None
4) neck, Asymptomatic taneous lesion containing large
shoulder Proportional vessels with flow voids; STIR
16 × 15 cm growth sequence hyperintensity, and
postcontrast enhancement with
T1W fat‐saturated sequences
Pediatric
Dermatology
|3

(Continues)
 4

TA B L E 1 (Continued)
|

Age
at last
evalu-
ation/ Anatomic site Symptoms and
Patient Sex Diagnosis and size atypical features Treatments and outcomes Imaging Histopathology and additional tests

5 5 y/M NICH Right chest Pain Long‐pulsed 755 nm US: 2.4 × 2.9 × 0.7 cm, subcutane‐ Multilobulated proliferation of thin‐walled
6 × 5.5 cm Disproportionate Alexandrite laser, 3 treat‐ ous collection of vessels with no capillaries lined by hobnailed endothelium.
growth, increased ments every 2‐3 mos, initially feeding artery Some lobules with a central thick‐walled or
bluish hue, with relief of pain, improve‐ MRI: 5.8 × 1.2 cm, soft tissue mass stellate draining blood vessel. GLUT1, D2‐40
Pediatric

increased venous ment of induration and soft with numerous serpiginous hy‐ and Prox1 all negative.
prominence tissue prominence. Pain every pointense and T2W hyperintense
Dermatology

2‐3 d recurred 1 month after tubular structures; associated

third treatment, thought due communicating vein with the
to inflammation and sclerosis right internal mammary vein
from laser treatment.
6 30 mos/F PICH or IH Right temple Asymptomatic Intralesional triamcinolone US: 3.4 × 1.3 × 3 cm hypervascular Vascular proliferation of numerous capillaries
2 × 1.5 cm Disproportionate (10 mg/mL) with no effect lesion with prominent arterial embedded within skeletal muscle. Dilation
growth waveforms of some of the vascular channels with oc‐
MRI: 3.2 x 1.4 x 2.8 cm well‐cir‐ casional hobnail endothelial cells. GLUT1
cumscribed mass containing weakly positive and D2‐40 and Prox‐1
linear structures; hypointense on highlights were rare.
T1W sequences, hyperintense on
T2W sequence, and homogene‐
ous enhancement
7 7 y/M NICH Upper arm Asymptomatic Surgical excision with None Dilated vascular spaces admixed with small
7.5 × 6.5 cm Decrease in size, resolution lobules of capillaries. GLUT1 negative.
decreased vascu‐
lar markings
8 19 y/F NICH (Figure Left thigh Pain, tenderness to Pulsed dye laser with limited MRI: 9.1 × 3.4 × 6.1 cm lobulated Vascular proliferation with mixture of small
5) 13 × 7 cm palpation improvement, surgical lesion exhibiting T2W hyperin‐ superficial capillaries and larger deep dermal
Increased size debulking of superficial com‐ tensity and contrast enhance‐ to subcuticular vessels with both thin and
ponent with no change in her ment, involving fascial margins of thick walls; WT1 and CD31 positive, GLUT1
pain, aspirin hamstring musculature; large flow and D2‐40 negative.
voids and dilated veins noted
Repeat MRI (4 y later, after
surgical debulking): similar
to above though measuring
11.8 × 4 × 4.6 cm
9 23 mos/F NICH Left back Asymptomatic No treatment US: localized hypervascular region, None
3 × 6 cm Disproportionate no definite enlarged draining vein
growth, venous
prominence
Abbreviations: IH, infantile hemangioma; mos, months; MRI, magnetic resonance imaging; NICH, noninvoluting congenital hemangioma; PICH, partially involuting congenital hemangioma; T1W, T1‐
weighted; T2W, T2‐weighted; US, ultrasound; y, years.
WEST et al.
WEST et al.
a poorly marginated heterogeneous hyperechoic soft tissue focus
with moderate internal vascularity, characterized by venous and ar‐
terial waveforms. MRI/MRA showed an 8.2 × 8.8 × 1.2 cm collection
of serpentine and linear structures within the subcutaneous soft
tissues of the medial left thigh, without a discrete arterial feeding
vessel. Lesional skin biopsy demonstrated several large and irregu‐
larly muscularized dermal veins with a minimal increase in small veins
throughout. Several small clusters of vessels of capillary‐venular cal‐
iber were noted, some with thick hyalinized basement membranes
and some with hobnailed endothelium. Cellular clusters were noted
within the lumens of multiple small vessels but no thrombosis was
seen. Immunohistochemical staining was negative for GLUT1, and
D2‐40 highlighted a few slightly dilated dermal lymphatic channels.
The clinical features, imaging studies, and histopathology were most
consistent with a partially involuting congenital hemangioma (PICH).
The acute pain and elevated D‐dimers suggested possible localized
intravascular coagulopathy (LIC), and he started aspirin 81 mg daily.
At reevaluation 8 months later, his pain had partially improved
with aspirin. Repeat D‐dimer and fibrinogen levels were within nor‐
mal limits. Physical examination revealed increased venous varicosi‐
ties within the lesion. Repeat MRI showed enlargement of the tumor,
now measuring 8.6 × 9.2 × 1.2 cm.
Because of persistent pain, he underwent sclerotherapy of the
superficial varicosities with 3% Sotradecol. Within 3 months of
sclerotherapy, his pain resolved. He discontinued aspirin, and he has
remained pain free 12 months following sclerotherapy.
These two patients as well as patients 3‐9 are summarized in
Table 1.
3 | D I S CU S S I O N
Prior reports describing NICH and PICH emphasize persistence
with growth proportional to somatic growth, but as our cases dem‐
onstrate, not all CH demonstrate these features. Six of our 9 pa‐
tients had disproportionate growth, with either lateral extension
or increased vascular markings including prominence of draining
veins, varicosities, and bluish hue over the course of follow‐up, rang‐
ing from 4 months to 19 years, with average of 5 years 3 months.
In 1 of the 9 patients, decrease in size and vascular markings was
noted, raising the possibility of a PICH. Enjolras et al reported on a
cohort of 53 cases of NICH and a subset of patients followed over
many years developed increased warmth and prominence of drain‐
ing veins, but the frequency of this occurrence was not reported.5
In a report of 30 patients with NICH, one‐third had subtle evolu‐
tion over time characterized by an increase in prominence and size
of adjacent superficial veins and increased protuberance. 2 A series
of 80 patients with NICH found atypical postnatal growth in 9 pa‐
tients, 5 of which also developed red papules on the surface, and 2
of which were associated with bleeding episodes.3 Disproportionate
growth was described in 2 other reports of NICH, beginning at age
7,6,7 and 2 other cases of segmental NICH were also noted to have
increased prominence of telangiectases over years of follow‐up.8
Pediatric | 5
Dermatology
Thus, gradual increased size and vascular prominence, though not
commonly recognized, should be considered as a possible outcome
of CH and should not necessarily prompt reconsideration of diagno‐
sis. CH often contain robust arterial connections, and hypothetically
increased flow over time could result in dilatation of existing vascu‐
lar channels, possibly via venous hypertension in the affected area.
Another possible explanation may come from the known activating
mutations in GNAQ, which may confer a growth advantage in the
affected tissue relative to the adjacent unaffected tissue, resulting
in gradual expansion over time. The thrombosis or LIC seen in some
cases could also contribute to intermittent swelling and vascular re‐
modeling, leading to further alteration of the affected tissue. While
LIC may account for episodic swelling, it would not explain progres‐
sive and sustained vascular prominence.
Another feature in our patients was intermittent pain, noted in
4 of the 9 patients, which occurred with and without concurrent
swelling. The severity of pain prompted therapeutic interventions
in all patients. Lee et al reported pain in approximately 40% of pa‐
tients with NICH, including one who experienced a painful recur‐
rence after surgical excision. 2 Another case series of 10 patients
with PICH noted that 5 required surgical resection either due to pain
or the appearance of their CH.9 Of the patients reported here who
experienced pain, treatments yielded variable effects. Aspirin and
sclerotherapy or the 755 nm Alexandrite laser led to improvement in
symptoms in 2 cases, though in another 2 cases neither embolization
and propranolol nor pulsed dye laser and surgical debulking were
effective in improving pain.
Of the 4 cases marked by pain, 1 of the 4 was an NICH with
associated LIC. Localized intervascular coagulopathy is a known
complication of vascular anomalies, particularly venous malforma‐
tions, and has been reported in cases of CH.10 In 2008, Baselga et al
presented a case series of RICH with transient thrombocytopenia,
F I G U R E 3 Patient 3 with segmental NICH. Slightly elevated
red‐blue compressible plaque with peripheral rim of pallor
extending from the left occipital scalp to the neck, shoulder, and
upper back. An exophytic tumor was excised from the involved area
during infancy
6 | Pediatric
Dermatology
(A) (B)
low fibrinogen, and elevated D‐dimers and distinguished this pre‐
sentation from Kasabach‐Merritt phenomenon (KMP).11 A more re‐
cent case series similarly describes CH associated with high‐output
cardiac failure, several of which were associated with coagulopathy
including LIC or reported KMP.12 In instances of persistently symp‐
tomatic CH, it is reasonable to investigate for LIC or thrombosis as
evidenced by elevated D‐dimer or decreased fibrinogen and con‐
sider directed intervention in an effort to alleviate pain.
Segmental distribution was noted in 3 of the 9 patients, which
differs substantially from most PICH and NICH. Enjolras noted an
average diameter of 5 cm, but reported one case involving a large
portion of the thigh.5 Lee et al noted size greater than 10 cm di‐
ameter in only 3/30 cases of NICH. 2 Two patients with segmental
F I G U R E 5 Patient 8 with NICH of left thigh. Thin, dull red,
and centrally violaceous plaque involving the left posterior thigh,
with surrounding telangiectases, prominent veins, and halo of
vasoconstriction
WEST et al.
F I G U R E 4 Patient 4 with segmental
NICH. A, On day 4 of life, he was noted to
have a red plaque with peripheral rim of
pallor involving the left scalp, neck, and
upper trunk. B, At 3‐years‐old, the NICH
appeared stable though with increased
reddish hue
patch‐type NICH of the upper trunk have also been reported.8 Of
note, our 3 segmental cases were all NICH and all involved the upper
trunk. Only 1 was correctly diagnosed as NICH from the outset, em‐
phasizing that it may be more difficult to distinguish from other vas‐
cular tumors or malformations, even with adequate radiologic and
histopathological evaluation (Table 2).
The application of next‐generation genomic sequencing to af‐
fected tissue allows for diagnosis of CH in clinically atypical cases.
As illustrated in patient 1, diagnosis of NICH was secured only after
evaluation of lesional tissue revealed a postzygotic somatic activat‐
ing missense mutation in GNAQ codon 209. Activating mutations in
GNAQ and GNA11 amino acid position 209 have been identified in
both RICH and NICH.4 In a case described by Funk et al, a large vas‐
cular tumor and innumerable smaller vascular tumors were present
at birth, and more vascular tumors developed postnatally. Tissue
genomics showed a mutation in GNA11, confirming diagnosis of mul‐
tifocal CH.19 This same mutation is seen in several other conditions,
including blue nevi and uveal melanomas. 20,21 GNAQ and GNA11
mutations also cause port‐wine stains, Sturge‐Weber syndrome, and
cases of diffuse capillary malformations with overgrowth, albeit at
a different locus. 22,23 GNAQ encodes the G‐alpha subunit of G pro‐
tein‐coupled receptors, which signal through the mitogen‐activated
protein kinase (MAPK) pathway. Mutations of codon 209 lead to de‐
creased intrinsic GTPase activity of the G‐alpha subunit, prompting
constitutive activation of MAPK signaling and ultimately tumor pro‐
liferation and inhibition of apoptosis. 20,22,24 The presence of large
segmental CH is likely due to the timing of a somatic mutation ear‐
lier in embryonic development, whereas smaller, more localized CH
likely occur later in fetal life.
Identification of the mutation driving CH provides a molecular
explanation for CH development and offers potential therapeutic
targets but also raises larger questions regarding the classification
of vascular anomalies. The International Society of the Study for
Vascular Anomalies (ISSVA) offers a concise framework for classifi‐
cation of vascular anomalies into either vascular tumors or malfor‐
mations and is based on morphology, natural history, and histological

TA B L E 2 Characteristic features of vascular anomalies
Vascular anomaly Clinical presentation
NICH Fully formed at birth
Lack of postnatal proliferation
Solitary pink to violaceous vascular
plaques or masses with overlying
coarse telangiectases and peripheral
rim of pallor
Often localize to the head, neck, or
extremities
Infantile hemangioma Premonitory mark at birth15
Growth in early infancy followed by
spontaneous involution
Brightly erythematous macule/patch,
papule/plaque if superficial, or bluish
nodule/tumor if deep
AVM May be apparent at birth or appear later
in life
Warm red patches or slightly raised
plaques, may have associated thrill
Risk of complication by local destruc‐
tion or cardiac decompensation
VM Often apparent at birth
Slow progressive enlargement
Compressible blue tumors, increase in
prominence with venous pressure or
dependent position
Abbreviations: AVM, arteriovenous malformation; MRI, magnetic resonance imaging; NICH, noninvoluting congenital hemangioma; T1W, T1‐weighted; T2W, T2‐weighted; US, ultrasound; VM, venous
malformation.
Radiologic findings
Doppler US: heterogeneous echostructure with
visible vessels and occasional calcifications13
MRI: well‐delineated subcutaneous tumor
with homogeneous or patchy enhancement,
fast‐flow, hyperintensity on T2W sequences,
possible fat stranding or flow voids
Doppler US: well‐defined, homogeneous echo‐
structure, high vessel density and high flow16
MRI: well‐circumscribed, densely lobulated
mass with an intermediate signal on T1W
images and a bright signal on T2W images,
possible flow voids
Doppler US: poorly defined cluster of vessels,
arterial and venous signals16
MRI: no focal mass, T1W and T2W images with
serpiginous signal voids
Doppler US: solid echogenic mass with phle‐
boliths, compressible, monophasic or no flow
pattern16
MRI: T1W heterogenous intermediate signal, no
flow voids
WEST et al.
Histopathology and immunohistochemistry Genomics
Large lobules of capillaries with thin base‐ Somatic activating mutation
ment membrane and hobnailed endothelial in GNAQ and GNA11 codon
cells, dysplastic veins often interspersed 2093,12
among lobules, larger stellate‐shaped ves‐
sels may be seen centrally4
WT1 positive, GLUT1 negative14
Densely packed plump endothelial cells Unknown
forming small capillaries, endothelial prolif‐
eration, and lobular architecture15
WT1 positive, GLUT1 positive1,14
Vascular channels with irregularly thick‐ Somatic mutation in
ened walls, may see direct communication MAP2K117
between arteries and veins
WT1 positive,14 GLUT1 negative
Interconnecting venous channels with flat Common VMs with somatic
endothelium and thin basement membrane, activating mutation in TIE218
not uncommonly with phleboliths, thrombi,
or papillary endothelial hyperplasia
WT1 negative,14 GLUT1 negative
Pediatric
Dermatology
|7
8 | Pediatric
Dermatology
findings. 25 We now know that both CH and capillary malformations
are driven by somatic activating mutations in the same gene, sug‐
gesting that the separation of tumors and malformations may not be
truly binary. While the current ISSVA classification provides a use‐
ful framework for organizing and classifying vascular anomalies, this
framework must continue to be reexamined as our understanding
of the molecular and genetic underpinnings of vascular anomalies
expands.
4 | CO N C LU S I O N S
Our cases expand the clinical phenotype of CH including cases with
segmental distribution, coagulopathy, expansion over time, and the
presence of chronic or intermittent pain, which in rare cases can be
severe. Radiographic and histopathological features shared between
CH and other vascular anomalies may result in diagnostic confusion,
but tissue genomics can serve as a novel diagnostic tool by demon‐
strating activating mutations in GNAQ or GNA11 in CH.
ORCID
Emily S. West https://orcid.org/0000-0003-1483-7111
REFERENCES
1. North PE, Waner M, Mizeracki A, Mihm MC. GLUT1: A newly dis‐
covered immunohistochemical marker for juvenile hemangiomas.
Hum Pathol. 2000;31:11‐22.
2. Lee PW, Frieden IJ, Streicher JL, McCalmont T, Haggstrom AN.
Characteristics of noninvoluting congenital hemangioma: A retro‐
spective review. J Am Acad Dermatol. 2014;70:899‐903.
3. Cossio ML, Dubois J, McCuaig CC, et al. Non‐involuting congenital
hemangiomas (NICH) with postnatal atypical growth: A case series.
Pediatr Dermatol. 2019;00:1‐5.
4. Ayturk UM, Couto JA, Hann S, et al. Somatic activating mutations in
GNAQ and GNA11 are associated with congenital hemangioma. Am
J Hum Genet. 2016;98:789‐795.
5. Enjolras O, Mulliken JB, Boon LM, Wassef M, Kozakewich H,
Burrows PE. Noninvoluting congenital hemangioma: A rare cutane‐
ous vascular anomalies. Plast Reconstr Surg. 2001;107:1647‐1654.
6. Ooi KG, Wenderoth JD, Francis IC, Wilcsek GA. Selective em‐
bolization and resection of a large noninvoluting congenital
hemangioma of the lower eyelid. Ophthalmic Plast Reconstr Surg.
2009;25:111‐114.
7. Stein JA, Heidary N, Pulitzer M, Schaffer JV, North PE. Noninvoluting
congenital hemangioma. Dermatol Online J. 2008;14:7.
8. Bonifazi E, Cutrone M. Unusually large patch‐type noninvoluting
congenital hemangioma of the shoulder: A report of two cases.
Pediatr Dermatol. 2015;32:710‐713.
9. Mulliken JB, Enjolras O. Congenital hemangiomas and infantile
hemangioma: Missing links. J Am Acad Dermatol. 2004;50:875‐882.
WEST et al.
10. Dompmartin A, Acher A, Thibon P, et al. Association of localized
intravascular coagulopathy with venous malformations. Arch
Dermatol. 2008;144:873‐877.
11. Baselga E, Cordisco MR, Garzon M, Lee MT, Alomar A, Blei F.
Rapidly involuting congenital haemangioma associated with tran‐
sient thrombocytopenia and coagulopathy: A case series. Br J
Dermatol. 2008;158:1363‐1370.
12. Weitz NA, Lauren CT, Starc TJ, et al. Congenital cutaneous heman‐
gioma causing cardiac failure: A case report and review of the liter‐
ature. Pediatr Dermatol. 2013;30:e180‐190.
13. Gorincour G, Kokta V, Rypens F, Garel L, Powell J, Dubois J. Imaging
characteristics of two subtypes of congenital hemangiomas: Rapidly
involuting congenital hemangiomas and non‐involuting congenital
hemangiomas. Pediatr Radiol. 2005;35:1178‐1185.
14. Trindade F, Tellechea O, Torrelo A, Requena L, Colmenero I. Wilms
tumor 1 expression in vascular neoplasms and vascular malforma‐
tions. Am J Dermatopathol. 2011;33:569‐572.
15. Liang MG, Frieden IJ. Infantile and congenital hemangiomas. Semin
Pediatr Surg. 2014;23:162‐167.
16. Lowe LH, Marchant TC, Rivard DC, et al. Vascular malformations:
Classification and terminology the radiologist needs to know. Semin
Roentgenol. 2012;47:106‐117.
17. Couto JA, Huang AY, Konczyk DJ, et al. Somatic MAP2K1 mutations
are associated with extracranial arteriovenous malformation. Am J
Hum Genet. 2017;100:546‐554.
18. Vikkula M, Boon LM, Iii KL, et al. Vascular dysmorphogenesis
caused by an activating mutation in the receptor tyrosine kinase
TIE2. Cell. 1996;87:1181‐1190.
19. Funk T, Lim Y, Kulungowski AM, et al. Symptomatic congeni‐
tal hemangioma and congenital hemangiomatosis associated
with a somatic activating mutation in GNA11. JAMA Dermatol.
2016;152:1015‐1020.
20. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent so‐
matic mutations of GNAQ in uveal melanoma and blue naevi.
Nature. 2009;457:599‐602.
21. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in
GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191‐2199.
22. Shirley MD, Tang H, Gallione CJ, et al. Sturge‐Weber syndrome and
port‐wine stains caused by somatic mutation in GNAQ. N Engl J
Med. 2013;368:1971‐1979.
23. Couto JA, Ayturk UM, Konczyk DJ, et al. A somatic GNA11 muta‐
tion is associated with extremity capillary malformation and over‐
growth. Angiogenesis. 2017;20:303‐306.
24. Patel M, Smyth E, Chapman PB, et al. Therapeutic implications of
the emerging molecular biology of uveal melanoma. Clin Cancer Res.
2011;17:2087‐2100.
25. Wassef M, Blei F, Adams D, et al. Vascular anomalies classification:
Recommendations from the International Society for the Study of
Vascular Anomalies. Pediatrics. 2015; 136:e203‐214.
How to cite this article: West ES, Totoraitis K, Yadav B, et al.
Atypical presentations of congenital hemangiomas:
Extending the clinical phenotype. Pediatr Dermatol.
2019;00:1–8. https​://doi.org/10.1111/pde.13930​