REVIEW

Pediatric Dermatology 1–15, 2016

Vascular Stains: Proposal for a Clinical

Classification to Improve Diagnosis and
Management
Eduardo Rozas-Mu~ noz, M.D.,* Ilona J. Frieden, M.D.,†,‡ Esther Roe,M.D.,*
Luis Puig, M.D., Ph.D.,* and Eulalia Baselga, M.D., Ph.D.*
*Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, †Departments of
Dermatology and ‡Pediatrics, University of California, San Francisco, California

Abstract: Vascular stains are a common reason for consultation in

pediatric dermatology clinics. Although vascular stains include all
vascular malformations, the term is most often used to refer to capillary
malformations, but capillary malformations include a wide range of
vascular stains with different clinical features, prognoses, and associated
findings. The discovery of several mutations in various capillary malfor-
mations and associated syndromes has reinforced these differences, but
clinical recognition of these different types of capillary vascular stains is
sometimes difficult, and the multitude of classifications and confusing
nomenclature often hamper the correct diagnosis and management. From
our own experience and a review of the most relevant literature on this
topic, we propose categorizing patients with capillary vascular stains into
seven major clinical patterns: nevus simplex, port-wine stain, reticulated
capillary malformation, geographic capillary malformation, capillary mal-
formation–arteriovenous malformation (CM-AVM), cutis marmorata
telangiectatica congenita, and telangiectasia. We also discuss the differ-
ential diagnosis of vascular stains as well as other conditions that can
closely resemble capillary malformations and thus may potentially be
misdiagnosed.

Vascular stains are a common reason for specialty
consultation. Although vascular stains include all
vascular malformations, they are most often due to
malformed capillaries (capillary malformations, the
most common of which are port-wine stains [PWS] and
nevus simplex [NS]). Nevertheless, there are many
other capillary malformations, and they differ not only
in clinical presentation, but also in prognosis and
associated findings. The genetic bases of many vascu-
lar stains and related syndromes have recently been
identified, with most being activating mutations affect-
ing the Ras-MAP-kinase or PI3K pathways (1–6).

Address correspondence to Eulalia Baselga, M.D., Department

of Dermatology, Hospital de la Santa Creu i Sant Pau, Sant Antoni
Mª Claret 167, 08025-Barcelona, Spain, or e-mail: dra.baselga@
gmail.com.

DOI: 10.1111/pde.12939

© 2016 Wiley Periodicals, Inc. 1

2 Pediatric Dermatology 2016

Recognition of a variety of diagnoses presenting as NEVUS SIMPLEX

capillary malformations is also reflected in a recent
NS is a common capillary malformation with a
article published by Happle (7) and in the updated
prevalence of up to 82% in newborns (9–11). It has
classification scheme that the International Society for
been described under a variety of names, including
the Study of Vascular Anomalies has adopted (8). In
angel’s kiss for lesions in the middle of the
this classification scheme, PWS and associated syn-
forehead, butterfly-shaped marks for lesions on
dromes (e.g., Sturge–Weber syndrome [SWS]), cutis
the lumbosacral area or erythema nuchae, and
marmorata telangiectatica congenita (CMTC),
stork bite for lesions on the nape of the neck (3–5).
telangiectasias, and NS are recognized under the
Lesions present as pale pink to bright red or
heading of capillary malformation (Table 1).
violaceous macules with characteristic indistinct
These factors and our own clinical experiences
borders. They are partially blanchable and become
led us to reconsider the classification of vascular
more visible with energetic activity and temperature
stains. We propose categorizing patients with cap-
changes. Sometimes eczema develops over the
illary vascular stains into seven major clinical
lesions.
patterns: NS, PWS, reticulated capillary malforma-
NS usually occurs in characteristic locations such
tion, geographic capillary malformation, capillary
as the eyelids, glabella, and nape of the neck, which
malformation–arteriovenous malformation (CM-
allow its recognition. Those involving the glabella
AVM), cutis marmorata telangiectatica congenita,
and forehead often have a V shape. Occasionally,
and telangiectasia (Table 2).
and virtually always in the context of more
Although overlapping clinical features can be
extensive facial stains, lateral forehead involvement
observed in some patients, in the great majority of
is evident. Other sites such as the philtrum,
cases, this clinical classification can aid clinicians in
occipital and parietal scalp, upper back, and the
better identifying vascular stains and help in deciding
lumbosacral area can also be affected. When
what further evaluations (if any) are needed. We also
extensive, the term NS complex has been proposed
discuss the differential diagnosis of vascular stains as
(10). Over time, NS typically fades and often
well as other conditions that can closely resemble
disappears, although in a minority of patients it
capillary malformation and thus may potentially be
persists, particularly when involving the nape and
misdiagnosed.
to a lesser extent the glabella (Fig. 1).
Distinguishing NS from PWS can be difficult, but
PWS is typically better demarcated and, with the
exception of the face, is more often located in more
TABLE 1. International Society for the Study of Vascular lateral locations.
Anomalies (ISSVA) Classification of Capillary Although there has been much controversy
Malformations and Correlation with the Proposed Clinical
Classification regarding whether NS in the lumbosacral area is a
sign of occult dysraphism (12–16), most authors
Proposed vascular stain agree that screening should be conducted only when
ISSVA classification classification
Capillary malformations Capillary malformations other cutaneous abnormalities such as lipoma,
aplasia cutis, pits, sinus tract, or localized hypertri-
Cutaneous and/or chosis are present (10,14–16). In these cases, mag-
mucosal CM (“port-wine” stain)
CM with bone and/soft Reticulated netic resonance imaging (MRI) is the gold standard
tissue overgrowth for evaluation of dysraphism, but ultrasound should
CM with CNS and/or Port-wine stains be used as an initial screening technique in very
ocular anomalies (SWS)
CM of CM-AVM CM-AVM young infants.
CM of microcephaly-CM Reticulated Although the vast majority of patients with NS are
(MICCAP) otherwise normal, the presence of NS can be a sign
CM of megalencephaly-CM Reticulated
polymicrogyria (MCAP) of several genetic syndromes, including Beckwith–
Telangiectasia Telangiectasia Wiedemann syndrome (17), Nova syndrome
Cutis marmorata Cutis marmorata (18), odontodysplasia (19), macrocephaly–capillary
telangiectatica congenita telangiectatica
Nevus simplex Congenita malformation syndrome, and Roberts–SC syn-
Others Nevus simplex drome (20). These syndromes typically have
Geographic other clinical signs and symptoms that allow their
CM, capillary malformation; CNS, central nervous system; SWS recognition.
 Rozas-Mu~
noz et al: Vascular Stains 3

TABLE 2. Clinical Patterns and Main Features of Vascular Stains

Name of the
malformation Synonyms Clinical characteristics Associations Workup

Nevus simplex Salmon patch Midline location None

Angel’s kiss Pink color
Stork bite Indistinct borders
Fading macular stains
Nevus roseus
Port-wine stain Nevus flammeus Solid stains SWS (only in facial PWS MRI in all
Light red to dark located over V1) asymptomatic
purple color Glaucoma (only in children
Persistent periocular PWS) Ophthalmologic
examination in all
periocular PWS
(every 3 months 1st
year, and every
6 months second
year, then annually)
Reticulated Reticulated stains Nonprogressive Regular clinical
capillary Poorly defined (diffuse overgrowth examination
malformations indistinct borders) Others: Orthopedic
Pale pink to light red subcutaneous veins, evaluation in cases
varicosities, with severe limb
syndactilia, discrepancy
macrodactyly
M-CM
Geographic Very sharply Capillary-lymphatic Varies depending on
stains demarcated borders venous malformation individualized
Geographic shapes in most cases (often evaluation: careful
(like map of a country) called “Klippel– evaluation for
Typically dark red– Trenaunay syndrome”) overgrowth, venous
purple, but and lymphatic
occasionally paler color anomalies)
Often associated with Orthopedic
overlying blebs evaluation in limb
overgrowth
MRI with and
without contrast
Capillary Multifocal round/oval Arteriovenous Consider brain and
malformation– stains malformations spinal MRI for
arteriovenous Peripheral halo patients and
malformation affected relatives
Cutis marmorata Congenital generalized Well-demarcated dark Body asymmetry Opthalmological
telangiectatica phlebectasia stains capillary evaluation in facial
congenita Nevus vascularis reticularis Reticulated bands malformations lesions to rule out
Congenital phlebectasia Epidermal atrophy Glaucoma in facial glaucoma
Congenital livedo Persistent with warmth stains
reticularis
Telangiectasia Multiple discrete Unilateral nevoid None
vascular papules and telangiectasia:
macules with radiating sporadic, linear or
finer vessels segmental distribution
Hereditary benign
telangiectasia:
Autosomal dominant,
widespread

PORT-WINE STAIN
PWSs are the second most common capillary malfor-
mation seen in infancy (21). Typical PWSs can be
recognized according to their characteristic clinical
features and persistence over time. Lesions present as
solid stains of varying size and shape and different
shades of pink, red, or purple. They can occur
anywhere on the body. Lesions may present as large
unilateral patches with a segmental distribution and
midline demarcation or as small stains.
4 Pediatric Dermatology 2016
A B
D E
Figure 1. Nevus simplex. (A) NS of the frontal midline with extension to both upper eyelids and philtrum. (B) NS on the
frontal midline and philtrum. Note the V-shaped morphology of the lesion characteristic of this location. (C) Extensive NS
involving the nape and back. (D) NS of the frontal midline with eczema. (E) NS of the nape with eczema.
The location of the PWS is helpful in predicting the
clinical behavior and risk of associated anomalies.
PWSs on the limbs or trunk are typically stable or in
some cases actually lighten, whereas facial PWSs may
become darker or violaceous over time, acquiring a
characteristic port-wine color, as the name suggests.
Some PWSs, particularly those involving the V2
dermatome, can develop pyogenic granulomas or
other epithelial or mesenchymal hamartomas (22,23).
In some cases, progressive hypertrophy of the soft
tissues or underlying bones develops. Gingival hyper-
trophy and subsequent dental abnormalities may also
be a feature (24). Although facial PWSs usually occur
as isolated birthmarks, up to 10% may be associated
with SWS (25–27) (Fig. 2).
SWS is a noninherited congenital vascular disorder
characterized by the association between a facial PWS
and a leptomeningeal capillary-venous malformation
or a choroidal malformation of the eye (28). Children
with SWS may develop neurologic and ophthalmo-
logic complications. Neurologic complications are
frequent and include cerebral atrophy, calcifications,
seizures, focal neurologic deficits, cognitive problems,
and headaches (21,29–35). Glaucoma is the most
frequent ophthalmologic complication and occurs in
10% to 30% of patients with periocular PWSs and
30% to 70% of patients with leptomeningeal involve-
ment. The most frequent presentation is congenital
C
glaucoma resulting in buphthalmos. Lesions are
usually unilateral, affecting the same side as the
PWS (14,23,28,36–40).
The risk of developing SWS and subsequent com-
plications is strongly associated with the extension and
anatomic distribution of the facial PWS. A preponder-
ance of data indicates that only infants with facial PWSs
located in the area with sensory innervations by the first
branch of the trigeminal nerve (V1) are at risk, with
greater risk with extensive and bilateral lesions (40–42).
Recently, Welchi et al (43) hypothesized that facial
PWSs follow embryonic vascular development of the
face. They found that the best predictor of SWS is a
PWS involving a newly delineated forehead area,
stretching from the midline of the forehead to a line
joining the outer canthus of the eye to the top of the ear
and including the upper eyelid (43).
Children at risk of SWS should have neurologic
and ophthalmologic evaluations. Neurologic involve-
ment is best detected using MRI with gadolinium and
susceptibility-weighted imaging (40,44). All symp-
tomatic children should be evaluated as soon as
possible. The need for imaging in asymptomatic
children is controversial. MRI has low sensitivity in
asymptomatic neonates, but a normal MRI at 2 years
of age in a child who was asymptomatic as an infant
can be reassuring since it will most likely excluded any
neurologic involvement (29,39). A consensus
 Rozas-Mu~
noz et al: Vascular Stains 5

A B

C D

Figure 2. Port-wine stain. (A) Facial PWS on the mandibular region. Lesions in this location have no risk of developing
SWS. (B) An extensive facial PWS involving the V1 and V2 branches of the trigeminal nerve. Despite being a high-risk
lesion, this patient did not have SWS. (C and D) Facial PWSs with progressive hypertrophy of the soft tissues. (E) Facial
PWS of the forehead area. Lesions in this location have a high risk of developing SWS.
6 Pediatric Dermatology 2016
approach we use includes discussions of the risks of
general anesthesia with the family, who take part in
the decision regarding timing of the MRI. A reason-
able approach is to obtain a study at approximately
6 months of age, which provides the family with a
level of relative reassurance if negative or heightened
awareness of the risk of developing a seizure disorder.
An ophthalmologic evaluation should be performed
in all children in early childhood, especially to exclude
glaucoma. Subsequent follow-up throughout life is
recommended (38–43).
RETICULATED CAPILLARY
MALFORMATIONS
Another form of capillary malformation is the
reticulated form, which Maari and Frieden described
as “blotchy/segmental” in 2003 (45). It is character-
ized by a reticulated, poorly defined, pale pink to
light red vascular stain. Lesions can be extensive,
sometimes affecting multiple anatomic regions (45).
Although reticulated and blotchy morphology helps
in recognition, other areas may be more homoge-
neous in their morphology, appearing to be more
typical PWSs. Many reticulated capillary malforma-
tions were previously misdiagnosed as CMTC, but
reticulated CMs have a blotchier, less “tram-track-
like” pattern and lack the atrophy or textural
changes common in CMTC. They are also typically
more pink–red than the blue–purple color of CMTC.
There are three major clinical scenarios in which
this form of capillary malformation is seen: isolated
capillary malformation with a reticulate pattern,
diffuse capillary malformation with overgrowth
(DCMO), and macrocephaly–capillary malformation
syndrome (M-CM).
Isolated capillary malformations are the most
common in this category and are usually not associ-
ated with other vascular malformations or systemic
abnormalities.
Diffuse capillary malformation with overgrowth is
characterized by more extensive involvement along
with proportional nonprogressive overgrowth sec-
ondary to hypertrophy of the bones and soft tissues.
Overgrowth may affect only one extremity, ipsilateral
or contralateral to the stain, or, less frequently, an
entire side of the body (45). Lee et al (46) proposed the
term, but Enjolras et al (47) gave a similar description
in 2004 under the name “diffuse capillary malforma-
tion with congenital hypertrophy of the limb”
(Fig. 3).
Diffuse capillary malformation with overgrowth is
often misdiagnosed as Klippel–Trenaunay syndrome
Figure 3. Reticulated capillary malformations. Pale pink
reticulated capillary malformation on the left limb and back.
Note the sharp midline demarcation and diffuse indistinct
borders. This case is associated with soft tissue
overgrowth (DMCO).
(KTS), but according to the ISSVA classification, the
term KTS should be reserved for individuals with
capillary-lymphatic-venous malformations. Patients
with DCMO may have prominent subcutaneous veins
and varicosities, but they do not have lymphatic
anomalies (46). Distinguishing these conditions is
particularly important because DCMO generally has
a far better prognosis than KTS, because individuals
with this condition lack the progressive overgrowth or
worsening lymphatic and venous disease (45–51).
Reticulated capillary malformations associated
with M-CM is less common, but can be associated
with severe morbidity. M-CM is characterized by the
presence of an extensive reticulated capillary malfor-
mation of the trunk and limbs, prominent NS
(especially involving the glabella or philtrum), and
macrocephaly or megalencephaly. Facial dysmor-
phism and asymmetric overgrowth are usually evident
early in life. Syndactyly and polydactyly are common,
as are neonatal hypotonia and mild to moderate
developmental delay (52). Patients with M-CM may
develop several complications such as cerebral asym-
metry, ventriculomegaly, Chiari type I malformation,
cerebellar herniation, cortical dysplasia, polymicro-
gyria, and Wilms tumor (52,53).
Evaluation of patients with reticulated capillary
malformations depends on the clinical scenario. For
those with reticulated capillary malformations with-
out other abnormalities or with DCMO, manage-
ment consists mainly of reassurance with periodic
follow-up. Most will present with only slight limb
overgrowth and have no functional effect. Those
with more pronounced overgrowth or asymmetry
require more frequent follow-up examinations
and referrals to specialists as appropriate (e.g.,
orthopedics, genetics) (46,47). Imaging studies

should be tailored for the specific clinical scenario
(50,51).
Patients with definite M-CM need multidisci-
plinary management. A baseline MRI at the time of
diagnosis and at 6-month intervals until 2 years old
are recommended, with subsequent evaluation every
3 years (53). Abdominal sonography every 3 to
6 months through the first 7 years of life is recom-
mended in all patients with hemihypertrophy to
exclude a Wilms tumor (52).
GEOGRAPHIC CAPILLARY
MALFORMATIONS
A fourth distinctive group of vascular stains are
geographic capillary malformations, which Maari
and Frieden first highlighted as a distinct subtype in
2003 (45). Lesions may range in size from a few
centimeters, but unlike reticulated capillary malforma-
tions, they rarely encompass an entire limb. The most
distinctive feature of these stains is their extremely
sharply demarcated borders and irregular shape,
resembling a continent or a country. Their color varies
from blue to purple. Small hemorrhagic papules or
vesicles may be present at birth or develop over time, and
venous varicosities including small superficial and larger
ectatic veins are common. These stains are most
A B
Figure 4. Geographic capillary malformations. (A) Extensive geographic capillary venous lymphatic malformation with limb
overgrowth. (B) Two geographic capillary malformations on the posterior left thigh with associated limb overgrowth. Note
the sharply demarcated borders, dark color, and country-shaped morphology of the lesions. Both patients developed KTS.
Rozas-Mu~
noz et al: Vascular Stains 7
frequently found on the extremities, especially lower
limbs and buttocks, although any site may be affected
(Fig. 4).
Patients with a geographic capillary malformation
often have associated overgrowth, venous anomalies,
and lymphatic malformations (47–50). In many
patients the venous and lymphatic anomalies are not
evident at presentation but develop later, and the
geographic stain may be a good predictor of devel-
oping such complications.
The lymphatic malformations in KTS often occur
over time and include superficial vascular blebs, most
often but not exclusively superimposed upon the
vascular stains and micro- or macrocystic lymphatic
malformations in adjacent tissues and lymphedema
(54–57).
Venous malformations in KTS usually manifest as
large, extensive superficial veins on the lateral aspect
of the leg (57), which often represent persistent
embryologic vein remnants, such as the “lateral
marginal vein.” They may be noted at birth or in
early infancy, but typically become more apparent in
adolescence. These venous anomalies can predispose
patients to several local or systemic complications
(48–51,58–60).
Hypertrophy in KTS is usually present at birth and
is often progressive. It generally affects a single
8 Pediatric Dermatology 2016
extremity, but involvement of two or more limbs has
been described (49,50).
Other vascular overgrowth syndromes can also
have geographic stains, including Proteus and con-
genital, lipomatous, vascular malformations, epider-
mal nevi, and spinal or skeletal anomalies or scoliosis
(CLOVES) syndromes (61–64). CLOVES syndrome
has many features similar to Proteus syndrome but
typically does not have prominent connective tissue
nevus of the plantar foot and lacks the severely
distorting and progressive bone overgrowth seen in
Proteus syndrome. CLOVES syndrome also charac-
teristically shows a sandal foot deformity and lipomas
not seen in Proteus syndrome. The capillary malfor-
mations in CLOVES syndrome are usually the geo-
graphic type often associated with underlying
lipomatous masses (65–69). Another recently
described condition—capillary malformation of the
lower lip, lymphatic malformation of the face and
neck, asymmetry of face and limbs and partial or
generalized overgrowth (CLAPO)—has geographic
stains of the lower face in addition to the other noted
anomalies (70).
Patients with geographic stains should undergo
individualized evaluation. Those with geographic
capillary malformations on the lower extremities are
at higher risk of developing functionally important
limb-length differences and need monitoring for this
throughout childhood. In those with limb
A B
C D
Figure 5. Capillary malformations-arteriovenous malformations. (A and B) Multiple small, round, pale pink to brown CMs
on the trunk and limbs in an 8-year-old girl. (C) The same patient with a more extensive CM on the left forearm with an
underlying AVM. (D) Two CMs on the left breast of the mother of the same child.
overgrowth, orthopedic evaluation should be consid-
ered between 1 and 2 years of age. There is no
consensus regarding which imaging studies are indi-
cated and at what age. In our experience, MRI with
and without contrast is particularly helpful in deter-
mining the presence of vascular anomalies (e.g.,
venous or lymphatic) and to delineate the extent and
type of soft tissue or bone overgrowth.
CAPILLARY MALFORMATIONS–
ARTERIOVENOUS MALFORMATIONS
CM-AVM is an autosomal dominant vascular disor-
der that Eerola et al (3) first described in 2003.
Affected patients present with small, multiple, some-
times subtle capillary malformations located any-
where on the body. Lesions are characterized by
small, homogeneous, round-to-oval stains of pale
pink to red or brown, most commonly located on the
trunk, limbs, head, and neck and rarely on the palms,
soles, or oral or nasal mucosa (3,71–73). A charac-
teristic small white halo often surrounds some of the
stains (3,72). An increase in local temperature and
blood flow detected using Doppler ultrasonography is
also a common feature (3). The lesions run in several
members of affected families and are usually multiple
and multifocal, with a characteristic random distri-
bution. Although most patients present with multifo-
cal capillary malformations at birth, new lesions

usually appear during adolescence or early adulthood.
RASA-1 mutations are identified in up to two-thirds
of cases of CM-AVM (3,72) (Fig. 5).
Identifying patients with CM-AVM is important
because up to one-third may present with associated
AVMs (AVM–arteriovenous fistula [AVF] or Parkes–
Weber) (3,72). The AVM can be located in the skin, soft
tissue, bones, brain, or spine. Life-threatening compli-
cations such as hemorrhage, neurologic deficits, ische-
mia, and congestive heart failure may arise (71–76).
Vascular lesions in hereditary benign telangiectasia
(HBT) may be similar to the capillary malformations in
CM-AVM syndrome, but lesions in HBT are more
likely tooccur on the face, upper trunk, and upper limbs,
and they lack the homogeneous capillary macules
present in CM-AVM. Overall, patients with HBT do
not present with the characteristic RASA-1 mutation
of CM. Type 1 neurofibromatosis may also enter in to
the differential diagnosis in patients with light brown
capillary stains that may simulate cafe au lait spots.
MRI to exclude AVM is recommended for patients
with suggestive signs or symptoms of internal disease
(74,76). Screening of asymptomatic patients for high-
flow brain and spinal AVM is recommended to prevent
possible life-threatening complications (72). Genetic
testing should also be performed whenever possible to
establish a genotype–phenotype correlation.
CUTIS MARMORATA TELANGIECTATICA
CONGENITA
CMTC is characterized by a congenital reticular
erythema that resembles livedo reticularis (77).
Lesions present as reticulated bands of well-defined
dark blue or purple vascular stains with a marble-like
pattern. They can be localized or generalized and they
are often unilateral. Erythema and telangiectasias
may be noted in association with the reticulated areas.
Focal atrophy or, less frequently, ulceration is some-
times seen in the involved skin. Lesions most com-
monly involve the lower limbs, followed by the trunk,
upper limbs, and face. Involvement of the lower limbs
with extension to the abdomen is also common. As the
child grows, lesions may disappear completely or
partially, but the atrophy usually persists throughout
life (Fig. 6).
The association between CMTC and other anoma-
lies (77–90) is controversial because some of these may
be considered chance associations, although is it
widely accepted that body asymmetry, capillary mal-
formations, and glaucoma are true associations,
because they have been reported in a significant
number of patients (90).
Rozas-Mu~
noz et al: Vascular Stains 9
Figure 6. A newborn with lesions of cutis marmorata
telangiectatica congenita in the right arm and leg.
The differential diagnosis of CMTC includes
reticulated capillary malformations. In fact, patients
with M-CM were previously considered to have
CMTC because of the reticulated nature of their
vascular stain (82). Infantile hemangiomas with min-
imal or absent growth (also known as reticular
hemangiomas) can also be misdiagnosed as CMTC.
Other disorders that may present with a clinical
picture reminiscent of CMTC include physiologic
cutis marmorata and neonatal lupus erythematosus
(NLE). Physiologic cutis marmorata is usually less
intense than CMTC, resolves with warming, and does
not have associated atrophic skin changes. NLE can
present with fixed livedo and with atrophy and
telangiectasias. The different clinical distribution,
with lesions usually located primarily on the scalp
and periorbital area, and the appropriate serologic
tests in the infant and mother allow correct diagnosis.
Patients with CMTC typically have an excellent
prognosis since the lesions improve during the first
years of life. No complementary tests are indicated
unless other signs or symptoms are present. In
patients with facial lesions, especially those involving
the periocular area, ophthalmologic evaluation is
recommended to exclude glaucoma. Some authors
recommend annual follow-up for the first 3 years to
exclude associated anomalies (87).
TELANGIECTASIAS
Telangiectasias are a heterogeneous group of capillary
malformations characterized by dilated capillary ves-
sels that appear as small punctate red stains with a
stellate or spider-like shape. Lesions can be solitary or
multiple. Solitary telangiectasias include the common
spider angiomas. These are the most frequent vascular
stains in the telangiectasia group and are easily
recognized and usually not confused with other
10 Pediatric Dermatology 2016
Figure 7. Telangiectasia. Multiple discrete vascular
papules and macules with radiating finer vessels in a
linear distribution on the right upper extremity.
vascular stains. Multiple telangiectasias may cause
diagnostic confusion. Three main clinical forms of
multiple telangiectasias have been described during
childhood: unilateral nevoid telangiectasia, HBT and
hereditary hemorrhagic telangiectasia, and Rendu–
Osler–Weber disease. Distinction between the first
two forms is not always clear and probably reflects
nosologic confusion. In general, unilateral nevoid
telangiectasia refers to a sporadic disorder character-
ized by multiple telangiectasias with a linear or
segmental distribution, usually located over the neck
or upper extremities (Fig. 7). Hereditary benign
telangiectasia refers to an autosomal dominant disor-
der that presents with multiple lesions of varying sizes
and shapes and a widespread disposition. Lesions
begin early in life, usually on the face, and then slowly
spread to the rest of the body until adolescence (91).
Hereditary benign telangiectasia and unilateral
nevoid telangiectasia have a good prognosis and are
not associated with other abnormalities or vascular
lesions. As such, complementary examinations and
follow-up are not needed and parents should be
reassured of the benign nature of both conditions.
Hereditary hemorrhagic telangiectasia, however,
presents with different clinical lesions, having a larger
central macule or papule and often lacking radial
branches with a spider-like shape evident in HBT.
Lesions also favor the face, lips, and hands, although
patients usually present with recurrent episodes of
epistaxis, mucosal lesions, and visceral hemorrhages
due to pulmonary and gastrointestinal AVM, which
are not seen in the other two diseases.
DIFFERENTIAL DIAGNOSIS
Other skin conditions resemble vascular stains and
may pose diagnostic difficulties for the untrained eye.
Infantile hemangioma (IH) precursors or IHs with
minimal or arrested growth are sometimes formidable
mimics of PWS and NS. Clues to IHs include the
presence of a peripheral white halo and coarser
telangiectatic vessels (particularly with dermoscopy),
the development of small cutaneous ulceration (which
never occurs with PWS or NS), and ultimately the
unique natural history of change and proliferation in
IHs. In rare circumstances, skin biopsy, demonstrat-
ing Glut-1-positive cells, could also be used for
diagnostic purposes.
AVM in the initial quiescent stages may be
impossible to differentiate from PWS. Clues include
warmth with palpation, very rapid capillary refill, and
local pain beyond what would generally be expected
for a PWS. The presence of a bruit or thrill, if present,
is also helpful. Bedside Doppler ultrasound can
sometimes detect high flow, but if AVM is truly
suspected, MRI, magnetic resonance angiography, or
conventional angiography may be necessary for
confirmation.
Congenital plaque-type glomuvenous malforma-
tions (GVMs) may present initially as pink to red or
violaceous stains, but with time, they thicken consid-
erably and develop new bluish papules and nodules.
Histology will help differentiate them.
Angiokeratoma circumscriptum initially can look
like a capillary malformation. The characteristic hyper-
keratosis and deep red color will ultimately develop.
Multifocal lymphangioendotheliomatosis with
thrombocytopenia (MLT) is another multifocal stain
disease, although usually at least some of the lesions
are palpable.
Linear morphea may present with an early inflam-
matory stage in which only a red stain is present,
without any induration of the skin, so linear morphea
presenting in the neonatal period (congenital linear
morphea) may not be suspected until areas of sclerosis
and induration develop (92).
PATHOGENESIS
The etiology and pathogenesis of many vascular
stains is unknown, but recent genetic findings have
provided several clues. A somatic activating muta-
tion in the GNAQ gene, located on chromosome 9,
has been identified in tissue samples of skin and
leptomeninges from patients with SWS and in those
with nonsyndromic PWSs (1) (Fig. 8). GNAQ
encodes a guanine nucleotide-binding protein G
involved in the activation of the mitogen-activated
protein kinase (MAPK) pathway, which regulates
several cellular signals implicated in cell
 Rozas-Mu~
noz et al: Vascular Stains 11

Figure 8. Intracellular signaling pathways involved in vascular stains. (Left) Receptor tyrosine kinase activates PIK3CA,
AKT, and mTOR. Different mutations in PIK3CA may lead to the development of megalencephaly-capillary malformation,
CLOVES syndrome, or Klippel-Trenaunay syndrome. (Center) Receptor tyrosine kinase activates the low molecular weight
G protein Ras with subsequent activation of Raf, MAP 2K 1/2, and MAPK3. Mutations in RAS may lead to the development
of CM-AVM and Parkes-Weber syndrome. (Right) A G protein-coupled receptor (GPCR) pathway. Different ligands such as
vasopressin or endothelin bind to a GPCR, which then activates a G protein alpha subunit such as GNAQ. GNAQ
hydrolyzes GTP and activates phospholipase Cb (PLC-b) producing inositol 1,4,5-triphosphate (IP3) and membrane-
associated diacylglycerol (DAG). DAG, through activation of protein kinase C (PKC), activates the Raf-MEK-ERK pathway
(Raf, MAP 2K 1/2, MAPK3). Mutations in GNAQ may produce Sturge-Weber syndrome and port-wine stains.
12 Pediatric Dermatology 2016
proliferation. An increase downstream of protein
signaling or a dysregulation of some of its coupled
receptors, such as endothelin, may activate MAPK
signaling and alter vasculogenesis. In addition, novel
somatic mutations in switch/sucrose nonfermenta-
ble-related, matrix associated, actin-dependent
regulator of chromatin, subfamily a, member 4,
ephrin type-A receptor 3, MYB, platelet-derived
growth factor receptor b, and phosphatidylinositol-
4,5-bisphosphate 3-kinase, catalytic subunit a
(PIK3CA) have been recently reported in a patient
with a hypertrophic PWS (2).
Several conditions with associated vascular stains
have been found to be due to somatic activating
mutations in the phosphoinositide 3-kinase pathway.
MCM and CLOVES syndrome have been found to be
due to different activating mutations in the PIK3CA
gene (93,94). Somatic activating mutations in the
AKT1 gene have been found in Proteus syndrome,
further implicating the PI3K–AKT angiogenic path-
way in the pathogenesis of these disorders (95,96). The
PI3K–AKT–mechanistic target of rapamycin
(mTOR) pathway is an intracellular signaling path-
way that plays an important role in the formation of
normal blood vessels during development. The timing
of the mutation in the PI3K–AKT–mTOR pathway
and the precise cell of origin may determine the
ultimate clinical phenotype (4,5).
Inactivating mutations in the RASA gene on
chromosome 5q have been detected in CM-AVM
(as discussed above) and in some sporadic cases of
Parkes–Weber syndrome, where it may be a
postzygotic somatic mutation (3,5,72). The product
of the RASA gene is a Ras GTPase-activating
protein, which regulates the RAS family of
GTPases. Ras-GTPase-activating proteins, convert
the GTP active state of RAS into an inactive GDP
state. Activation of RAS stimulates a wide range of
downstream signaling pathways, including the
MAPK and PI3K pathways (95–97), so deficiency
of Ras-GTPases may cause an increase of the two
pathway signals.
Most likely, the RAS, MAPK, and PI3K–AKT
pathways act in interrelated ways, leading to vascu-
lar anomalies (including vascular stains) with vary-
ing and (at times) overlapping phenotypes (Fig. 8).
Future advances regarding the genetic basis of these
conditions may allow us to understand the exact
mechanisms underlying all the clinical phenotypes
that can present in patients and—it is hoped—
provide more specific diagnosis, prognostic informa-
tion, and novel treatment approaches.
REFERENCES
1. 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.
2. Lian CG, Sholl LM, Zakka LR et al. Novel genetic
mutations in a sporadic port-wine stain. JAMA Der-
matol 2014;150:1336–1340.
3. Eerola I, Boon LM, Mulliken JB et al. Capillary
malformation-arteriovenous malformation, a new clin-
ical and genetic disorder caused by RASA1 mutations.
Am J Hum Genet 2003;6:1240–1249.
4. Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic
activating mutation in AKT1 associated with the
Proteus syndrome. N Engl J Med 2011;365:611–619.
5. Kurek KC, Luks VL, Ayturk UM et al. Somatic mosaic
activating mutations in PIK3CA cause CLOVES syn-
drome. Am J Hum Genet 2012;90:1108–1115.
6. Lubeck BA, Lapinski PE, Bauler TJ et al. Blood
vascular abnormalities in Rasa1R780Q knockin mice:
implications for the pathogenesis of capillary malfor-
mation-arteriovenous malformation. Am J Pathol
2014;184:3163–3169.
7. Happle R. Capillary malformations: a classification
using specific names for specific skin disorders. J Eur
Acad Dermatol Venereol 2015;29:2295–2305.
8. Wassef M, Blei F, Adams D et al. Vascular anomalies
classification: recommendations from the International
Society for the Study of Vascular Anomalies. Pediatrics
2015;136:203–214.
9. Kanada KN, Merin MR, Munden A et al. A prospec-
tive study of cutaneous findings in newborns in the
United States: correlation with race, ethnicity, and
gestational status using updated classification and
nomenclature. J Pediatr 2012;161:240–245.
10. Juern AM, Glick ZR, Drolet BA et al. Nevus simplex: a
reconsideration of nomenclature, sites of involvement,
and disease associations. J Am Acad Dermatol
2010;63:805–814.
11. Patrizi A, Neri I, Orlandi C et al. Sacral medial
telangiectatic vascular nevus: a study of 43 children.
Dermatology 1996;192:301–306.
12. Metzker A, Shamir R. Butterfly-shaped mark: a variant
form of nevus flammeus simplex. Pediatrics
1990;85:1069–1071.
13. Ben-Amitai D, Davidson S, Schwartz M et al. Sacral
nevus flammeus simplex: the role of imaging. Pediatr
Dermatol 2000;17:469–471.
14. Guggisberg D, Hadj-Rabia S, Viney C et al. Skin
markers of occult spinal dysraphism in children: a
review of 54 cases. Arch Dermatol 2004;140:1109–1115.
15. McAtee-Smith J, Hebert AA, Rapini RP et al. Skin
lesions of spinal axis and spinal dysraphism: fifteen
cases and a review of the literature. Arch Pediatr
Adolesc Med 1994;148:740–748.
16. Drolet BA, Chamlin SL, Garzon MC et al. Prospective
study of spinal anomalies in children with infantile
hemangiomas of the lumbosacral skin. J Pediatr
2010;157:789–794.
17. Elliott M, Bayly R, Cole T et al. Clinical features and
natural history of Beckwith-Wiedemann syndrome:

presentation of 74 new cases. Clin Genet 1994;46:168–
174.
18. Nova HR. Familial communicating hydrocephalus,
posterior cerebellar agenesis, mega cisterna magna,
and port-wine nevi. J Neurosurg 1979;51:862–865.
19. Walton JL, Witkop CJ, Walker PO. Odontodyspla-
sia. Report of three cases with vascular nevi overly-
ing the adjacent skin of the face. Oral Surg
1978;46:675–684.
20. Satar M, Atici A, Bisak U et al. Roberts-SC pho-
comelia syndrome: a case with additional anomalies.
Clin Genet 1994;45:107–108.
21. Comi AM. Advances in Sturge-Weber syndrome. Curr
Opin Neurol 2006;19:124–128.
22. Sanchez-Carpintero I, Mihm MC, Mizeracki A et al.
Epithelial and mesenchymal hamartomatous changes in
a mature port-wine stain: morphologic evidence for a
multiple germ layer field defect. J Am Acad Dermatol
2004;50:608–612.
23. Dutkiewicz AS, Ezzedine K, Mazereeuw-Hautier J
et al. A prospective study of risk for Sturge-Weber
syndrome in children with upper facial port-wine stain.
J Am Acad Dermatol 2015;72:473–480.
24. Greene AK, Taber SF. Sturge-Weber syndrome: soft
tissue and skeletal overgrowth. J Craniofac Surg
2009;20:1629–1630.
25. Thomas-Shol KA, Vaslow DF, Maria B. Sturger-
Weber syndrome: a review. Pediatr Neurol
2004;30:303–310.
26. Chang S, Tan ST. Facial port-wine stains- clinical
stratification and risks of neuro-ocular involvement.
J Plast Reconstr Aesthet Surg 2008;61:889–893.
27. Enjolras O, Riche MC, Merland JJ. Facial port-wine
stains and Sturge-Weber syndrome. Pediatrics
1985;76:48–51.
28. Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-
Fragua R et al. . Can J Neurol Sci 2008;35:301–307.
29. Garzon MC, Huang JT, Enjolras O et al. Vascular
malformations. Part II: associated syndromes. J Am
Acad Dermatol 2007;56:541–564.
30. Griffiths PD. Choroid plexus size in young children with
Sturge-Weber syndrome. Am J Neuroradiol
1996;17:175–180.
31. Griffiths PD. Sturge-Weber syndrome revisited: the
role of neuroradiology. Neuropediatrics 1996;27:284–
294.
32. Sujansky E, Conradi S. Sturge-Weber syndrome: age of
onset of seizures and glaucoma and the prognosis for
affected children. J Child Neurol 1995;10:49–58.
33. Bebin EM, Gomez MR. Prognosis in Sturge-Weber
disease: comparison of unihemispheric and bihemi-
spheric involvement. J Child Neurol 1988;3:181–184.
34. Sujansky E. Outcome of Sturge-Weber syndrome in 52
adults. Am J Med Genet 1995;57:35–45.
35. Kossoff EH, Comi AM. Comorbidity of epilepsy and
headache in patients with Sturge-Weber syndrome.
J Child Neurol 2005;20:678–682.
36. Sullivan TJ, Clarke MP, Morin JD. The ocular man-
ifestations of the Sturge-Weber syndrome. J Pediatr
Ophthalmol Strabismus 1992;29:349–356.
37. Baselga E. Sturge-Weber syndrome. Semin Cutan Med
Surg 2004;23:87–98.
Rozas-Mu~
noz et al: Vascular Stains 13
38. Khaier A, Nischal KK, Espinosa M et al. Periocular
port wine stain: the great Ormond Street Hospital
experience. Ophthalmology 2011;118:2274–2278.
39. Comi AM. Update on Sturge-Weber syndrome: diag-
nosis, treatment, quantitative measures, and controver-
sies. Lymphat Res Biol 2007;5:257–264.
40. Tallman B, Tan OT, Morelli JG et al. Location of port-
wine stains and the likelihood of ophthalmic and/or
central nervous system complications. Pediatrics
1991;87:323–327.
41. Hennedige AA, Quaba AA, Al-Nakib K. Sturge-Weber
syndrome and dermatomal facial port-wine stains:
incidence, association with glaucoma, and pulsed tun-
able dye laser treatment effectiveness. Plast Reconstr
Surg 2008;121:1173–1180.
42. Piram M, Lorette G, Sirinelli D et al. Sturge-Weber
syndrome in patients with facial port-wine stain. Pediatr
Dermatol 2012;29:32–37.
43. Waelchli R, Aylett SE, Robinson K et al. New vascular
classification of port wine stains: improving prediction
of Sturge-Weber risk. Br J Dermatol 2014;171:861–867.
44. Marti-Bonmati L, Menor F, Poyatos C et al. Diagnosis
of Sturge-Weber syndrome: comparison of the efficacy
of CT and MR imaging in 14 cases. Am J Roentgenol
1992;158:867–871.
45. Maari C, Frieden IJ. Klippel-Trenaunay syndrome: the
importance of “geographic stains” in identifying lym-
phatic disease and risk of complications. J Am Acad
Dermatol 2004;51:391–398.
46. Lee MS, Liang MG, Mulliken JB. Diffuse capillary
malformation with overgrowth: a clinical subtype of
vascular anomalies with hypertrophy. J Am Acad
Dermatol 2013;69:589–594.
47. Enjolras O, Chapot R, Merland JJ. Vascular anomalies
and growth of limbs. J Pediatr Orthop B 2004;13:349–
357.
48. Redondo P, Aguado L, Martınez-Cuesta A. et al.
Diagnosis and management of extensive vascular mal-
formations of the lower limb: part I. Clinical diagnosis.
J Am Acad Dermatol 2011;65:893–906.
49. Redondo P, Bastarrika G, Aguado L et al. Foot or
hand malformations related to deep venous system
anomalies of the lower limb in Klippel-Trenaunay
syndrome. J Am Acad Dermatol 2009;61:621–628.
50. Uihlein LC, Liang MG, Fishman SJ et al. Capillary-
venous malformation in the lower limb. Pediatr Der-
matol 2013;30:541–548.
51. Bastarrika G, Redondo P, Sierra A et al. New tech-
niques for the evaluation and therapeutic planning of
patients with Klippel-Trenaunay syndrome. J Am Acad
Dermatol 2006;56:242–249.
52. Wright DR, Frieden IJ, Orlow SJ et al. The misnomer
“macrocephaly-cutis marmorata telangiectatica con-
genita syndrome”: report of 12 new cases and support
for revising the name to macrocephaly-capillary mal-
formations. Arch Dermatol 2009;145:287–293.
53. Conway RL, Pressman BD, Dobyns WB et al. Neu-
roimaging findings in macrocephaly-capillary malfor-
mation: a longitudinal study of 17 patients. Am J Med
Genet A 2007;143:2981–3008.
54. van der Stricht J. Klippel-Trenaunay syndrome and
phacomatoses. Phlebologie 1980;33:21–30.
14 Pediatric Dermatology 2016
55. Gloviczki P, Hollier LH, Telander RL et al. Surgical
implications of Klippel Trenaunay syndrome. Ann Surg
1983;197:353–362.
56. Liu NF, Lu Q, Yan ZX. Lymphatic malformation is a
common component of Klippel-Trenaunay syndrome.
J Vasc Surg 2010;52:1557–1563.
57. Cohen MM Jr. Klippel-Trenaunay syndrome. Am
J Med Genet 2000;93:171–175.
58. Bird LM, Jones MC, Kupperman N et al. Gram negative
bacteremia in four patients with Klippel-Trenaunay-
Weber syndrome. Pediatrics 1996;97:739–741.
59. Baskerville PA. The Klippel-Trenaunay syndrome:
clinical, radiological and haemodynamic features and
management. Br J Surg 1985;72:232–236.
60. Neubert AG, Golden MA, Rose NC. Kasabach-Merrit
coagulopathy complicating Klippel-Trenaunay syndrome
in pregnancy. Obstet Gynecol 1995;85: 831–833.
61. Biesecker L. The challenges of Proteus syndrome:
diagnosis and management. Eur J Hum Genet
2006;14:1151–1157.
62. Hoeger PH, Martinez A, Maerker J et al. Vascular
anomalies in Proteus syndrome. Clin Exp Dermatol
2004;29:222–230.
63. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment
of the Proteus syndrome literature: application of
diagnostic criteria to published cases. Am J Med Genet
A 2004;130:111–122.
64. Cohen MM Jr. Proteus syndrome: clinical evidence for
somatic mosaicism and selective review. Am J Med
Genet 1993;47:645–652.
65. Sapp JC, Turner JT, van de Kamp JM et al. Newly
delineated syndrome of congenital lipomatous over-
growth, vascular malformations, and epidermal nevi
(CLOVE syndrome) in seven patients. Am J Med Genet
A 2007;15:2944–2958.
66. Alomari AI. CLOVE(S) syndrome: expanding the
acronym. Am J Med Genet A 2009;149:294.
67. Alomari AI. Characterization of a distinct syndrome
that associates complex truncal overgrowth, vascular,
and acral anomalies: a descriptive study of 18 cases of
CLOVES syndrome. Clin Dysmorphol 2009;18:1–7.
68. Alomari AI, Chaudry G, Rodesch G et al. Complex
spinal-paraspinal fast-flow lesions in CLOVES syn-
drome: analysis of clinical and imaging findings in 6
patients. Am J Neuroradiol 2011;32:1812–1817.
69. Gucev ZS, Tasic V, Jancevska A et al. Congenital
lipomatous overgrowth, vascular malformations, and
epidermal nevi (CLOVE) syndrome: CNS malforma-
tions and seizures may be a component of this disorder.
Am J Med Genet A 2008;146:2688–2690.
70. Lopez-Gutierrez JC, Lapunzina P. Capillary malfor-
mation of the lower lip, lymphatic malformation of the
face and neck, asymmetry and partial/generalized
overgrowth (CLAPO): report of six cases of a new
syndrome/association. Am J Med Genet A
2008;146:2583–2588.
71. Revencu N, Boon LM, Mulliken JB et al. Parkes Weber
syndrome, vein of Galen aneurysmal malformation, and
other fast-flow vascular anomalies are caused by
RASA1 mutations. Hum Mutat 2008;29:959–965.
72. Revencu N, Boon LM, Mendola A et al. RASA1
mutations and associated phenotypes in 68 families
with capillary malformation-arteriovenous malforma-
tion. Hum Mutat 2013;34:1632–1641.
73. Catal a A, Roe E, Vikkula M et al. Capillary malfor-
mation-arteriovenous malformation syndrome: a report
of 2 cases, diagnostic criteria, and management. Actas
Dermosifiliogr 2013;104:710–713.
74. Larralde M, Abad ME, Luna PC et al. Capillary
malformation arteriovenous malformation: a clinical
review of 45 patients. Int J Dermatol 2014;53:458–461.
75. Wooderchak-Donahue W, Stevenson DA, McDonald J
et al. RASA1 analysis: clinical and molecular findings in
a series of consecutive cases. Eur J Med Genet
2012;55:91–95.
76. Boon LM, Mulliken JB, Vikkula M. RASA1: variable
phenotype with capillary and arteriovenous malforma-
tions. Curr Opin Genet Dev 2005;15:265–269.
77. Van Lohuizen CHJ. Cutis marmonata telangiectatica
congenita. Acta Derm Venereol 1922;3:202–211.
78. Bedell RF, Allison JR Jr. Congenital generalized
phlebectasia. Arch Dermatol 1964;90:83–84.
79. Brain RT. Nevus vascularis reticularis (two cases). Proc
R Soc Med 1954;47:172–173.
80. Lynch PJ, Zelickson AS. Congenital phlebectasia: a
histopathologic study. Arch Dermatol 1967;95:98–101.
81. Champion RH. Livedo reticularis. A review. Br J
Dermatol 1965;77:167–179.
82. Toriello HV, Mulliken JB. Accurately renaming macro-
cephaly-cutis marmorata telangiectatica congenita
(M-CMTC) as macrocephaly-capillary malformation
(M-CM). Am J Med Genet A 2007;143:3009.
83. Amitai DB, Fichmann S, Merlob P et al. Cutis
marmorata telangiectatica congenita: clinical find-
ings in 85 patients. Pediatr Dermatol 2000;17:100–
104.
84. Devillers ACA, de Waard-van der Spek FB, Oranje
AP. Cutis marmorata telangiectatica congenita. Clin-
ical features in 35 cases. Arch Dermatol 1999;135:34–
38.
85. Amitai DB, Merlob P, Metzker A. Cutis marmorata
telangiectatica congenita and hypospadias: report of 4
cases. J Am Acad Dermatol 2001;45:131–132.
86. Kienast AK, Hoeger PH. Cutis marmorata telang-
iectatica congenita: a prospective study of 27 cases and
review of the literature with proposal diagnostic criteria.
Clin Exp Dermatol 2009;34:319–323.
87. Weilepp AE, Eichenfield LF. Association of glaucoma
with cutis marmorata telangiectatica congenita: a
localized anatomic malformation. J Am Acad Dermatol
1996;35:276–278.
88. Miranda I, Alonso MJ, Jimenez M et al. Cutis mar-
morata telangiectatica congenita and glaucoma. Oph-
thalmic Paediatr Genet 1990;11:129–132.
89. Lynch PJ. Cutis marmorata telangiectatica congenita
associated with congenital glaucoma. J Am Acad
Dermatol 1990;22:857.
90. Sato SE, Herschler J, Lynch PJ et al. Congenital
glaucoma associated with cutis marmorata telangiectat-
ica congenita: two case reports. J Pediatr Ophthalmol
Strabismus 1988;25:13–17.
91. Puppin D Jr, Rybojad M, Morel P. Hereditary benign
telangiectasia: two case reports. J Dermatol
1992;19:384–386.

92. Nijhawan RI, Bard S, Blyumin M et al. Early localized
morphea mimicking an acquired port-wine stain. J Am
Acad Dermatol 2011;64:779–782.
93. Riviere JB, Mirzaa GM, O’Roak BJ et al. De novo
germline and postzygotic mutations in AKT3,
PIK3R2 and PIK3CA cause a spectrum of related
megalencephaly syndromes. Nat Genet 2012;44:934–
940.
94. Rios JJ, Paria N, Burns DK et al. Somatic gain-of-
function mutations in PIK3CA in patients with macro-
dactyly. Hum Mol Genet 2013;22:444–451.
Rozas-Mu~
noz et al: Vascular Stains 15
95. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ et al.
Clinical delineation and natural history of the PIK3CA-
related overgrowth spectrum. Am J Med Genet A
2014;164A:1713–1733.
96. Keppler-Noreuil KM, Rios JJ, Parker VE et al.
PIK3CA-related overgrowth spectrum (PROS): diagnos-
tic and testing eligibility criteria, differential diagnosis,
and evaluation. Am J Med Genet A 2014;167:287–295.
97. Castellano E, Downward J. RAS interaction with PI3K:
more than just another effector pathway. Genes Cancer
2011;2:261–274.