REVIEW

CURRENT
OPINION Vascular malformations syndromes: an update
Antonio Martinez-Lopez a,b, Luis Salvador-Rodriguez a,
Trinidad Montero-Vilchez a, Alejandro Molina-Leyva a,b,
Jesus Tercedor-Sanchez a,b, and Salvador Arias-Santiago a,b,c

Purpose of review
To provide an update of vascular malformation syndromes by reviewing the most recent articles on the
topic and following the new International Society for the Study of Vascular Anomalies (ISSVA) 2018
classification.
Recent findings
This review discusses the main features and diagnostic approaches of the vascular malformation
syndromes, the new genetic findings and the new therapeutic strategies developed in recent months.
Summary
Some vascular malformations can be associated with other anomalies, such as tissue overgrowth. PIK3CA-
related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth
caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of
rare disorder that are associated with the appearance of overgrowth. CLOVES syndrome and Klippel–
Trénaunay syndrome are PROS disease. Proteus syndrome is an overgrowth syndrome caused by a somatic
activating mutation in AKT1. CLOVES, Klippel–Trénaunay and Proteus syndromes are associated with high
risk of thrombosis and pulmonary embolism. Hereditary hemorrhagic telangiectasia is an autosomic
dominant disorder characterized by the presence of arteriovenous malformations. New therapeutic
strategies with bevacizumab and thalidomide have been employed with promising results.
Keywords
overgrowth syndromes, PIK3CA-related overgrowth spectrum, vascular malformations, vascular
malformation syndromes

INTRODUCTION Study of Vascular Anomalies (ISSVA) classification

Vascular malformations are complex congenital for vascular anomalies. This classification groups the
lesions composed by dysplastic vessels lined by nor- different vascular malformations into simple (capil-
mal endothelium, originated from abnormal mor- lary, lymphatic, venous and arteriovenous malfor-
phogenesis of the vascular tissue [1]. As described by mations), combined vascular malformations,
Mulliken and Glowacki [2] in 1982, vascular mal- vascular malformations associated with other
formations are present at birth (although sometimes anomalies and provisionally unclassified vascular
they are not detected until adolescence or adult- anomalies. The recent description of the genes
hood) and they usually grow proportionally with involved in the development of syndromes associ-
the patient, may expand in response to hormonal ated with vascular malformations has led to an
changes or trauma, and do not regress spontane- update in the ISSVA classification in May 2018
&&

ously [1]. Some vascular malformations can be [4 ]. This review will set out what’s new about
linked to other anomalies, such as tissue over- the characteristics and classification of principal
growth. Overgrowth syndromes were defined by
Tatton-Brown et al. [3] as a ‘global or regional excess a
Dermatology Unit, Hospital Universitario Virgen de las Nieves, bInstituto
growth compared with an equivalent body part or de Investigación Biosanitaria ibs.GRANADA and cDermatology Depart-
the age-related peer group’. The classification of the ment, University of Granada, Granada, Spain
vascular malformations and their related syndromes Correspondence to Alejandro Molina-Leyva, MD, PhD, Avenida de
has undergone several stages, from the biological Madrid, 15, 18012 Granada, Spain. Tel: +34 686731837;
classification based on their clinical and histologic e-mail: [email protected]
findings proposed by Mulliken and Glowacki to the Curr Opin Pediatr 2019, 31:747–753
development of the International Society for the DOI:10.1097/MOP.0000000000000812

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Genetics

these mutations arise during embryonic develop-

KEY POINTS ment, with their timing and location critically influ-
&

 The updated characteristics and classification of encing the resulting disease phenotype [6 ].
vascular malformation syndromes are provided. Likewise, PIK3CA mutations have been recently
described in the lymphatic tissue of generalized
 PIK3CA-related overgrowth spectrum (PROS) now lymphatic anomaly [7]. Genetic diagnosis of PROS
encompasses CLOVES, Klippel–Trénaunay,
can be difficult. An American study has found a 56%
megalencephaly-capillary malformation, dysplastic
megalencephaly, fibroadipose hyperplasia or diagnostic yield in affected tissues of clinically sus-
overgrowth, hemihyperplasia multiple lipomatosis, pected PROS patients employing a next-generation
fibroadipose infiltrating lipomatosis and some cases sequencing (NGS) panel. This study has also shown
of macrodactily. a greater number of allelic pathogenic variants in
tumors or benign masses and in capillary malforma-
 Antithrombotic prophylaxis should be employed in the &

obstetric management of Klippel–Trénaunay patients in tions [8 ]. Conversely, PIK3CA mutations in over-

order to avoid deep vein thrombosis and growth syndromes have recently been targeted with
pulmonary embolism. the mTOR inhibitor Sirolimus, leading to a change
in the mean percentage of total tissue volume at
 Systemic bevazizumab has shown promising results in
affected sites, but not at unaffected sites. However,
the treatment of bleeding in patients with hereditary
hemorrhagic telangiectasia. because of the high rate of adverse events, such as
infection, blood or lymphatic disorders, neutrope-
nia, interstitial pneumonitis or sirolimus hypersen-
sitivity syndrome, this treatment should be used at
vascular malformations syndromes, the new low doses and weighing risk–benefit in each patient
genetic findings and the strategies to perform an [9]. Several PIKC3A inhibitors are under develop-
early treatment to avoid the development of further ment as treatments for oncological conditions. One
complications. of these drugs, BYL719, has been employed in PROS
patients with therapeutic failure and life-threaten-
ing complications. All the 17 patients treated with
PIK3CA-RELATED OVERGROWTH BYL719 have shown clinical and radiological
SPECTRUM improvement with a low-rate of side effects, present-
PIK3CA-related overgrowth spectrum (PROS) is a ing PIK3CA blockade as a good therapeutic strategy
group of rare genetic disorders with asymmetric &&
in PROS patients [10 ].
overgrowth caused by somatic mosaic in the phos-
phatidylinositol-4,-5-bisphospate 3-kinase, catalytic
subunit alpha gene (PIK3CA) [5]. PROS term encom- CLOVES SYNDROME
passes a heterogeneous group of rare disorders that CLOVES syndrome (congenital lipomatous over-
are associated with the appearance of overgrowth growth, vascular malformations, epidermal naevi,
(Table 1). PIK3CA mutations are often found in solid scoliosis/skeletal and spinal syndrome, OMIM
cancers and, as in cancer, PIK3CA mutations in 612918) is considered as a PROS syndrome associ-
PROS arise postzygotically, but unlike in cancer, ated with regional bony and/or soft tissue over-
growth, vascular malformations and skeletal
anomalies, such as scoliosis (Fig. 1). The association
Table 1. PIK3CA-related overgrowth spectrum of this entity with Wilms tumor has been hypothe-
sized because of the important oncogenic role of
PIK3CA-related overgrowth spectrum
PIK3CA mutations. A recent retrospective study has
Congenital lipomatous overgrowth, vascular malformations, reported a 3.3% incidence of Wilms tumor in
epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome patients with CLOVES, which was significantly
Klippel–Tréaunay syndrome higher than in the general population, 0.01%.
Megalencephaly-capillary malformation (MCAP or M-CM) Authors suggest periodic ultrasound studies in these
&

Dysplastic megalencephaly (DMEG) patients up to the age of 7 years [11 ]. Also, it has
Fibroadipose hyperplasia or overgrowth (FAO) been observed a higher incidence of pulmonary
Hemihyperplasia multiple lipomatosis (HHML)
thromboembolic events in patients with CLOVES
and in another PROS syndrome such as Klippel–
Fibroadipose infiltrating lipomatosis/facial infiltrative lipomatosis
Trénaunay syndrome (KTS, OMIM 149000), espe-
Macrodactyly
cially after an sclerotherapy surgery [12]. Although
Extracted from ISSVA 2018 classification. PROS, PIK3CA-related overgrowth the main approach to genetic diagnosis remains the
spectrum. study in affected tissue, a recent study has shown the

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 Vascular malformations syndromes: an update Martinez-Lopez et al.

FIGURE 2. Limb asymmetry in a Klippel–Tréaunay patient.

FIGURE 1. Capillary malformation associated with scoliosis

the thromboembolic risk, such as pregnancy.
and lipomatous overgrowth in a congenital lipomatous
Recently, a study of a Dutch group has observed
overgrowth, vascular malformations, epidermal nevi,
a high relative risk of deep vein thrombosis [rela-
scoliosis/skeletal and spinal syndrome patient.
tive risk (RR) 108.9, 95% confidence interval (CI)
46.48-255.03] and pulmonary embolism (RR
presence of PIK3CA mutations in the urine of 106.2, 95% CI 26.97–418.10) during pregnancy
&
patients with CLOVES [13 ]. and in early postpartum period. These findings
outline the importance of antithrombotic prophy-
laxis in the obstetric management of patients with
KLIPPEL–TRÉNAUNAY SYNDROME &
KTS [16 ]. Moreover, some psychiatric complica-
KTS is a PROS syndrome characterized by the tions, such as pain, depression and anxiety are also
presence of a triad of asymmetric limb hypertro- associated with KTS [17]. In addition, a recent
phy, localized capillary malformation and congen- retrospective study has observed a high risk of
ital lower extremity varicosities (Fig. 2). Although development of choroidal melanoma in KTS
KTS is usually a benign condition, several compli- patients presenting with phakomatosis pigmento-
cations related to the affected limb may arise. vascularis [18].
Capillary malformations are present on the hyper-
trophied limb and are the commonest vascular
malformation in this entity. Limb length discrep- MEGALENCEPHALY-CAPILLARY
ancy is most often secondary to underlying soft MALFORMATION
tissue growth but can be associated with long bone Megalencephaly-capillary malformation (MCAP,
hypertrophy and lymphatic malformations [14]. OMIM 602501) is a PROS syndrome that usually
Varicosities usually appear on the lateral aspect presents with macrocephaly, macrosomia and vas-
of the limb and are slightly less common than cular malformations, such as cutis marmorata
capillary malformations, but a recent radiological (Fig. 3). Although neurological comorbidities are
case series have demonstrated the presence of the main complication in this syndrome, a recent
varicosities in 93% of the studied patients, a study has addressed high risk of clinically significant
higher percentage than was previously reported hypoglycaemia because of the relationship between
&
in other clinical studies [15 ]. These varicosities the PI3K-AKT pathway and glucose homeostasis.
may be related with the development of life- The authors suggest that suspected MCAP patients
threatening complications, such as venous throm- should be screened for low blood glucose levels
&
boembolism, especially in situations that increase during childhood [19 ].

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Genetics

malformations (leptomeningeal angiomatosis), and

glaucoma. The majority of cases are caused by a
somatic activating mutation in GNAQ (Table 2).
Infants at higher risk of suffering from this syndrome
are those in which PWS affects skin derived from the
frontonasal placode (forehead, hemifacial or median
phenotype). For years, many authors have recom-
mended MRI screening of asymptomatic infants with
at-risk PWS for SWS. However, in a recent review, the
authors conclude that there is not enough evidence to
determine that early MRI (before 6 months) results in
better neurodevelopmental outcomes for infants with
SWS, and given the potential for false negatives, a
negative MRI does not exclude this syndrome. They
suggest that electroencephalography in presymptom-
atic SWS could be useful as it is a noninvasive diagnos-
tic method and it is usually associated with rhythm
&&
and voltage asymmetry in these patients [20 ]. How-
ever, its utility is already unestablished. They advocate
for early referral to pediatric neurologist in high-risk
PWS phenotypes for counseling, early symptom rec-
ognition and early management of seizures. The onset
of epileptic seizures within 1 year and poor response to
anticonvulsant therapy is associated with increased
likelihood of cognitive impairment [21]. Regarding
ocular involvement, glaucoma is the most common
FIGURE 3. Radiographic macrocephaly in a ocular complication. It shows poor response to the
megalencephaly-capillary malformation patient. standard medical treatment and surgery is required in
many cases [22]. However, surgical success rates are
OTHER SYNDROMES WITH GROWTH usually low.
ANOMALIES

Sturge–Weber syndrome Proteus syndrome

Sturge–Weber syndrome (SWS, OMIM 185300) is a Proteus syndrome (OMIM 176920) is an unusual
rare, sporadic, congenital, neurocutaneous syndrome disorder characterized by asymmetric overgrowth,
characterized by cutaneous capillary malformations connective tissue nevi, epidermal nevi, disregulated
[port-wine stain (PWS)], cerebral capillary-venous adipose tissue and vascular malformations. It is
caused by a somatic activating mutation in AKT1
(Table 2). The plantar cerebriform connective tissue
Table 2. Casual genes of vascular malformations nevus (CCTN) is the most specific cutaneous mani-
syndromes festation of this syndrome. In a recent study, the
CLOVES PIK3CA authors found that the CCTN relative area increased
Klippel–Tréaunay PIK3CA
with age in children by 5.6% per year. They also
found positive relationship between CCTN growth
MCAP PIK3CA
rate and AKT1 mutant allele frequency, so they
Proteus AKT1
propose that monitoring of CCTN size may be useful
Parkes-Weber RASA1
for evaluating drug response in treatment of Proteus
Bannayan–Riley–Ruvalcaba PTEN &&
syndrome [23 ]. A therapeutic trial using the AKT1
Hereditary hemorrhagic telangiectasia ALK-1/Endoglin inhibitor ARQ 092 is underway (NCT02594215).
Blue rubber bleb nevus TEK (TIE2) This syndrome is associated with high risk of
Diffuse capillary malformation GNA11 thrombosis and/or pulmonary embolism, which is
with overgrowth one of the leading causes of death in these patients. It
Maffucci IDH1/IDH2 has recently been proposed that the increased risk for
thrombosis in these patients is due not only to stasis
CLOVES, congenital lipomatous overgrowth, vascular malformations,
epidermal nevi, scoliosis/skeletal and spinal; MCAP, megalencephaly- associated with vascular malformation but also with
capillary malformation. specific vascular and/or platelet dysfunction caused

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 Vascular malformations syndromes: an update Martinez-Lopez et al.

&
by the AKT1 p.E17K mutation [24 ]. D-dimmer might OTHER SYNDROMES WITH VASCULAR
be a useful screening for the presence of thrombosis if MALFORMATIONS
level is above 0.5 mg/dl.
In addition to thrombosis, causes of death in Hereditary hemorrhagic telangiectasia
these patients also include an apparent increased Hereditary hemorrhagic telangiectasia (HHT, OMIM
susceptibility to cancer. One retrospective study 187300) also known as Osler–Weber–Rendu syn-
found that the majority of deaths occurs in infancy drome is an autosomic dominant disorder character-
and the beginning of the third decade with a con- ized by the presence of vascular lesions that are
siderable decrease in mortality rate from the age of arteriovenous malformations and involve the skin
25 years onwards [25]. They conclude that clinical and mucous membranes as well as internal organs.
studies and therapeutic trials should be performed These arteriovenous malformations have a propensity
in the pediatric age range. to bleed. The first manifestation is usually epistaxis
during childhood. HHT can frequently be complicated
by the presence of clinically significant arteriovenous
Parkes–Weber syndrome malformations in the brain, lung, gastrointestinal
Parkes–Weber syndrome (PWS, OMIM 608354) is a tract and liver. It is important to screen individuals
congenital disorder caused by a mutation in RASA1 suspected to have HHT for visceral arteriovenous mal-
(Table 2), which is characterized by cutaneous vas- formations. In particular, arteriovenous malforma-
cular malformations [capillary, venous, lymphatic tions in the lungs and brain are often asymptomatic
and arteriovenous malformation (AVM)] associated prior to the sudden development of life-threatening
with overgrowth. It may affect either the upper or complication. The preferred screening test for pulmo-
the lower extremities, including pelvic vessels. The nary arteriovenous malformations, which lead to
high-flow malformation represents the main defect right-to-left shunting, is transthoracic contrast echo-
of this syndrome and it allows us to differentiate it cardiography (bubble study), although computed
from KTS in which there are only low-flow malfor- tomography has become the gold standard imaging
mations. It is associated with many complications, test to establish its presence [29]. Cerebral arteriove-
such as venous hypertension, which leads to nous malformations are rare in nonsymptomatic HHT
chronic venous and lymphatic insufficiency patients, but screening scans commonly detect silent
(venous ulceration is frequent), high-output heart cerebral infarction [30]. It is recommended to evaluate
failure, and distal ischemia. Because of these rea- all patients with suspected or confirmed HHT every 5–
sons, treatment is usually necessary. There are many 10 years with a transthoracic contrast echocardiogra-
options, which include continuous elastic compres- phy (bubble study) and a brain MRI to detect pulmo-
sion, embolization, surgical excision of accessible nary and cerebral arteriovenous malformations,
AVM, and use of stent-graft in patients with con- respectively. HHT patients greater than 35 years of
comitant aneurysmatic lesions [26]. Absolute indi- age should also be checked with annual hemoglobin
cations for invasive treatment include: hemorrhage, and hematocrit testing to detect substantial bleeding
distal ischemia, refractory ulcers, and high-output related to gastrointestinal. Moreover, patients with
heart failure. signs or symptoms of heart failure or hepatobiliary
disease should be made a Doppler ultrasonography or
triphasic spiral CT of liver to rule out hepatic
Bannayan–Riley–Ruvalcaba syndrome arteriovenous malformations.
Bannayan–Riley–Ruvalcaba syndrome (BRRS, Arteriovenous malformations bleeding is a com-
OMIM 158350) is an autosomal dominant congen- mon cause of morbidity of HHT patients. Recent
ital disorder of pediatric onset characterized by investigations have evaluated the usefulness of two
macrocephaly, Hashimoto’s thyroiditis, vascular systemic angiogenesis inhibitors bevacizumab and
malformations (capillary, venous and lymphatic thalidomide to minimize bleeding risk. Studies on
malformations), hamartomatous gastrointestinal systemic bevacizumab have shown promising
polyps and freckling of the glans penis. Almost results with a pooled reduction of bleeding of
60% of patients with this disorder have a germline 88% (171/195) of the patients, but evidence regard-
&
mutation in the PTEN gene (Table 2). Because of ing of its intranasal use is conflicting [31 ,32]. On
the mutation in this tumor suppressor gene, these the other hand, Thalidomide have shown a reduc-
patients have a higher risk of developing different tion in the risk of epistaxis and in the need of
&&
kind of cancers (breast, thyroid, endometrial and transfusions [33 ]. However, the benefit–risk ratio
colon mainly) [27]. Many cases of gastrointestinal should be weighted in patients for these systemic
bleeding because of hamartomatous polyps has therapies as adverse events are common and both
been reported [28]. medications are currently being used off-label [34].

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Genetics

In addition, there is an ongoing clinical trial to long-term follow-up including 98 patients did not
evaluate the effectiveness of intranasal tranexamic observe any case of Wilm’s tumor, both authors con-
acid [35]. Pulmonary hemorrhage is a potential clude that surveillance should be probably indicated
&
cause of death in patients with HHT. Recent pub- only when hemihypertrophy is present [11 ,43].
lished data have evaluated long-term follow-up of
embolization of pulmonary arteriovenous malfor-
mations. Successful primary embolization was asso- Maffucci syndrome
ciated with the use of treated detachable silicone Maffucci syndrome (OMIM 614569) is a rare genetic
balloons, the complexity of the malformation and disease characterized by multiple benign vascular
the size of the feeding artery [36]. anomalies and enchondromas present on the distal
The most common mutated genes in HHT are extremities. The use of mTOR inhibitors has been
ALK-1 and Endoglin (Table 2). Novel animal also tried in these patients but the outcomes are not
research has evidenced that BMP-binding endothe- as satisfactory as in BRBNS. Current scientific evi-
lial regulator could be a biologic target to improve dence supports their use as adjuvant therapy in
vessel integrity in patients with HTT [37]. combination with surgery to improve vascular
lesions of this disorder [44,45].

Blue rubber bleb nevus syndrome

The blue rubber bleb nevus syndrome (BRBNS, CONCLUSION
OMIM 112200) also known as Bean syndrome is a This updated review of vascular malformation syn-
rare venous malformation that presents with multi- dromes has presented the clinical description and
ple slow-flow venous malformations in the skin and the mutations that lead to their pathogenesis. These
gastrointestinal tract. The main cause of morbidity new findings are helping to develop promising treat-
is gastrointestinal hemorrhage and one of the main ments for these disorders.
challenges is to detect the position of the vascular
lesions along the gastrointestinal tract. Innovative Acknowledgements
imaging techniques have been proposed to facilitate To our patients with vascular malformations for encour-
this task. First, the use of an endoscopic capsule aging our daily work.
magnetically operated could be used in children
above 6 years old [38]. Photoacustic imaging is a Financial support and sponsorship
novel technology that combines features of optical
None.
imaging and ultrasonography [39]. Regarding treat-
ment, lesion directed therapy has been tried
Conflicts of interest
through endoscopic injection sclerotherapy but
the most promising evidence is pointing towards There are no conflicts of interest.
systemic treatment with mTOR inhibitors everoli-
mus and sirolimus [40]. These drugs play a key role
REFERENCES AND RECOMMENDED
in the signal pathway of angiogenesis and subse-
READING
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of studies shows a good safety profile, a reduction in been highlighted as:
& of special interest
lesion size and overall clinical improvement && of outstanding interest
&
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