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

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

1040-8703 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved. www.co-pediatrics.com

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Genetics
KEY POINTS
 The updated characteristics and classification of
vascular malformation syndromes are provided.
 PIK3CA-related overgrowth spectrum (PROS) now
encompasses CLOVES, Klippel–Trénaunay,
megalencephaly-capillary malformation, dysplastic
megalencephaly, fibroadipose hyperplasia or
overgrowth, hemihyperplasia multiple lipomatosis,
fibroadipose infiltrating lipomatosis and some cases
of macrodactily.
 Antithrombotic prophylaxis should be employed in the
obstetric management of Klippel–Trénaunay patients in
order to avoid deep vein thrombosis and
pulmonary embolism.
 Systemic bevazizumab has shown promising results in
the treatment of bleeding in patients with hereditary
hemorrhagic telangiectasia.
vascular malformations syndromes, the new
genetic findings and the strategies to perform an
early treatment to avoid the development of further
complications.
PIK3CA-RELATED OVERGROWTH
SPECTRUM
PIK3CA-related overgrowth spectrum (PROS) is a
group of rare genetic disorders with asymmetric
overgrowth caused by somatic mosaic in the phos-
phatidylinositol-4,-5-bisphospate 3-kinase, catalytic
subunit alpha gene (PIK3CA) [5]. PROS term encom-
passes a heterogeneous group of rare disorders that
are associated with the appearance of overgrowth
(Table 1). PIK3CA mutations are often found in solid
cancers and, as in cancer, PIK3CA mutations in
PROS arise postzygotically, but unlike in cancer,
Table 1. PIK3CA-related overgrowth spectrum
PIK3CA-related overgrowth spectrum
Congenital lipomatous overgrowth, vascular malformations,
epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome
Klippel–Tréaunay syndrome
Megalencephaly-capillary malformation (MCAP or M-CM)
Dysplastic megalencephaly (DMEG)
Fibroadipose hyperplasia or overgrowth (FAO)
Hemihyperplasia multiple lipomatosis (HHML)
Fibroadipose infiltrating lipomatosis/facial infiltrative lipomatosis
Macrodactyly
Extracted from ISSVA 2018 classification. PROS, PIK3CA-related overgrowth
spectrum.
748 www.co-pediatrics.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
these mutations arise during embryonic develop-
ment, with their timing and location critically influ-
&
encing the resulting disease phenotype [6 ].
Likewise, PIK3CA mutations have been recently
described in the lymphatic tissue of generalized
lymphatic anomaly [7]. Genetic diagnosis of PROS
can be difficult. An American study has found a 56%
diagnostic yield in affected tissues of clinically sus-
pected PROS patients employing a next-generation
sequencing (NGS) panel. This study has also shown
a greater number of allelic pathogenic variants in
tumors or benign masses and in capillary malforma-
&
tions [8 ]. Conversely, PIK3CA mutations in over-
growth syndromes have recently been targeted with
the mTOR inhibitor Sirolimus, leading to a change
in the mean percentage of total tissue volume at
affected sites, but not at unaffected sites. However,
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
low doses and weighing risk–benefit in each patient
[9]. Several PIKC3A inhibitors are under develop-
ment as treatments for oncological conditions. One
of these drugs, BYL719, has been employed in PROS
patients with therapeutic failure and life-threaten-
ing complications. All the 17 patients treated with
BYL719 have shown clinical and radiological
improvement with a low-rate of side effects, present-
ing PIK3CA blockade as a good therapeutic strategy
&&
in PROS patients [10 ].
CLOVES SYNDROME
CLOVES syndrome (congenital lipomatous over-
growth, vascular malformations, epidermal naevi,
scoliosis/skeletal and spinal syndrome, OMIM
612918) is considered as a PROS syndrome associ-
ated with regional bony and/or soft tissue over-
growth, vascular malformations and skeletal
anomalies, such as scoliosis (Fig. 1). The association
of this entity with Wilms tumor has been hypothe-
sized because of the important oncogenic role of
PIK3CA mutations. A recent retrospective study has
reported a 3.3% incidence of Wilms tumor in
patients with CLOVES, which was significantly
higher than in the general population, 0.01%.
Authors suggest periodic ultrasound studies in these
&
patients up to the age of 7 years [11 ]. Also, it has
been observed a higher incidence of pulmonary
thromboembolic events in patients with CLOVES
and in another PROS syndrome such as Klippel–
Trénaunay syndrome (KTS, OMIM 149000), espe-
cially after an sclerotherapy surgery [12]. Although
the main approach to genetic diagnosis remains the
study in affected tissue, a recent study has shown the
Volume 31  Number 6  December 2019
 Vascular malformations syndromes: an update Martinez-Lopez et al.
FIGURE 1. Capillary malformation associated with scoliosis
and lipomatous overgrowth in a congenital lipomatous
overgrowth, vascular malformations, epidermal nevi,
scoliosis/skeletal and spinal syndrome patient.
presence of PIK3CA mutations in the urine of
&
patients with CLOVES [13 ].
KLIPPEL–TRÉNAUNAY SYNDROME
KTS is a PROS syndrome characterized by the
presence of a triad of asymmetric limb hypertro-
phy, localized capillary malformation and congen-
ital lower extremity varicosities (Fig. 2). Although
KTS is usually a benign condition, several compli-
cations related to the affected limb may arise.
Capillary malformations are present on the hyper-
trophied limb and are the commonest vascular
malformation in this entity. Limb length discrep-
ancy is most often secondary to underlying soft
tissue growth but can be associated with long bone
hypertrophy and lymphatic malformations [14].
Varicosities usually appear on the lateral aspect
of the limb and are slightly less common than
capillary malformations, but a recent radiological
case series have demonstrated the presence of
varicosities in 93% of the studied patients, a
higher percentage than was previously reported
&
in other clinical studies [15 ]. These varicosities
may be related with the development of life-
threatening complications, such as venous throm-
boembolism, especially in situations that increase
1040-8703 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 2. Limb asymmetry in a Klippel–Tréaunay patient.
the thromboembolic risk, such as pregnancy.
Recently, a study of a Dutch group has observed
a high relative risk of deep vein thrombosis [rela-
tive risk (RR) 108.9, 95% confidence interval (CI)
46.48-255.03] and pulmonary embolism (RR
106.2, 95% CI 26.97–418.10) during pregnancy
and in early postpartum period. These findings
outline the importance of antithrombotic prophy-
laxis in the obstetric management of patients with
&
KTS [16 ]. Moreover, some psychiatric complica-
tions, such as pain, depression and anxiety are also
associated with KTS [17]. In addition, a recent
retrospective study has observed a high risk of
development of choroidal melanoma in KTS
patients presenting with phakomatosis pigmento-
vascularis [18].
MEGALENCEPHALY-CAPILLARY
MALFORMATION
Megalencephaly-capillary malformation (MCAP,
OMIM 602501) is a PROS syndrome that usually
presents with macrocephaly, macrosomia and vas-
cular malformations, such as cutis marmorata
(Fig. 3). Although neurological comorbidities are
the main complication in this syndrome, a recent
study has addressed high risk of clinically significant
hypoglycaemia because of the relationship between
the PI3K-AKT pathway and glucose homeostasis.
The authors suggest that suspected MCAP patients
should be screened for low blood glucose levels
&
during childhood [19 ].
www.co-pediatrics.com 749
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

750 www.co-pediatrics.com Volume 31  Number 6  December 2019

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

 Vascular malformations syndromes: an update Martinez-Lopez et al.
&
by the AKT1 p.E17K mutation [24 ]. D-dimmer might
be a useful screening for the presence of thrombosis if
level is above 0.5 mg/dl.
In addition to thrombosis, causes of death in
these patients also include an apparent increased
susceptibility to cancer. One retrospective study
found that the majority of deaths occurs in infancy
and the beginning of the third decade with a con-
siderable decrease in mortality rate from the age of
25 years onwards [25]. They conclude that clinical
studies and therapeutic trials should be performed
in the pediatric age range.
Parkes–Weber syndrome
Parkes–Weber syndrome (PWS, OMIM 608354) is a
congenital disorder caused by a mutation in RASA1
(Table 2), which is characterized by cutaneous vas-
cular malformations [capillary, venous, lymphatic
and arteriovenous malformation (AVM)] associated
with overgrowth. It may affect either the upper or
the lower extremities, including pelvic vessels. The
high-flow malformation represents the main defect
of this syndrome and it allows us to differentiate it
from KTS in which there are only low-flow malfor-
mations. It is associated with many complications,
such as venous hypertension, which leads to
chronic venous and lymphatic insufficiency
(venous ulceration is frequent), high-output heart
failure, and distal ischemia. Because of these rea-
sons, treatment is usually necessary. There are many
options, which include continuous elastic compres-
sion, embolization, surgical excision of accessible
AVM, and use of stent-graft in patients with con-
comitant aneurysmatic lesions [26]. Absolute indi-
cations for invasive treatment include: hemorrhage,
distal ischemia, refractory ulcers, and high-output
heart failure.
Bannayan–Riley–Ruvalcaba syndrome
Bannayan–Riley–Ruvalcaba syndrome (BRRS,
OMIM 158350) is an autosomal dominant congen-
ital disorder of pediatric onset characterized by
macrocephaly, Hashimoto’s thyroiditis, vascular
malformations (capillary, venous and lymphatic
malformations), hamartomatous gastrointestinal
polyps and freckling of the glans penis. Almost
60% of patients with this disorder have a germline
mutation in the PTEN gene (Table 2). Because of
the mutation in this tumor suppressor gene, these
patients have a higher risk of developing different
kind of cancers (breast, thyroid, endometrial and
colon mainly) [27]. Many cases of gastrointestinal
bleeding because of hamartomatous polyps has
been reported [28].
1040-8703 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
OTHER SYNDROMES WITH VASCULAR
MALFORMATIONS
Hereditary hemorrhagic telangiectasia
Hereditary hemorrhagic telangiectasia (HHT, OMIM
187300) also known as Osler–Weber–Rendu syn-
drome is an autosomic dominant disorder character-
ized by the presence of vascular lesions that are
arteriovenous malformations and involve the skin
and mucous membranes as well as internal organs.
These arteriovenous malformations have a propensity
to bleed. The first manifestation is usually epistaxis
during childhood. HHT can frequently be complicated
by the presence of clinically significant arteriovenous
malformations in the brain, lung, gastrointestinal
tract and liver. It is important to screen individuals
suspected to have HHT for visceral arteriovenous mal-
formations. In particular, arteriovenous malforma-
tions in the lungs and brain are often asymptomatic
prior to the sudden development of life-threatening
complication. The preferred screening test for pulmo-
nary arteriovenous malformations, which lead to
right-to-left shunting, is transthoracic contrast echo-
cardiography (bubble study), although computed
tomography has become the gold standard imaging
test to establish its presence [29]. Cerebral arteriove-
nous malformations are rare in nonsymptomatic HHT
patients, but screening scans commonly detect silent
cerebral infarction [30]. It is recommended to evaluate
all patients with suspected or confirmed HHT every 5–
10 years with a transthoracic contrast echocardiogra-
phy (bubble study) and a brain MRI to detect pulmo-
nary and cerebral arteriovenous malformations,
respectively. HHT patients greater than 35 years of
age should also be checked with annual hemoglobin
and hematocrit testing to detect substantial bleeding
related to gastrointestinal. Moreover, patients with
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
arteriovenous malformations.
Arteriovenous malformations bleeding is a com-
mon cause of morbidity of HHT patients. Recent
investigations have evaluated the usefulness of two
systemic angiogenesis inhibitors bevacizumab and
thalidomide to minimize bleeding risk. Studies on
systemic bevacizumab have shown promising
results with a pooled reduction of bleeding of
88% (171/195) of the patients, but evidence regard-
&
ing of its intranasal use is conflicting [31 ,32]. On
the other hand, Thalidomide have shown a reduc-
tion in the risk of epistaxis and in the need of
&&
transfusions [33 ]. However, the benefit–risk ratio
should be weighted in patients for these systemic
therapies as adverse events are common and both
medications are currently being used off-label [34].
www.co-pediatrics.com 751
Genetics
In addition, there is an ongoing clinical trial to
evaluate the effectiveness of intranasal tranexamic
acid [35]. Pulmonary hemorrhage is a potential
cause of death in patients with HHT. Recent pub-
lished data have evaluated long-term follow-up of
embolization of pulmonary arteriovenous malfor-
mations. Successful primary embolization was asso-
ciated with the use of treated detachable silicone
balloons, the complexity of the malformation and
the size of the feeding artery [36].
The most common mutated genes in HHT are
ALK-1 and Endoglin (Table 2). Novel animal
research has evidenced that BMP-binding endothe-
lial regulator could be a biologic target to improve
vessel integrity in patients with HTT [37].
Blue rubber bleb nevus syndrome
The blue rubber bleb nevus syndrome (BRBNS,
OMIM 112200) also known as Bean syndrome is a
rare venous malformation that presents with multi-
ple slow-flow venous malformations in the skin and
gastrointestinal tract. The main cause of morbidity
is gastrointestinal hemorrhage and one of the main
challenges is to detect the position of the vascular
lesions along the gastrointestinal tract. Innovative
imaging techniques have been proposed to facilitate
this task. First, the use of an endoscopic capsule
magnetically operated could be used in children
above 6 years old [38]. Photoacustic imaging is a
novel technology that combines features of optical
imaging and ultrasonography [39]. Regarding treat-
ment, lesion directed therapy has been tried
through endoscopic injection sclerotherapy but
the most promising evidence is pointing towards
systemic treatment with mTOR inhibitors everoli-
mus and sirolimus [40]. These drugs play a key role
in the signal pathway of angiogenesis and subse-
quent development of BRBNS an increasing number
of studies shows a good safety profile, a reduction in
lesion size and overall clinical improvement
&
[41 ,42].
Diffuse capillary malformation with
overgrowth
Diffuse capillary malformation with overgrowth
(DCMO, OMIM 163000) is a syndrome character-
ized by the presence of large capillary malforma-
tions involving more than one body region.
Patients usually present bony or soft tissue over-
growth that do not correlate with the extent of the
capillary malformation. Wilm’s tumor screening
has been recommended for these patients, as other
overgrowth syndromes like CLOVES present an
elevated risk. Two retrospective case series with
752 www.co-pediatrics.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
long-term follow-up including 98 patients did not
observe any case of Wilm’s tumor, both authors con-
clude that surveillance should be probably indicated
&
only when hemihypertrophy is present [11 ,43].
Maffucci syndrome
Maffucci syndrome (OMIM 614569) is a rare genetic
disease characterized by multiple benign vascular
anomalies and enchondromas present on the distal
extremities. The use of mTOR inhibitors has been
also tried in these patients but the outcomes are not
as satisfactory as in BRBNS. Current scientific evi-
dence supports their use as adjuvant therapy in
combination with surgery to improve vascular
lesions of this disorder [44,45].
CONCLUSION
This updated review of vascular malformation syn-
dromes has presented the clinical description and
the mutations that lead to their pathogenesis. These
new findings are helping to develop promising treat-
ments for these disorders.
Acknowledgements
To our patients with vascular malformations for encour-
aging our daily work.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Carqueja IM, Sousa J, Mansilha A. Vascular malformations: classification,
diagnosis and treatment. Int Angiol 2018; 37:127–142.
2. Mulliken J, Glowacki P. Hemangiomas and vascular malformations in infants
and children. A classification based on endothelial characteristics. Plast
Reconstr Surg 1982; 69:412–422.
3. Tatton-Brown K, Weksberg R. Molecular mechanisms of childhood over-
growth. Am J Med Genet C Semin Med Genet 2013; 163:71–75.
4. ISSVA Classification of Vascular Anomalies ß2018 International Society for
&& the Study of Vascular Anomalies Available at ‘‘issva.org/classification’’ Ac-
cessed [12/05/2019].
This review outlines and updates the Vascular Anomalies classification after the
ISSVA 2018 meeting in May 2018 in Amsterdam, The Netherlands. The new
edition of this classification adds new genes discovered in vascular malformations
syndromes and reclassifies some entities.
5. Frisk S, Taylan F, Blaszczyk I, et al. Early activating somatic PIK3CA mutations
promote ectopic muscle development and upper limb overgrowth. Clin Genet
2019; 96:118–125.
6. Madsen RR, Vanhaesebroeck B, Semple RK. Cancer-associated PIK3CA
mutations in overgrowth disorders. Trends Mol Med 2018; 24:856–870.
&
An exhaustive review about the relationship between PIK3CA mutations in cancer
and overgrowth syndromes.
Volume 31  Number 6  December 2019
 Vascular malformations syndromes: an update Martinez-Lopez et al.
7. Rodriguez-Laguna L, Agra N, Ibañz K, et al. Somatic activating mutations in
PIK3CA cause generalized lymphatic anomaly. J Exp Med 2019; 216:407–418.
8. Chang F, Liu L, Fang E, et al. Molecular diagnosis of mosaic overgrowth
& syndromes using a custom-designed next-generation sequencing panel. J Mol
Diagn 2017; 19:613–624.
A study that presents a new NGS panel for mosaic overgrowth syndromes with up
to 56% of mutated alleles in affected tissues of PROS patients.
9. Parker VER, Keppler-Noreuil KM, Faivre L, et al. Safety and efficacy of low-
dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med
2019; 21:1189–1198.
10. Venot Q, Blanc T, Rabia SH, et al. Targeted therapy in patients with PIK3CA-
&& related overgrowth syndrome. Nature 2018; 558:540–546.
A study that demonstrates the safety and efficacy of a new drug in 17 PROS
syndrome with life-threatening complications after the development of a mouse
model. In this study, the authors have found a critical improvement of the symptoms
without any substantial side effects.
11. Peterman CM, Fevurly RD, Alomari AI, et al. Sonographic screening for Wilms
& tumor in children with CLOVES syndrome. Pediatr Blood Cancer 2017;
64:e26684.
A retrospective study that have found a 3.3% incidence of Wilms tumor in
CLOVES patients.
12. Reis J, Alomari AI, Trenor CC, et al. Pulmonary thromboembolic events in
patients with congenital lipomatous overgrowth, vascular malformations,
epidermal nevi, and spinal/skeletal abnormalities and Klippel-Tréaunay syn-
drome. J Vasc Surg Venous Lymphat Disord 2018; 6:511–516.
13. Michel ME, Konczyk DJ, Yeung KS, et al. Causal somatic mutations in urine
& DNA from persons with the CLOVES subgroup of the PIK3CA-related
overgrowth spectrum. Clin Genet 2018; 93:1075–1080.
This study have found a 35% of PIK3CA mutated alleles in urine samples of
CLOVES patients.
14. Wang SK, Drucker NA, Gupta AK, et al. Diagnosis and management of the
venous malformations of Klippel-Tréaunay syndrome. J Vasc Surg Venous
Lymphat Disord 2017; 5:587–595.
15. Alwalid O, Makamure J, Cheng Q-G, et al. Radiological aspect of Klippel-
& Tréaunay syndrome: a case series with review of literature. Curr Med Sci
2018; 38:925–931.
An interesting case series that describes the radiological characteristics of
vascular malformations in KTS.
16. Horbach SE, Lokhorst MM, Oduber CE, et al. Complications of pregnancy
& and labour in women with Klippel-Tréaunay syndrome: a nationwide cross-
sectional study. BJOG 2017; 124:1780–1788.
A very interesting Dutch study that have observed a high risk of deep vein
thrombosis and pulmonary embolism in KTS female patients during pregnancy.
With this results, the authors suggest the need of implement antithrombotic
prophylaxis in the obstetric management of these patients.
17. Harvey JA, Nguyen H, Anderson KR, et al. Pain, psychiatric comorbidities, and
psychosocial stressors associated with Klippel-Trenaunay syndrome. J Am
Acad Dermatol 2018; 79:899–903.
18. Shields CL, Di Nicola M, Pellegrini M, Shields JA. Choroidal melanoma in
phakomatosis pigmentovascularis with Klippel-Trenaunay syndrome. Retina
2018; 38:2220–2227.
19. McDermott JH, Hickson N, Banerjee I, et al. Hypoglycaemia represents a
& clinically significant manifestation of PIK3CA- and CCND2-associated seg-
mental overgrowth. Clin Genet 2018; 93:687–692.
This study recommends to perform a periodic glucose screening in children with
overgrowth syndromes because of the high risk of hypoglycaemia in patients with
PI3K-AKT mutations.
20. Zallmann M, Leventer RJ, Mackay MT, et al. Screening for Sturge-Weber
&& syndrome: a state-of-the-art review. Pediatr Dermatol 2018; 35:30–42.
A review of SWS that have demonstrated the presence of a significant number of
false negatives in early cerebral MRI for the detection of leptomeningeal angio-
matosis. In this study, the authors recommend performing electroencephalography
in presymptomatic patients.
21. Marañ A, Ruiz-Falcó ML, Puertas V, et al. Analysis of Sturge-Weber syndrome:
a retrospective study of multiple associated variables. Neurologia 2017;
32:363–370.
22. Javaid U, Ali MH, Jamal S, et al. Pathophysiology, diagnosis, and management
of glaucoma associated with Sturge-Weber syndrome. Int Ophthalmol 2018;
38:409–416.
23. Nathan NR, Patel R, Crenshaw MM, et al. Pathogenetic insights from
&& quantification of the cerebriform connective tissue nevus in Proteus syn-
drome. J Am Acad Dermatol 2018; 78:725–732.
A retrospective study that have observed a positive relationship between the
plantar cerebriform connective tissue nevus growth rate and the frequency of
AKT1 mutant allele.
1040-8703 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
24. Keppler-Noreuil KM, Lozier JN, Sapp JC, et al. Characterization of thrombosis
& in patients with Proteus syndrome. Am J Med Genet A 2017;
173:2359–2365.
This retrospective study have showed that deep vein thrombosis in Proteus
syndrome patients is also associated with vascular and/or platelet dysfunction
caused by the AKT1 p.E17K mutation.
25. Sapp JC, Hu L, Zhao J, et al. Quantifying survival in patients with Proteus
syndrome. Genet Med 2017; 19:1376–1379.
26. Banzic I, Brankovic M, Maksimovi Ž, et al. Parkes Weber syndrome-Diagnostic
and management paradigms: A systematic review. Phlebology 2017;
32:371–383.
27. Ngeow J, Sesock K, Eng C, et al. Breast cancer risk and clinical implications
for germline PTEN mutation carriers. Breast Cancer Res Treat 2017;
165:1–8.
28. Kethman W, Rao A, Devereaux K, et al. Say What? Bannayan-Riley-Ruvalcaba
syndrome presenting with gastrointestinal bleeding due to hamartoma-in-
duced intussusception. Dig Dis Sci 2017; 62:2293–2297.
29. Saboo SS, Chamarthy M, Bhalla S, et al. Pulmonary arteriovenous malforma-
tions: diagnosis. Cardiovasc Diagn Ther 2018; 8:325–337.
30. Fatania G, Gilson C, Glover A, et al. Uptake and radiological findings of
screening cerebral magnetic resonance scans in patients with hereditary
haemorrhagic telangiectasia. Intractable Rare Dis Res 2018; 7:236–244.
31. Zhang D, Zhou F, Zhao X, et al. Endoglin is a conserved regulator of
& vasculogenesis in zebrafish - implications for hereditary haemorrhagic telan-
giectasia. Biosci Rep 2019; 39:.
A zebrafish experimental study that has proposed that targeting BMP-binding
endothelial regulator (bmper) could be a potential therapy in HHT.
32. Stokes P, Rimmer J. Intranasal bevacizumab in the treatment of HHT -related
epistaxis: a systematic review. Rhinology 2018; 56:3–10.
33. Rosenberg T, Fialla AD, Kjeldsen J, Kjeldsen AD. Does severe bleeding in
&& HHT patients respond to intravenous bevacizumab? Review of the literature
and case series. Rhinology 2019. [Epub ahead of print]
This literature review has considered systemic bevazizumab as a promising
treatment for HHT patients. The authors suggest that bevazizumab might be an
effective treatment in patients with severe epistaxis and gastrointestinal bleeding.
34. Harrison L, Kundra A, Jervis P. The use of thalidomide therapy for refractory
epistaxis in hereditary haemorrhagic telangiectasia: systematic review. J
Laryngol Otol 2018; 132:866–871.
35. Buscarini E, Botella LM, Geisthoff U, et al., VASCERN-HHT. Safety of
thalidomide and bevacizumab in patients with hereditary hemorrhagic telan-
giectasia. Orphanet J Rare Dis 2019; 14:28.
36. Reuben A, Appelboam A, Barton A, et al. Novel use of tranexamic acid to
reduce the need for Nasal Packing in Epistaxis (NoPac) randomised con-
trolled trial: research protocol. BMJ Open 2019; 9:e026882.
37. Andersen PE, Duvnjak S, Gerke O, Kjeldsen AD. Long-term single-center
retrospective follow-up after embolization of pulmonary arteriovenous mal-
formations treated over a 20-year period: frequency of re-canalization with
various embolization materials and clinical outcome. Cardiovasc Intervent
Radiol 2019. (in press).
38. Gu Z, Wang Y, Lin K, et al. Magnetically controlled capsule endoscopy in
children: a single center, retrospective cohort study. J Pediatr Gastroenterol
Nutr 2019; 69:13–17.
39. Lavaud J, Coll J-L, Cracowski J-L, et al. Photoacoustic imaging as an
innovative technique for the exploration of blue rubber bleb naevus. Br J
Dermatol 2019. [Epub ahead of print]
40. Kumei T, Toya Y, Shiohata T, et al. Gastrointestinal: Endoscopic injection
sclerotherapy for duodenal vascular malformation in blue rubber bleb nevus
syndrome. J Gastroenterol Hepatol 2019; 34:963.
41. Bevacqua M, Baldo F, Pastore S, et al. Off-label use of sirolimus and
& everolimus in a pediatric center: a case series and review of the literature.
Paediatr Drugs 2019; 21:185–193.
An interesting case series that employs mTor inhibitors for the treatment of a
patient with BRBNS.
42. Zhang B, Li L, Zhang N, et al. Efficacy and safety of sirolimus in the treatment
of blue rubber bleb nevus syndrome in pediatric patients. Clin Exp Dermatol
2019. [Epub ahead of print]
43. Liu KX, Prajapati VH, Liang MG, et al. A cross-sectional survey of long-term
outcomes for patients with diffuse capillary malformation with overgrowth. J
Am Acad Dermatol 2018; 78:1023–1025.
44. Gupta V, Mridha AR, Khaitan BK. Unsatisfactory response to sirolimus in
Maffucci syndrome-associated spindle cell hemangiomas. Dermatol Ther
2019; 32:e12851.
45. Lekwuttikarn R, Chang J, Teng JMC. Successful treatment of spindle cell
hemangiomas in a patient with Maffucci syndrome and review of literatures.
Dermatol Ther 2019; 32:e12919.
www.co-pediatrics.com 753