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Diffuse capillary malformation with overgrowth: A clinical subtype of vascular anomalies with hypertrophy

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Categorization of vascular anomalies with overgrowth is evolving rapidly with the aid of massively parallel genomic sequencing; however, accurate clinical diagnosis is still essential. We identified a group of patients with an extensive, diffuse, reticulate capillary malformation (CM) and variable hypertrophy without major complications. We sought to study a subset of patients with diffuse CM to better define prognosis and management. Chart review identified 73 patients with diffuse CM who did not fit the criteria for known disorders with CM and/or overgrowth. Soft-tissue or bony overgrowth did not correlate with location, morphology, or intensity of the vascular stain. Patients required periodic follow-up to monitor for leg length discrepancy. They were found to exhibit normal neurologic development and proportionate overgrowth rather than progressive, disproportionate asymmetry or vascular complications. This retrospective review was limited to observations documented at clinic visits; these patients require long-term assessment. Further studies are necessary to accurately assess Wilms tumor risk and clinical outcomes in older adults. We propose the term "diffuse capillary malformation with overgrowth" to designate this extensive reticular vascular staining with proportionate overgrowth. We differentiate diffuse capillary malformation with overgrowth from other disorders with CM and hypertrophy.
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Diffuse capillary malformation with overgrowth:
A clinical subtype of vascular anomalies with
hypertrophy
Margaret S. Lee, MD, PhD,
a
MarilynG.Liang,MD,
a
and John B. Mulliken, MD
b
Boston, Massachusetts
Background: Categorization of vascular anomalies with overgrowth is evolving rapidly with the aid of
massively parallel genomic sequencing; however, accurate clinical diagnosis is still essential. We identified
a group of patients with an extensive, diffuse, reticulate capillary malformation (CM) and variable
hypertrophy without major complications.
Objective: We sought to study a subset of patients with diffuse CM to better define prognosis and
management.
Methods: Chart review identified 73 patients with diffuse CM who did not fit the criteria for known
disorders with CM and/or overgrowth.
Results: Soft-tissue or bony overgrowth did not correlate with location, morphology, or intensity of the
vascular stain. Patients required periodic follow-up to monitor for leg length discrepancy. They were found
to exhibit normal neurologic development and proportionate overgrowth rather than progressive,
disproportionate asymmetry or vascular complications.
Limitations: This retrospective review was limited to observations documented at clinic visits; these
patients require long-term assessment. Further studies are necessary to accurately assess Wilms tumor risk
and clinical outcomes in older adults.
Conclusion: We propose the term ‘‘diffuse capillary malformation with overgrowth’’ to designate this extensive
reticular vascular staining with proportionate overgrowth. We differentiate diffuse capillary malformation with
overgrowth from other disorders with CM and hypertrophy. ( J Am Acad Dermatol 2013;69:589-94.)
Key words: capillary malformation; hemihyperplasia; hemihypertrophy; hyperplasia; hypertrophy;
overgrowth.
Many patients with extensive capillary stain-
ing do not fit the criteria for established
conditions with asymmetric overgrowth
and a vascular anomaly, eg, Klippel-Trenaunay
syndrome (KTS), cutis marmorata telangiectatica
congenita (CMTC), and macrocephaly-capillary mal-
formation (CM) syndrome (M-CM).
1-3
We disagree
with broad definitions of KTS that include any patient
with a CM and/or venous malformation (VM) and
overgrowth.
4
We define the clinical characteristics of
a distinct subset of patients for whom we propose the
descriptive term ‘‘diffuse capillary malformation with
overgrowth’’ (DCMO).
METHODS
A retrospective chart review was approved by our
internal review board to evaluate patients with
diffuse CM in our vascular anomalies center database
and the authors’ clinical files, spanning consultations
and clinical encounters over more than 30 years.
The major inclusion criterion was a documented
extensive CM extending beyond 1 anatomic region.
From the Dermatology Program
a
and Department of Plastic and
Oral Surgery,
b
Boston Children’s Hospital, Harvard Medical
School.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication May 26, 2013.
Reprint requests: Margaret S. Lee, MD, PhD, Dermatology Program,
Boston Children’s Hospital, 300 Longwood Ave, Fegan 6,
Boston, MA 02115. E-mail: margaret.lee@childrens.harvard.edu.
Published online July 31, 2013.
0190-9622/$36.00
Ó2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.05.030
589
Exclusion criteria were clinical features associated
with a defined disorder: CMTC, M-CM, KTS, Parkes
Weber or Sturge-Weber syndromes, phakomatosis
pigmentovascularis, hemihypertrophy-lipomatosis,
and Proteus or congenital lipomatous overgrowth
and vascular malformation with epidermal nevus
and skeletal abnormalities (CLOVES) syndrome.
The patients’ demographic
and clinical information were
compiled in a deidentified da-
tabase and evaluated for CM
in the following 11 anatomic
regions: head/neck; right or
left upper limb region (upper
extremity, shoulder and lat-
eral chest or upper aspect of
back); isolated right or left
side of chest; right or left side
of abdomen; right or left side
of back; right or left lower
limb region (including lower
extremity, buttock, perineum,
suprapubic/abdomen). A CM
extending contiguously more
than 2 to 3 cm beyond 1 of these regions was
considered ‘‘diffuse.’’ A CM involving an entire lower
extremity and ipsilateral buttock was considered
‘‘regional’’ and excluded from the study.
Each CM was evaluated for appe aran ce. ‘‘Reticulate’’
was defined as a networklike, blotchy, nonuniform
stain without distinct borders. The term ‘‘homoge-
neous’’ described stains with a uniform, solid color
and obvious demarcation. Numbered lesion maps
documented areas that were reticulate versus homo-
geneous, and the extent of involvement (number of
anatomic regions).
Other findings were mapped using the same
numeric regions. ‘‘Overgrowth’’ was defined as dif-
fuse enlargement of a body region compared with
the contralateral side and in context of overall body
proportions. Patients with suspected leg length dis-
crepancy had orthopedic consultations and were
serially measured (often by scanograms). Medical
histories were compiled to identify any additional
clinical patterns. Soft-tissue overgrowth was differ-
entiated from bony overgrowth whenever possible.
Location and total number of regions with CM
was correlated with overgrowth and other clinical
findings. Statistical analysis was performed using
paired ttests with significant Pvalue of .05.
RESULTS
There was no sex predilection; 37 patients were
male and 36 were female. The average age at
presentation was 4 years but more than half were
infants. The maximum duration of follow-up for
any individual patient was 14 years. The oldest
patient was 55 years old. Table I summarizes the
demographic data. Most patients had Fitzpatrick
cutaneous phototype II skin.
5
There were 3 patients
with skin type IV, and none with type V or VI. There
was no family history of vascular staining with
overgrowth.
All CM were present at
birth; extension over time
corresponded with patient
growth. The CM often light-
ened over the first several
months of life. The average
number of body regions af-
fected with CM was 7.2 out of
a possible 11. Eight patients
(11% of total) had a distinct
centrofacial stain (nose, phil-
trum, or vermilion) that was
not a medial extension of a
large facial stain. Midline de-
marcation was often seen on
the abdomen (Fig 1), but
never on the back.
Nearly half the patients had only a reticulate CM
(Table II). The remainder had a combination of
extensive reticulate staining with focal areas of
confluent, homogenous stains, usually at acral sites,
ie, head and neck, hands and feet. No patients had
only a homogeneous CM. Clinically prominent
subcutaneous veins were documented in one-third
of patients.
The most common nonvascular finding was soft-
tissue and/or bony overgrowth (Table III). There
was no statistical correlation between the region(s)
of overgrowth and location or intensity of CM
staining (Fig 2), nor between number of regions
with CM and presence of overgrowth (P= .14). Leg
length discrepancy was noted in 55% of patients.
Overgrowth was proportionate to that of the child,
as documented by observation and scanograms.
Interestingly, 3 of 10 patients with notable facial
asymmetry (23%) had no facial CM.
The majority of subjects had overgrowth of just
1 extremity. True or total hemihypertrophy (over-
growth of ipsilateral face, body, and extremities) was
documented in 8 patients (11%), 7 of whom had
hemihypertrophy on the left side. An additional 10
patients exhibited overgrowth of an upper and lower
extremity (ipsilateral or opposite sides) without
facial asymmetry. The bones in all patients were
structurally normal on imaging studies. There was a
statistically significant relationship (P= .025) be-
tween total number of regions with CM and presence
CAPSULE SUMMARY
dTerminology for vascular malformations
associated with overgrowth continues to
be debated.
dWe propose the term ‘‘diffuse capillary
malformation with overgrowth’’ as a
clinical subtype distinct from Klippel-
Trenaunay syndrome and other more
serious disorders.
dDiagnosis of this subtype is reassuring
for families and provides clinicians with a
focused management plan.
JAMACAD DERMATOL
OCTOBER 2013
590 Lee, Liang, and Mulliken
of hemihypertrophy (with or without facial over-
growth); ie, patients with hemihypertrophy had
more diffuse staining. Although hemihypertrophy
syndromes are associated with an increased risk of
Wilms tumor, this malignancy was not found in our
study.
Digital anomalies were noted in 30% of patients:
soft-tissue syndactyly, especially involving the sec-
ond and third toes; a widened first pedal webspace
(ie, ‘‘sandal gap’’); and macrodactyly (fingers or
toes). There was an association between extent of
staining (number of regions involved) and soft-tissue
syndactyly (P= .052). Children with hemifacial
hypertrophy often displayed ipsilateral accelerated
dental eruption. Two patients were documented
with limb hypotrophy and CM.
No patient exhibited developmental delay. One
patient with generalized CM on the trunk and extrem-
ities (sparing the face), had seizures at 2 years of age
without macrocephaly or intracranial abnormalities.
A 14-year-old normocephalic patient had a centrofa-
cial CM, generalized diffuse CM, asymptomatic Chiari I
malformation, and history of resolved tics.
DISCUSSION
CM may be reticulate, pale pink, or dark and
homogeneous.
6,7
If a patient has focal, discrete CM in
more than one anatomic region, the precise term is
‘‘multifocal’’ rather than ‘‘diffuse’’ CM. CM in DCMO are
typically reticulate, pale, extensive, and diffuse, in that
multiple anatomic regions are stained contiguously.
If a CM is diffuse and other associated disorders
are excluded, the child should be assessed for areas
of soft-tissue or bony hypertrophy. Patients with an
enlarged lower extremity or pedal asymmetry
require regular orthopedic evaluation for limb length
discrepancy through the pubertal growth spurt, as
proper management of these problems can prevent
joint pain, abnormal ambulation, or scoliosis.
Overgrowth may not be apparent at birth or
during infancy (11% of patients in our study), but a
provisional diagnosis of DCMO can be made
based on the reticulate nature and extent of the
CM. Because overgrowth is proportionate, absence
of obvious asymmetry at birth predicts clinically
insignificant asymmetry in adulthood. One of our
patients was symmetric at birth, but by 4 years of age
there was subtle soft-tissue enlargement of the right
buttock and minor hypertrophy of the distal right
foot, discernible by careful examination.
Speech, occupational, or physical therapy may be
needed to address lingual or digital asymmetry. In
patients with facial hypertrophy, orthodontic, and
possibly orthognathic, correction may be necessary
during adolescence. Early initiation of laser therapy
should be considered for CM, particularly on the
head and neck.
DCMO versus KTS
Half our patients with DCMO were referred with a
diagnosis of KTS. We restrict the designation of
KTS to the triad of a capillary-lymphatic-venous
Fig 1. Infant with diffuse capillary malformation (CM)
with overgrowth, demonstrating midline demarcation of
extensive reticulate CM along abdomen and/or chest.
Reticulate CM may be incorrectly diagnosed as cutis
marmorata telangiectatica congenita. Note overgrowth of
left lower extremity corresponding to staining.
Table I. Age at presentation and average length of
follow-up of patients with diffuse capillary
malformation with overgrowth
Age at initial visit, y
#1 1-18 [18
No. of patients 41 27 5
Average length of
follow-up from initial
visit, y (range)
3.2 (0-9) 0.9 (0-14) 0.1 (0-7)
Average age at last
visit (y)
3.6 6.4 30.6
Abbreviations used:
CLOVES: congenital lipomatous overgrowth and
vascular malformation with epidermal
nevus and skeletal abnormalities
CLVM: capillary-lymphatic-venous
malformation
CM: capillary malformation
CMTC: cutis marmorata telangiectatica
congenita
DCMO: diffuse capillary malformation with
overgrowth
KTS: Klippel-Trenaunay syndrome
LM: lymphatic malformation
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VOLUME 69, NUMBER 4
Lee, Liang, and Mulliken 591
malformation (CLVM) in a limb; specifically, there is
no diffuse CM.
8
The variably prominent subcutane-
ous veins in DCMO are quite different from the
persistent embryologic vessels and other deep
venous anomalies characteristic of KTS.
Some authors include CM-VM with overgrowth of
the ipsilateral limb without LM in the KTS
spectrum.
6,9,10
Oduber et al
4
propose that a diagno-
sis of KTS does not require both CM and VM, LM,
or colocalization of the vascular anomaly with
overgrowth. We believe such broad categorizations
lead to uncertainty in prognosis and management.
A newborn with diffuse CM and no obvious VM or
LM should be provisionally given the diagnosis of
DCMO. Magnetic resonance imaging is only indicated
when there is evidence of lymphatic vesicles, edema,
and/or grossly abnormal veins. Patients with CLVM
are at risk for cellulitis, localized intravenous coagu-
lopathy, pulmonary embolism, and progressive over-
growth through life. None of these complications
were seen in cases we designated as DCMO.
DCMO versus M-CM
Patients with either DCMO or M-CM can have
facial asymmetry (with/without facial CM), limb
overgrowth, hand and foot enlargement with sub-
cutaneous and/or bony overgrowth, or 2- to 3-toe
syndactyly.
1,11
In addition to macrocephaly/mega-
lencephaly and neuroimaging abnormalities, M-CM
can usually be distinguished from DCMO by features
such as neonatal hypotonia, hydrocephalus, and
developmental delay.
12
Many clinicians note cuta-
neous or joint laxity or describe the skin as ‘‘doughy’’
in M-CM.
3
Craniofacial dysmorphism such as frontal
bossing and orbital hypertelorism may also be
observed.
13
Over half the reported patients with
M-CM have an isolated centrofacial CM (on nose,
philtrum, lips without other facial skin in-
volved).
3,12,13
Only 11% of our patients with DCMO
had centrofacial staining.
A normocephalic patient with diffuse CM and
absence of neurologic findings should provisionally
be given the diagnosis of DCMO, rather than M-CM.
Serial neuroimaging is not indicated but head
circumference and neurologic development should
be monitored closely in infants with diffuse CM. A
newborn with macrocephaly, generalized diffuse
CM,facialdysmorphism,markedlyasymmetric
overgrowth, and multiple digital syndactyly should
be provisionally given the diagnosis of M-CM, even
in the absence of neurologic defects. Conway et al
12
note that developmental delay becomes evident
within the first year of life in M-CM and abnormal-
ities progress over time in brain images. A family
history of benign macrocephaly supports a diagno-
sis of DCMO, but close observation is warranted.
If developmental milestones and brain imaging
results are normal in the first 2 years, a child with
primary macrocephaly and diffuse CM has a good
prognosis.
12
DCMO versus CMTC
CMTC is entirely different from DCMO and M-CM
(sometimes incorrectly designated M-CMTC).
1-3
CMTC stains have a strikingly reticulate, well-
defined vascular pattern. The affected skin is
atrophic and sometimes ulcerated in at least part of
the lesion. There may be hypotrophy of the ipsilat-
eral limb. There is considerable improvement or
resolution of the staining in early childhood.
14
Fig 1
shows a patient with DCMO who has reticulate, cutis
marmorataelike staining. We noted that patients
with DCMO often have physiologic cutis marmorata
as well. Whereas reticulate CM may fade during
infancy, there is never the degree of improvement
seen in CMTC.
DCMO versus CLOVES and Proteus syndromes
Many patients previously thought to have vascu-
lar anomalies and Proteus syndrome probably have
a newly identified overgrowth disorder called
Table II. Characteristics of capillary malformations
in patients with diffuse capillary malformation with
overgrowth
No. of
patients*
Total
patients
Reticulate CM 31/73 42%
Homogeneous CM 0/73 0%
Reticulate 1homogeneous CM 39/73 53%
Facial CM present 34/73 47%
Philtral/nasal CM 7/73 10%
CM, Capillary malformation.
*In 3 patients, specific information on reticulate vs homogeneous
staining pattern was not available.
Table III. Pattern of overgrowth in patients with
diffuse capillary malformation with overgrowth
No. of
patients
Total
patients
Total patients with overgrowth 65 89%
Leg length discrepancy 40 55%
Facial asymmetry 17 23%
Facial asymmetry without facial
capillary malformation
37%
Patients with total hemihypertrophy 8 11%
JAMACAD DERMATOL
OCTOBER 2013
592 Lee, Liang, and Mulliken
CLOVES syndrome.
15,16
Patients with CLOVES and
Proteus syndrome experience disproportionate
overgrowth, which is unpredictable, exceeds the
overall growth of the child, and may continue
throughout life.
17
In DCMO the hypertrophy is
proportionate. Patients with CLOVES syndrome are
often born with triangular-shaped feet because of
marked distal widening, with enlarged and/or
dysmorphic toes, and display truncal vascular
malformations typically containing lymphatic, ve-
nous, and capillary components.
15,16
Patients with
DCMO lack the complex vascular malformations
and scoliosis typical of CLOVES syndrome.
DCMO versus isolated hemihypertrophy
syndromes with lipomatosis
The terms ‘‘hemihypertrophy’’ or ‘‘hemihyperpla-
sia’’ are often applied loosely to describe overgrowth
of any body part, with equal emphasis placed on
enlargement of one limb as that of an entire half of
the body. We support differentiating 3 types of
hemihypertrophy because of prognostic implica-
tions. Hemihypertrophy is ‘‘total’’ if it involves an
entire half of the body, ‘‘regional’’ if it involves an
anatomic territory such as a limb, or ‘‘crossed’’ if
opposite parts of the body are overgrown (eg, left
arm and right leg).
18
Patients with total hemihyper-
trophy, as in hemihypertrophy-lipomatosis or
Beckwith-Wiedemann syndrome, have an increased
risk of Wilms tumor.
19,20
Of our patients, 11% had total hemihypertrophy,
but no abdominal malignancies were found, sug-
gesting that serial abdominal ultrasonography to rule
out Wilms tumor may be unnecessary for most
patients with DCMO. Two studies have shown that
Wilms screening is unnecessary in patients with
KTS.
21,22
Lapunzina
20
conducted a thorough litera-
ture review of overgrowth syndromes, including
M-CM, KTS, Proteus, and PTEN hamartoma syn-
dromes, and found that a high risk of embryonal
tumors tends to be associated with generalized
overgrowth disorders, whereas partial overgrowth
syndromes have a high risk of benign tumors such
as lipomas, but a minor to moderate risk of
malignancies. Two patients with CLOVES syndrome
in our center developed Wilms tumor. Because the
region of overgrowth does not correlate with areas
of vascular staining in DCMO, there may be
genetic similarities to hemihypertrophy-lipomatosis
or Beckwith-Wiedemann syndrome. Risk of malig-
nancy in DCMO, by this reasoning, is likely to be low
in patients with regional hemihypertrophy. It is
prudent to conduct Wilms tumor screening in patients
with DCMO and total hemihypertrophy.
Spectrum of disorders with diffuse CM
In time, genetic studies will help us differentiate
the overlapping clinical spectrum of vascular
anomaly-overgrowth syndromes and diagnostic lines
may be redrawn. Somatic mutations in PIK3CA have
recently been identified in CLOVES syndrome
23
and
M-CM.
24
A mosaic activating mutation in AKT1 was
found in Proteus syndrome.
25
A 2-hit theory has been
proposed to explain many congenital cutaneous
anomalies, such as CM and pigmented lesions.
26
In conclusion, DCMO is a more benign and
common condition than M-CM, KTS, or CLOVES
syndrome. We do a disservice to anxious parents and
patients by providing an unnecessarily worrisome
diagnosis. We hope this analysis of the differential
diagnosis of diffuse capillary staining will help clarify
the prognosis and care of these patients. Long-term
outcome studies of DCMO are needed.
The authors are grateful to Dr Richard A. LaBrie for
statistical analysis of our data.
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... According to literature, patients were classified based on clinical phenotype as following: MCAP/M-CM, 33 34 CLOVES, 35 36 FAO, FIL, 5 37 HHML, 37 KTS, DCMO, 40 IVM, CLAPO, 38 FH/MH, 32 isolated macrodactyly 39 and epidermal naevus syndrome (ENS) (see online supplemental file 1 for definitions). In the statistical analysis, we grouped together entities with overlapping clinical features in which a clear-cut differentiation was not always easy or possible: for example, KTS+DCMO, MCAP+M-CM, FAO+FIL+HHML, IVM+-CLAPO, FH+MH. ...
... In this respect, it seems relevant to point out that the cases we studied have been accumulated over 10 years, a time period in which some clinical definitions have changed, such as that between KTS and DCMO, and this might have impacted on our clinical classification. 40 Interestingly, PIK3R1 variants have been recently shown to activate the PI3K pathway leading to phenotypes overlapping PROS. 54 Remarkably, we found no variant in such gene: either they are very rare, or this could be due to ascertainment bias or differences in methodology. ...
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Background Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA -related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA- mutated patients, analysing our new data with previous literature to give a comprehensive picture. Methods We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ , GNA11 , RASA1 and TEK . Additionally, 914 patients previously reported were systematically reviewed. Results 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ , GNA11 , RASA1 or TEK . Conclusion We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA .
... Patients with CM affecting multiple anatomical regions and proportionate soft tissue overgrowth, but lacking symptoms typical of other diseases of the PROS spectrum (e.g., MCAP, CLOVES, or KTS) or of SWS, were classified as DCMO [9]. All 11 patients affected with DCMO (Table 1, n. 14-24) had diffuse reticulate CM, with focal areas of homogeneous stain in 6 cases, including 3 cases with centrofacial and/or philtrum stain ( Figure 3). ...
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Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes—mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent GNAQ somatic mutation p.Arg183Gln, while two had PIK3CA mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known PIK3CA mutations, and the remaining 3 had pathogenic GNA11 variants. Recurrent PIK3CA mutations were identified in the patients with megalencephaly–CM–polymicrogyria (MCAP), CLOVES, and Klippel–Trenaunay syndrome. Interestingly, PIK3CA somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic TEK mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an RASA1 mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic KRAS somatic variants, showing the variability of phenotypic features associated with KRAS mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies.
... The lesions initially appear as flat, pink patches, 1,2 most of which will gradually grow into red to purple, hypertrophic or nodular lesions, severely affecting the appearance. 3,4 It has been reported that the pathogenesis of PWS involves gene mutation. Variants (c.548G→A, p.Arg183Gln; c.547C>G, p.Arg183Gly) in GNAQ was found in PWS. 5 Somatic mutations of RASA1 and PIK3CA were also found in PWS. ...
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Background: Port wine stain (PWS) is a congenital skin lesion involving capillary malformations. Most PWS lesions will gradually become hypertrophic and appear nodular in contour. Current research shows that rapamycin, an mTOR inhibitor, is probably a promising adjunctive therapy for PWS, which suggests that the mTOR signaling pathway may play an important role in its pathological process. Methods: From January 2013 to January 2019, 13 samples were obtained during the surgical excision. Each sample was divided into 3 parts according to the type of lesion, namely, the flat, hypertrophic and nodular lesions. Pathologic structures of each type were observed under the microscope after HE staining. The expression of mTORC1, p70S6, p-p70S6, eIF4EBP1 and p-eIF4EBP1 was examined by immunohistochemical staining and western blotting. The location of the expression of mTORC1, p-p70S6 and p-elF4EBP1 was further detected by immunofluorescence staining. Results: Large amounts of dilated and malformed vessels were observed in all types of PWS lesions. Abundant hyperplastic hair follicles/glands were shown in the hypertrophic or nodular lesions. Phosphorylation level of p70S6 and elF4EBP1 in PWS was significantly higher than those in normal skin and increased accordingly in the progression of PWS. Activated molecules in mTOR signaling pathway were mostly located in the endothelium of malformed vessels. They were also located in the hyperplastic hair follicles/glands of hypertrophic and nodular lesions. Conclusion: The mTOR signaling pathway was increasingly activated during the progression of PWS. Enhanced activation of mTOR signaling pathway may contribute to the hypertrophy and nodularity of PWS. The results provide preliminary evidence for treating PWS and related syndromes by inhibiting mTOR signaling pathway.
... Diffuse capillary malformation with overgrowth (DCMO) is a clinical diagnosis identifying patients with multiple and extensive capillary malformations (CM) associated with overgrowth of a body segment, usually an entire hemisome or limb. CM in DCMO are typically reticulate, pale, extensive, and diffuse, characterized by multiple anatomic regions contiguously stained [86]. The absence of deep venous varicosities, the persistence of embryonic vessels or lymphatic components differentiate DCMO from KTS, together with being virtually free of major complications and limited evolution over time. ...
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Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.
... Segmental overgrowth has been vastly and consistently reported in patients with congenital vascular anomalies. These disorders are currently grouped under the PIK3CA-related overgrowth spectrum (PROS), 1,2 Proteus, 3 Parkes-Weber, 4 and diffuse capillary malformation with overgrowth (DCMO) 5 terms, among others. In the last decade, most of these syndromes have been described as caused by postzygotic pathogenic variants, which generate a great phenotypic variability that not only depends on the gene involved but also on both the moment of the embryonic development in which the variant arose and the different cells/tissues affected in each individual. ...
Article
Segmental overgrowth has been widely described in patients with congenital vascular anomalies. However, segmental undergrowth has been poorly characterized, and no large series of patients have been published. We present the clinical and molecular characteristics a cohort of 37 patients with vascular malformations and segmental undergrowth. True undergrowth was only considered when the musculoskeletal system was involved to avoid confusion with other causes of segmental reduction, as in lipodystrophy or the long-term osteopenia seen in patients with Servelle-Martorell syndrome. Deep high-throughput sequencing was performed in tissue samples from 20 patients using a custom panel. We identified three groups: undergrowth associated with 1) venous, 2) capillary-venous, and 3) lymphatic-capillary-venous malformations. Congenital or early childhood onset undergrowth can occur with or without associated overgrowth. Different likely pathogenic or pathogenic variants were detected in 13 of 20 (65%) tissue samples in the PIK3CA, TEK, GNAQ, or GNA11 genes. In conclusion, the eponymous Servelle-Martorell syndrome should not be used as a synonym for undergrowth. Segmental undergrowth should be considered a characteristic associated with vascular malformations. Patients with PIK3CA variants show all different combinations of overgrowth and undergrowth. Thus, the term PROS (PIK3CA-Related Overgrowth Spectrum) does not cover the entire spectrum.
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PIK3CA encodes the class I PI3Kα isoform and is frequently mutated in cancer. Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with frequent vascular involvement. In PROS, PIK3CA mutations arise postzygotically, during embryonic development, leading to a mosaic body pattern distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favoring some mesoderm-derived and ectoderm-derived tissues is observed but not understood. Here, we summarize our current knowledge of the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias, and extrinsic factors, which refers to environmental modifiers. We also include a section on PIK3CA-related vascular malformations given that the vasculature is frequently affected in PROS. Increasing our biological understanding of PIK3CA mutations in PROS will contribute toward unraveling the onset and progression of these conditions and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insights into one will also inform about the other. In this Review, the authors provide an overview of the pathogenic effects of somatic activating PIK3CA mutations in congenital disorders and discuss how the interplay between genetics, cell identity and the environment explains the onset, progression and severity of these disorders with a special focus on the vasculature.
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Background and purpose: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS. Methods: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. Results: We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. Conclusions: We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.
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Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of “nevus vascularis mixtus”. Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype.
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Background: Port-wine stain (PWS) patients may simultaneously have accompanied soft tissue hypertrophy. The outcome of laser therapy can be poor. Objective: To study the imaging and histopathological characteristics of PWS patients with facial overgrowth. Materials and methods: We retrospectively assessed the effect of therapy on a subset of PWS patients with facial overgrowth. The degree of hypertrophy and the density of enhanced signals on T1-weighted magnetic resonance imaging (MRI) were independently graded by two radiologists using a quartile scale. Biopsies/resection of tissue deep to the facial muscle was reviewed and compared with flat PWS. Results: Thirty-two PWS patients with facial hypertrophy and 15 patients with flat PWS were included. MRI revealed a statistically significant correlation between the degree of hypertrophy and the density of enhanced signals (3.02 ± 0.92 vs. 2.47 ± 0.69; p < 0.01). Histological features of a subset of patients showed that vascular malformations existed in the dermis and also in the subcutaneous fat and muscle with much larger vessel diameters (fat, 0.048 vs. 0.020; muscle, 0.035 vs. 0.017) and thicker vessel walls (fat, 0.014 vs. 0.006; muscle, 0.010 vs. 0.006) (both p < 0.05). Conclusions: The imaging and pathological findings indicate that capillary malformation in subcutaneous tissue might be a major cause of poor therapeutic effect of laser therapy for PWS. Clinical trial registration no.: ChiCTR1800014278.
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Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
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The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).
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Hemihyperplasia is characterized by asymmetric growth of cranium, face, trunk, limbs, and/or digits, with or without visceral involvement. It may be an isolated finding in an otherwise normal individual, or it may occur in several syndromes. Although isolated hemihyperplasia (IHH) is of unknown cause, it may represent one end of the clinical spectrum of the Wiedemann‐Beckwith syndrome (WBS). Uniparental paternal disomy of 11p15.5 or altered expression of insulin‐like growth factor 2 (IGF2) from the normally silent maternal allele have been implicated as causes of some cases of WBS. IHH and other mild manifestations of WBS may represent patchy overexpression of the IGF2 gene following defective imprinting in a mosaic fashion. The natural history of IHH varies markedly. An association among many overgrowth syndromes and a predisposition to neoplasia is well recognized. Heretofore the risk for tumor development in children with IHH was unknown. We report on the results of a prospective multicenter clinical study of the incidence and nature of neoplasia in children evaluated because of IHH. One hundred sixty‐eight patients were ascertained. A total of 10 tumors developed in nine patients, for an overall incidence of 5.9%. Tumors were of embryonal origin (similar to those noted in other overgrowth disorders), including Wilms tumor, hepatoblastoma, adrenal cell carcinoma, and leiomyosarcoma of the small bowel in one case. These data support a tumor surveillance protocol for children with IHH similar to that performed in other syndromes associated with overgrowth. Am. J. Med. Genet. 79:274–278, 1998. © 1998 Wiley‐Liss, Inc.
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Hemihyperplasia is characterized by asymmetric growth of cranium, face, trunk, limbs, and/or digits, with or without visceral involvement. It may be an isolated finding in an otherwise normal individual, or it may occur in several syndromes. Although isolated hemihyperplasia (IHH) is of unknown cause, it may represent one end of the clinical spectrum of the Wiedemann-Beckwith syndrome (WBS). Uniparental paternal disomy of 11p15.5 or altered expression of insulin-like growth factor 2 (IGF2) from the normally silent maternal allele have been implicated as causes of some cases of WBS. IHH and other mild manifestations of WBS may represent patchy overexpression of the IGF2 gene following defective imprinting in a mosaic fashion. The natural history of IHH varies markedly. An association among many overgrowth syndromes and a predisposition to neoplasia is well recognized. Heretofore the risk for tumor development in children with IHH was unknown. We report on the results of a prospective multicenter clinical study of the incidence and nature of neoplasia in children evaluated because of IHH. One hundred sixty-eight patients were ascertained. A total of 10 tumors developed in nine patients, for an overall incidence of 5.9%. Tumors were of embryonal origin (similar to those noted in other overgrowth disorders), including Wilms tumor, hepatoblastoma, adrenal cell carcinoma, and leiomyosarcoma of the small bowel in one case. These data support a tumor surveillance protocol for children with IHH similar to that performed in other syndromes associated with overgrowth. Am. J. Med. Genet. 79:274–278, 1998. © 1998 Wiley-Liss, Inc.
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We describe 13 unrelated children with abnormalities of somatic growth, face, brain, and connective tissue including vasculature. Although the condition in these children falls under the general group of disorders known as cutis marmorata telangiectatica congenita (CMTC), the constellation of abnormalities appears to constitute a distinct and easily recognizable phenotype within this general group. In contrast to most children reported with CMTC, children in this subgroup have a high risk for neurologic abnormalities, including developmental delay, mental retardation, megalencephaly, and hydrocephalus. Early recognition of this condition is important for appropriate surveillance for known complications and parental counseling. Am. J. Med. Genet. 70:67–73, 1997. © 1997 Wiley-Liss, Inc.
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Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.
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There is significant confusion in the literature when describing vascular anomalies, and vascular malformations are often misnamed or incorrectly classified. Part I of this two-part series on the diagnosis and management of extensive vascular malformations of the lower limbs will discuss the dermatologist's role in the diagnosis of these lesions. At least nine types of vascular malformations with specific clinical and radiologic characteristics must be distinguished in the lower limbs: Klippel-Trénaunay syndrome, port-wine stain with or without hypertrophy, cutis marmorata telangiectatica congenita, macrocephaly-capillary malformation, Parkes Weber syndrome, Stewart-Bluefarb syndrome, venous malformation, glomuvenous malformation, and lymphatic malformation. This article highlights the differences in clinical appearance and discusses the differential diagnosis of extensive vascular malformations in an attempt to ensure earlier diagnosis and better outcomes for these patients.
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Macrocephaly-capillary malformation (M-CM) is a genetic syndrome of unknown etiology characterized by an enlarged head circumference and patchy, reticular capillary malformation. We describe the clinical features of 13 cases, report on the genome-wide Copy Number Variation characterization of these patients, analyze the main clinical features of this syndrome and propose a modification of the current diagnostic criteria: the inclusion of both overgrowth/asymmetry and neuroimaging alterations as major criteria.
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The condition known as macrocephaly-cutis marmorata telangiectatica congenita syndrome (M-CMTC) is a rare congenital syndrome of unknown etiology characterized by macrocephaly and vascular lesions that have been described as either cutis marmorata or cutis marmorata telangiectatica congenita (CMTC). Most patients also exhibit facial and limb asymmetry; somatic overgrowth; developmental delay; capillary malformations of the nose, philtrum, and/or upper lip; neurologic abnormalities; syndactyly or polydactyly; craniofacial abnormalities; and joint laxity or soft skin. We describe 12 patients with this condition from tertiary care medical centers (8 cases) and accrued via an M-CMTC support group Web site (4 cases). All patients showed reticulated or confluent port-wine stains (PWS), not CMTC. Seven of the 12 patients also had centrofacial capillary malformations. In our comprehensive review of 100 previously reported cases, only 34 were accompanied by photographs that were sufficiently clear to review for diagnostic purposes. None had true CMTC, with most having reticulated PWS or persistent cutis marmorata. Reticulated or confluent PWS and persistent capillary malformations of the central face, rather than CMTC, are the most characteristic cutaneous vascular anomalies seen in so-called M-CMTC syndrome. The name macrocephaly-capillary malformations (M-CM) more accurately reflects the features of this syndrome.