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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
JAMACAD DERMA TOL
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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