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37
I
PROTEUS SYNDROME
!
LESLIE G. BIESECKER
Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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Proteus syndrome is a disorder of segmental or mosaic
overgrowth that can affect any tissue. The most common
complications include overgrowth that can lead to orthopedic
complications, soft tissue overgrowth of the feet, linear nevi,
vascularmalformations,and tumor predisposition.All confirmed
casesare sporadic,and it hasbeenhypothesizedthat the disorder
is causedby a postzygoticmutation in a growth-promotinggene.
Proteus syndromeis rare and overdiagnosed. There are fewer
than 100 documentedcasesin the literature, and many people
who carry the diagnosis cannot be confirmed as affected when
publisheddiagnostic criteria are rigorously applied.
INTRODUCTION
Proteus syndrome is a disorder of segmental or mosaic
overgr~wt.h th~t can affect any tissue. The most comm~n
compl~cat~ons
mclud~ overgrowth that can lead to .orthopedl~
complicatIons, soft. tIssue overgrowth ~f th~.feet, linear neVI,
vascularmalform~tlons,an~tumor predIsposItIon.~ll confirmed
c~ses are. sporadIc, and It has be.en hypo.thesl.zedthat the
dlsorde~ IS caused by a postzygotlc mut~tlon m a growthpromoting gene. The syndrome was delmeated by Cohen
and Hayden (Cohen and Hayden, 1979) and was named by
Wiedem~nn(~iedem~n et al., 1983).The earliest known case
waspublishedm the nIneteenthcentury by Treves(Treves,1885;
Cohen, 1987).
Incidence
Proteussyndrome is rare and overdiagnosed.There are fewer
than 100 documentedcasesin the literature, and many people
who carry the diagnosis cannot be confirmed as affected
when published diagnostic criteria (Biesecker et al., 1999) are
rigorously applied.
Diagnostic Criteria
There has been substantial confusion about the diagnosis of
Proteus syn~ro~~. This was first ~ecognize~at a gath'ering~f
18 affected mdlvlduals at the NatIonal InstItutes of Health m
1998 (Bieseckeret al.., 1998). At this meeting, it was clear that
the individuals who carried this diagno.sis,:ere heterogeneous.
A number of those affected had pnmanly postnatal onset
of overgrowth with aggressive,irregular, and disproportionate
hyperplasia;progressivebony distortion; venous,capillary, and
lymphatic vascular malformations; connective tissue nevi of
the feet; and linear verrucous epidermal nevi of the skin.
These distinct manifestationsand natural history are consistent
with the original description and warra.ntthe ~iag~ost!c label
of Proteus syndrome. Subsequently,dIagnostIc cntena were
devised and are summarizedin Table 37.1. While the authors
of these criteria have found them useful for research and
for counseling and managingindividuals, substantialconfusion
persists.In the National Institutes of Health Proteussyndrome
research program, most individuals referred with a diagnosis
of Proteus syndrome are rediagnosedwith another condition
upon application of the diagnostic criteria. Although it may be
arguedthat thesecriteria are excessivelystrict and that Proteus
syndromemay be part of a continuousspectrum,the careful use
of these criteria reliably divides individuals into a progressive
high-risk group (Proteussyndrome)and a static, low-risk grou~
(hemihyperplasia,seebelow) (personalexperience).
It is imperativeto understandthe intent of eachof the criteria
as outlined in Table 37.1. Progressiveovergrowth in Proteus
syndromeis almost always relentlessand, in most cases,severe.
It should not be confused with the growth of a lipoma in a
person with hemihyperplasia.Severe overgrowth will occur in
areas of the body that were entirely normal at birth. Another
critical feature of the overgrowth seen in Proteus syndromeis
its irregularity, leading to distortion of cutaneous,subcutaneous,
cartilaginous,and bony tissues.In contrast,the overgrowth seen
Management of Genetic Syndromes, Second Edition, Edited by SuzanneB. Cassidy and Judith E. Allanson
ISBN 0-471-30870-6
2005 by Wiley-Liss, Inc.
449
TABLE 37.1 DiagnosticCriteria for ProteusSyndrome"
Mr. Merrick's medical condition was describedin detail by his
General Criteria: Mosaic distribution AND Progressivecourse,AND
sporadic occurrence
surgeon (Treves, 1885): and good evidenc.e has been presented
to show that Mr. Memck was affected with Proteus syndrome
CategoryA: cerebriformconnective
tissuenevus
CategoryB
1. Epidermalnevus
2. Disproportionate
overgrowthof two of: limbs,skull,external
auditorycanal,vertebrae,
or viscera
(Cohen, 1987). However, he was affected to a severe degree,
and the many negativeconnotationsaffiliated with that story are
either not useful or even harmful to those who are affected by
the disorder. Therefore, the use of that pejorative diagnosis is
discouraged.
3. Bilateral ovarian cystadenomasor monomorphic adenomasof the
parotid gland in childhood
CategoryC
I. Dysregulated adipose tissue (either lipoatrophy or lipomas)
2. Vascularmalformations:
capillary,venous,or lymphatic
3. Facialphenotype:
long face,dolichocephaly,
down-slanted
palpebral
fissures,low nasalbridge,wideor anteverted
nares,openmouthat
rest
a
..
To make
diagnosIs
offrom
Proteus
syndrome
requires
either
oneafrom
A, two
B, or
threefrom
C. all three generalcriteria plus
Source:
Adapted
fromBiesecker
et al.(1999).
in hemihyperplasiais highly regular, a "ballooning," resulting
in a body part that is large but easily recognizable.In general,
upon radiographic examination, the bones underlying these
enlarged body parts in hemihyperplasiaare enlarged but are
nonnal in structure. In contrast, in Proteus syndrome, bony
and cartilaginous structures are distorted, sometimes beyond
recognition.
A second critical feature of Proteus syndrome is the
connectivetissue nevus, also known as a cerebrifonn lesion or
moccasin lesion when present on the sole of the foot, which
is common. While many individuals with Proteus syndrome
may not have this lesion, when present, it is very helpful for
making the diagnosis. However, there is confusion regarding
this sign as well. This lesion is causedby hyperplasia of the
cutaneousand subcutaneous
tissueswith thickening of more than
a centimeter. This overgrowth is irregular, leading to marked
thickening adjacent to deep furrows, which may resemble the
surfaceof the brain. This was the genesisof the tenDcerebriform
hyperplasia. This tissue is much finDer than the corresponding
tissue that it replaces.Although this lesion is most common on
the soles,it can also occur on the hands,perinasalarea,or near
the canthus.
The specific diagnostic criteria in categoriesA, B, and C
(see Table 37.1) are accompaniedby three general diagnostic
features that must all be present. First, the overgrowth must
be patchy or mosaic. There are no individuals with Proteus
syndrome who have evenly distributed overgrowth, and this
manifestation is predicted not to occur by the etiological
model below. Second, the occurrence must be sporadic, as
there are no confinned familial cases; again, this is thought
to be impossible by the pathogenetic model of the disease.
Third, all casesmust be progressive,as defined above. These
generalcriteria are basedon the mosaicismmodel below, which
has so far proven to be remarkably useful for understanding
this disorder.
Finally, it must be mentioned that a fonDer name for
Proteus s~ndrome is "Elephant man disease," after the book
and mOVie of the same title describing the life of Joseph
Carey Merrick who lived in England from 1862 to 1890.
Etiology, Pathogenesis,and Genetics
In all confinned cases of Proteus syndrome described to
date, the individuals were affected in a patchy or mosaic
pattern and were sporadic. The disorder is pan ethnic and
there are no data to suggest any differences in frequency
among the major ethnic groups. Interestingly, there have been
f
..
.
t,:o cases 0 monozygotic twms who are discordant for the
disorder (although the diagnoseshave not been independently
confinned in these cases).These observationshave been used
to generate a model of Proteus syndrome (Happle, 1987).
This model proposes that Proteus syndrome is caused by a
postzygotic mutation in a gene that causes deregulation of
growth in the daughter cells of that lineage. Furthennore,
the model proposes that the mutation, if present in all
cells, would be lethal at an early stage of development, or
perhaps even in the gamete. Thus, affected persons have
only unaffected children. At least three affected adults have
had four pregnancies, all of which were unaffected. This
model is likely relevant to an entire class of disorders
such as hemihypertrophy with multiple lipomatosis, KlippelTrenaunay syndrome, and the McCune-Albright syndrome.
Although the gene mutated in McCune-Albright syndrome is
known, the germline lethality hypothesisis not fonnally proven
for proteus syndrome. It is hypothesized that each of these
disorders is caused by mutations in distinct genes, but in
mosaic fonD.
Much confusion has been generatedsurrounding the issue
of mutations of the gene PTEN in Proteus syndrome. Some
individuals with PTEN mutations are claimed to have Proteus syndrome or "Proteus-like syndrome," the latter being
a designation that engenderslittle clarity (Zhou et al., 2001;
Smith et al., 2002). These reports have been reviewed, and
it has been concluded that there are either insufficient data
to diagnose Proteus syndrome or, when the data are sufficient, it is clear that the diagnosis is wrong. We suspect
that there are some individuals with PTEN mutations who
have overgrowth syndromes(such as Bannyan-Riley-Ruvalcaba
syndrome or less distinct patterns of overgrowth) that can
be confused with Proteus syndrome. However, astute clinicians recognize the importance of careful phenotypic evaluations and thoughtful application of recognized diagnostic
criteria.
D
.
.
T
.
iagnostlc J.estlng
There are no known molecular or biochemical tests that are
useful in individuals who meet the clinical diagnostic criteria
describedabove.Thosewho do not meet thesecriteria may have
one of a numberof overlappingdisordersof somaticovergrowth
..,.,
(seebelow). In those cases,appropriatemolecular testing, such
asPTEN sequencing,
maybe considered"
~
~
"
---
cause leg length discrepancy (in one case more than 15 cm).
Many personshave a lipodystrophythat includeslipomasor
t
The most commondisorderthat shouldbe consideredin a person
with segmental overgrowth is hemihyperplasia with multiple
lipomatous infiltration of muscles and viscera in some parts
of the body and lipoatrophy in other parts of the body. Some
. "
. d " .d al I h
&& d m
allecte
IVI usa so ave slgmfi cant undergrowth of some
muscle groups,the upper extremitiesbeing most often involved.
There is no known biochemicalor hormonal explanationfor this
i
lipomatosis(Bieseckeret al., 1998)and otherforms of hemi-
observation,althoughit has not beeninvestigatedrigorously.
I
hyperplasia(Cohen et al., 2002a). The majority of individuals
referred to the National Institutesof Health for the Proteussyndrome study have been rediagnosedwith hemihyperplasiawith
multiple lipomatosison review of records,clinical photographs,
and plain radiographs.The main featuresthat distinguish hemi-
It has been claimed that Proteus syndrome "burns out" with
adolescenceinsofar as some individuals seem to experiencea
cessation or marked diminution of their overgrowth near the
end of puberty. While this is not universal, it may be common,
and this considerationis critical for planning treatment.
:
hyperplasia with multiple lipomatosis from Proteus syndrome
are nonprogressivity(the overgrown limb grows in a commen-
Evaluation
surate manner to the rest of the body), capillary vascular malformations, and lipomas. The overgrowth in hemihyperplasia
..,
.
.
. Apparent faIlure to thnve should be InvestIgated m a
D "'"
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t " I D"
hleren la
"
lagnosls
with multiple lipomatosisis typically describedas "ballooning,"
:
standardmanner.
whereasin Proteusit is distorting. In general,the prognosisof
hemihyperplasiawith multiple lipomatosisis lessgravethan that
of
Proteus
although there isTya potential
association
with
Wilmssyndrome,
tumor and hepatoblastoma.
ical hemih
e lasia
lreatment
. excesscalories does n?t appearto be helpful to
Feedmg
treat the underdevelopmentor lIpoatrophy.
.
.
..
p
.yp. ~
IS not progressIve,whIch meansthat most affected IndIvIduals
areborn with asymmetryand, as they grow, the asymmetrystays
proportionateand is commensuratewith the;overall growth of
the child throughout life. In any case, isolated hemihyperpla-
sia is a manifestation of overgrowth, not a diagnosis (Cohen
et al., 2002a).Klippel. Trenauilaysyndrome
., consistsof capillary,
venous,and lymphatIc vascularmalformatIons(sometImesthese
malformations are mixtures of vessel types), with overgrowth
that is typically in the samesegmentas the vascularmalformation (Cohenet al., 2002b).The bonesin overgrown segmentsare
enlargedbut not typically distorted, and the affected individuals do not have hyperostoses,or connectivetissue or epidermal
nevi. Maffucci syndromeis defined as multiple enchondromatosis with vascular malformations, and the former is sometimes
confusedwith hyperostosis(Cohenet al., 2002c). Maffucci syndrome has no other overlap with Proteussyndrome.
.
D
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t dB h .
eveopmen an
e avlor
Development can be delayed, and a minority of affected individuals are mentally retarded (probably less than 10-15%,
although these estimatesare problematic becauseof ascertainment bias.) There are no known stereotypicalor common behavioral problems.
Evaluation
.
Developmentalmilestonesshould be monitored
. If developmental delay is evident and unexplained by
structural abnormalities,formal developmentalassessment
should take place.
MANIFESTATIONS AND MANAGEMENT
It must be borne in mind that Proteus syndrome is a very
rare disorder and experienceis limited. The National Institutes
of Health series of 35 affected individuals is the largest in
the world, yet it is an inadequate sample from which to
draw clear conclusions or make firm recommendationsfor
managementof all cases.The disorder is usually severe and
affects many body systems;therefore decisions about treating
anyone
y system near y a ways mvo ve consl eratlons
of many other involved body systems.Effective management
generallyrequiresa large anddiverseteamof medical specialists
willing to invest time to make thoughtful decisions about
diagnosisand treatment.
bod
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.
I
.
d
'
Growth and Feeding
Growth issuescan be challenging in Proteus syndrome.Most
affectedindividuals havesevereasymmetricovergrowththat can
The use of growth-stimulating or androgenichormonesto
treat this manifestationis not recommendedbecauseof the
unknown effects of such treatmenton hyperplastic tissues.
lreatment
. Appropriate interventions and therapies,including educational programmi~g, should be instituted, as indicated by
the defects identified.
M
uscu
I
os
k
e
I
eta
I
The musculoskeletalmanifestationsof Proteussyndromeare as
common as they are daunting [for review, see Cohen et al.
(2002d)]. The relentlessly progressive nature of the disorder
and the frequent involvement of bones, cartilage, muscle, and
connectivetissuescausesymptomsin nearly all affectedindividuals. Most haveasymmetricovergrowththat primarily affectsthe
length of the tubular bonesbut can also affect bone width, joint
capsule,connectivetissues,and muscles;Lipomatousinfiltration
of muscle groups can causean underestimateof the degreeof
can
the
rapid
deformities
is hyperplasia
at
of the
Respiratory
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manlIestatlon
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become
widely
Involvement
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y no
pam
more
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three-dImensIonal
important
wheQ
of
sudden
I
an orthopedist
should
h
h
h
.
t an w en t ere IS
ater
contributors
syndrome.
technique
is
be implemented
fi
occur
early,
cer.
1 .
unctlona
Impact
E
managed
The
by
timing
an appropriate
of
asymmetric
to
epiphyseodesis
these
correction
reduce
epiphyseal
by
procedures
curettage
is crucial
of angulation
bone
length
manipulation
be
or balancing
may
alone
used
to
is indicated
develop,
is
be
also
required
insufficient.
shorten
for
and/or
when
of
persons
pulmonary
effective
perfonned
vertebral
successfully
associated
lesions,
The
the
later
degrees
is
strongly
knees,
of
of
is
of
have,
Spinal
in persons
with
future
Bracing
or
major
od
may
avol
of
be
with
leg
length
is
the
asymmetry,
pathologic
of
the
tubular
bone
by
Tre a t men t
primary
. Individuals
to opti-
without
shoe
lifts
with
that
prosthetic
have
joints
lost
bones,
bone.
may
any
age
t
h
.
an d rapl
The
in
should
be
otherwise.
od
d
lagnostlc
.
.
classic
algorithm
followed
by
pulmonary
some
situations,
but
is
consuming.
with
as the
and
mobility
is
be useful.
(hips,
lung
need
atelectasis.
They
are
to the
febrile,
poor
to
of
the
be
monitored
should
be
as pneumonia
clearance
lungs
but
for
carefully
is a likely
of secretions
from
tissue.
with
vigorous
degeneration
symptoms
they
due
. Individuals
have
cystic
when
the cystic
Avoiding
epiphyseodesis
their
preferred
or c h es t paino
proven
e ffi ectlve
.
embolism.
with
should
scanning.
clency
'
ffi
of
scanning
be
Individuals
degeneration
until
t d
pulmonary
obvious
evaluated
pulmonary
pulmonary
cystic
toilet
degeneration
during
should
postoperative
con-
valescence.
.
of joints
t
ventilation/perfusion
is chalI.
Ica-
recommended
nonnal
msu
0
syndrome
IS
. t h e most
may
1994).
of cystic
embolism
h
for
time
prompt
tomography
comp
preferred
generally
lengthening
generally
the
not
Proteus
I t.
more
computed
ventilation-perfusion
pulmonary
angiography
been
pneumonia,
should
syndrome
timing
may
of
compromise,
0 f pu I monary
contrast
technique
may
has
Proteus
Again,
are
irregular
fusion
worsening
surgery
or
preferred.
etc.)
a person
H . h
straighten
asymmetric
bodies.
technique
bone
Replacement
.
are
.
d
procedures
et al.,
degrees
for
onset
complication
purpose
overgrowth
that
the chest
to exclude
cystic
malfonnations.
most
effective
imaging
modality
for
this
pneumonia
lIizarov
shorter
can
.
believed
associate
WIt h Pr oteus
can be effective
and should
high-resolution
be considered
considered
growth.
lesser
a I so
symptoms
0
surgical
(Newman
Th e acute
in
This
are indicated.
for
.
with
however,
who
compromise.
there
using
modem
surgical
techniques.
I
.
be
I
.
engmg
cause
ear y correction
tions
rome
.
IS
embolism
pulmonary
significant
venous
fusion
to
of
It
pulmonary
major
of
of
the
clinically
.
can
overgrowth
.
for
complication
to
bones.
less
ed
and is a major
challenge
with
the diagnosis
and
onset
early
mortalIty
management
of chronic
need
scanning
This
is
epiphyseal
.
Osteotomy
likely
d
al.,
ect
I
t'
vaualon
u
and
of growth.
. Spinal
syn
a ffi
emergently.
-reso
overgrowth
is best
tubular
oteus
catastrophIc.
and
to the
Aggressive
. Symptoms
of
stapling.
. For
Pr
The
outcome
thrombosis
Ig
. Treatment
mize
pneumonIa.
problems.
the
consideration
technique
puts
.
venous
Treatment
be
lor
these
and
or the
effect
et
ut
m
reconstruc-
that
b
.
as young
as 9 years of age
pediatricians
are unfamiliar
management
be
overgrowth.
growth
.
available.
of
.
from
.
with
Proteus
(Newman
asymptomatic
"
ns
anse
of
lungs
.
tomography
may
more
if
be
the
.
fil
deep
tarn
.
of
y.
Computed
or
can
.
Icatlons
.
manIfestatIon
.
es
0
h
lograp
tion
.
.
appen
d
ua
d
ra
d
an
I
pulmonary
degeneration
..
comp
-
al
o
ua
I
ary
.
A
IVI
pnmary
cystIc
I
children
as most
Evaluation
.
Th IS.
d. .d
d
econ
d
I
bol .
d
h
b
.
d.
pre Isposes to eep venous t rom
OSIS an pu monary
em
Ism
SI
.
k
I
2000)
Th .
I ..
h
d .
( avotlne
et a .,
.
IS comp Icatlon
as occurre
m
subsequent
do
Isease.
ung
The
..
IS
.
S
Isease.
.
scolioSIs.
1994)
.
monary
..
syndrome
skele-
the
n
from
ave
d
pu
.
h
axIal
ary
y
ua s a. so
The
secon
near
I
IVI
..
rapIdly
.
.
.
lew
cases,
muscles.
.
to
I
"
and
asymmetnc
.
leadmg
..
restnctlve
A
o
tendons
manIfest
0
bodIes
l
I Ity.
some
ntra
also
o
I
m
I
can
mo
.
an,
th
ton
b
0
Jomt
0
d
rapl
e
ectopIc
f
oss
.
'
. d
to
compu
ete
o
mg
es
.
d
ea
.
I
c
I
comp
I
y
I
d
WI
common
d . .d
y
I
most
.
..
...
cartllagmoustIssuessurroundmgthe Jomts(kneesand dIgIts
or
or valgus
(see
section).
.
varus,
manifestation
plate
to
raise
anticoagulation
pnmary
severe
common
growth
leading
Respiratory
prophylactic
operat-
should
h
Another
growth,
proximal
of
prolonged
immobility
ave
of bowing,
the knees.
epiphyseal
of
consideration
requires
omograp
development
rates
the
that
convalescent
can
of a primary
different
is in the
or
d
phenomenon
this
most
of the
time
rome
of
One
room
syn
bone.
procedure
ing
Pr
sides
a single
surgical
is the
oteus
two
markedly
within
. Any
asymme-
structures
h
where
have
simple
Ion
tibia
manifestations
than
of bony
WIt
overgrowth
common
troubling
of a pair
s
asymmetric
More
of one member
ua
underdevelopment.
try of the length
IVI
muscle
Individuals
ing
may
tissue,
with
chronic
be considered
although
there
ventilation-perfusion
for
resection
is no experience
mismatch-
of dysfunctional
with
this
lung
treatment.
,cl
~;
"
. The acuteonsetof symptomsassociated
with deep
.
venous thrombosis and pulmonary embolism should be
promptly and aggressively treated with anticoagulation.
Considerationmay be given to focal treatmentwith thrombolytic agents,although their use in Proteussyndromehas
I
j
to.
,
I
-
.
;,.,;
! ,
i'
jli ,,':
,
c.
t%' ',,\.
0.
~
.
l
'
j,
tI
'
'(.1i
not beendemonstrated
to be safeor effective.
Following recovery from an acute pulmonary embolism,
anticoagulation
therapymustbeindivi~ualized,
asthere~re
'"
c
!-'
.
.
.
.
syndrome should be undertaken with a full appreciation
of the peculiar nature of the disorder and the possibility of
.
rarelesion~or abnormala.natomy.
~Ithough .It has been claImed that surgery on. abnormal
tIssueactIvatesor .aggravates
the ove~growth.m
Proteus
syndrome, sup~ortmg ~ata. are I~cking. ~I~ concern
should not weigh heavily m making a decIsion about
...
Chronic antIcoagulatIonand ProphylactIc antIcoagulatIon
.
are not routInely recommended.The ]~ng-term nsks and
benefits are unknown and must be weighed carefully for
each individual. Some individuals may benefit from such
therapy, but the risks of anticoagulationmay be high in
children and in personswith vascularmalformations.
operatingon a child with an acutelesion,especiallyan
acute abdomen.
Neurologic
One of the most common centra] nervous systemabnormalities
is hemimega]encephaly (en]argement of one side of the brain),
which is presumably caused by the same mechanism as the
Gastrointestinal
I
.
. SurgIcal treatment of gastroIntestInallesIons m Proteus
no data to allow generalrecommendatIonsfor the duratIon
of anticoagulation.
;.
,
Treatment
Severa]individuals have had gastrointestinalcomplications
overgrowthsin other tissuesand organs.Severa]individuals with
Proteussyndromehave been found to have neuronal migration
abnormalities,althoughthe frequencyand severity of this
f'"'-' ,
including recta] pro]apse.and gastric outlet ~bs~.ction from
problem are not well characterized.Seizuresare uncommonbut,
f
I
.t
hamartomatousgut wall tIssue,and numerousIndiVIdualshave
intraabdominal lipomatous infiltration (Lublin et a]., 2002).
There may be significant gastrointestinal blood loss from
hemorrhagicbowel masses.It might be expectedthat individuals
with Proteussyndro~e would be at risk for intussusce~tionor
acute bowel obstructIon secondaryto hamartomasor lIpomas.
when present, are often associatedwith hemimega]encephaly
or other centra] nervous system abnormalities, A potentially
problematic lesion is hyperostosis of the skull, which is
uncommon but can exceed 5 cm in thickness in severecases.
A]though this lesion appears to have the potentia] to cause
centra] nervous system symptoms by cortical compressionor
I
A]thoughonly a singlecasehasbeendocumented
in the past
distortion,this is not a commonproblem,as most affected
(Costaet a]., 1985), it is important to be aware of this potential
complication.
individuals are asymptomaticfrom a neurologic perspective.
t;
~~
f
I
Eva]uation
Eva]uation
,
. Rectal prolapseshould be evaluatedby standardimaging
.
.
.
modalities such as barium enema and flexible or rigid
endoscopy.This manifestation has been associatedwith
hamartomasof the bowel wall, which should be readily
identifiable with thesetechniques.
Contrast imaging studies such as upper gastrointestinal
series with small-bowel follow through or oral contrast
computedtomographymay be useful if intussusceptionor
acute bowel obstruction is suspected.
Gastrointestinal blood loss should be excluded in any
individual with anemia or melena using standard clinical techniques.
As in all cases of bowel obstruction, regardless of
cause, urgent diagnosis and treatment are critical to
avoid complications, In Proteus syndrome, the urgency
of relieving obstruction and avoiding bowel perforation
must be balanced by an appreciation of the difficulties
inherent in operatingon individuals who have multisystem
diseaseand who may have markedly abnormal anatomy
or lesionsthat are difficult to resect (e,g., lymphatic
vascular malformations).Careful thought should be given
to balancing the urgency to operate with the benefits of
obtaining a thorough preoperativeevaluation by detailed
imaging studiesand consultations.
. A full developmental and neurologic evaluation should
be carried out at diagnosis and repeated periodically
until puberty,
. Computedtomographyor magnetic resonanceimaging of
the brain are effective modalities for imaging. Computed
tomography is preferable for imaging the skull and magnetic resonanceimaging preferable for the brain. Indications for cranial imaging include significant skull asymmetry or focal overgrowth, neurologic symptoms including
seizures or focal neurologic signs on examination, and
developmentaldelay or mental retardation.
. E]ectroencephalogramis useful for the characterizationof
potential seizures.
Treatment
. ,.
,.
Seve~aImdlvId~als ~ho h~ve su~nsmg degreesof hyperOStOSIS
and CO~ICal
dIstortIon or ~Isplaceme~thave shown
no apPa.rentsIgns ~f neurologIc dysfunctIon .(persona]
observatIon). For thIS reason, s~ull ,hyperost~sI.S
.shou]d
generally m~aged.by observatI?nIf and untIl It ISclear
that the lesIon IS causIngneurologIc symptoms,
There is no treatmentfor hemimegalencephaly.
. Seizuresshould be treatedsymptomatically,as one would
in the generalpopulation,
.
.
~
'1:1'1
t'KU I ~u~
~ I l"UJ'-VIVIJ:;
. The only known treatmentfor extrinsic compressionof the
Ophthalmology
. .
There have been several reports Imkmg Proteus syndrome to
disorders of the globe and surrounding tissues (Bouzas et al.,
1993).Epibulbar benign tumors are probably the most common
manifestationin the globe, whereasthe most common periorbital
lesions are hyperostosesand connectivetissuenevi. Lesions can
occur anywhere in the neuro-optic pathway including physical
impingementof the periorbital tissues,compressionof the globe
by tumors, epibulbar dermoids that expand over the cornea,
retinal lesions,compressionof the optic nerve or tract by tumors,
or lesions of the occipital cortex.
Evaluation
.
Thorough evaluation of the optic axis is recommendedfor
any individual with Proteussyndrome and an ophthalmologic complaint.
.
Common
rect
airway from hyperostosesof the vertebra is to bypassthe
obstruction with a tracheostomy.
Genitourinary
Ovarian cystadenomasare common in Proteus syndrome and
should be excised when symptomatic (Gordon et al., 1995).
Other hyperplastic lesions of the genital tract have also been
encountered.Cystic lesions of the epidydymis are common
in males, but they appear to be benign. Inguinal hernias are
common in Proteussyndromeand may be isolatedor associated
with lipomas of the inguinal canal.
Evaluation
.
modalities
for
ophthalmoscopy,
evaluation
include
direct
electroretinograms,
and indi-
magnetic
reso-
.
.
nance Imagmg, or computed tomography of the eye and
surroundingstructures.
Tre t
t
a men
. Surgical treatment of lesions that impinge on the optical
axis is useful and appropriate. Due to the progressive
nature of the disorder, such proceduresmust be planned
carefully because some procedures must be performed
repeatedlydue to regrowth of a lesion such as periorbital
hyperostosis.
When
be
ma
abdominal
or pelvic
d fi
e
.
.
or ovarian
h'
pain
.
IS present,
cys t a d enomas
a search
should
or 0 th er t umors,
even
m young c Ild ren.
.
.,
.
. Ultrasound IS the preferred pnmary Imagmg tool for the
pelvic lesions of Proteus syndrome. Magnetic resonance
imaging and computed tomographyare also useful.
. Inguinal hernias should be evaluated by ultrasound and
exploration.
Treatment
.
Surgical excision of ovarian masses is the recommendedtreatment.
. We recommendmonitoring epididymal cystic massesand
Otolaryngology
Several affected
individuals have .had. soft tissue overgrowth
.
.
of
the
airway
that
obstructs
respiration.
Hyperplasia
of
..
.
tonsils
and
E t . .
I
.
the
x nnslc
b
adenoids
compressIon
h
t
.
may
0
be
f th
common
t .
and
can
be
II f th
e pos enor wa
0
f th
rt b I bod '
h
asymmetnc.
h
e p arynx
be
an
.
operating only when they appearto be expansile or have
other characteristicsof malignancy.
Repalr . 0 f mguma
. . I hernlas. s h ou Id b e accompame . d b y
I d I.
I
h .
d"
Issectlon
to
exc
u
e
lpomas
.
d
or
ymp
atlc
vascu
I ar
.
malformations. The latter may be difficult to resect, but
.
resectIon
arynx y yperososes0 e ve e ra
les as en seenm
I . d. .d I H
. f h
I d.
1
severa m IVI ua s. yperostosls0 t e externa au ItOry cana
can lead to complete occlusion of the canal and conductive
hearing loss.
..
IS nonetheless
Important
.
may predIsposeto recurrence.
because
these
.
anomalIes
Dermatologic
Evaluation
. Standardmodalities of polysornnography,flexible endoscopy, pulmonary function tests, and imaging studies
including computedtomographyand virtual bronchoscopy
may be used when upper airway compressionor obstruction is suspected.
.
The external auditory canalsshould be examinedperiodically to excludehyperostosisof the externalauditory canal.
Tre tm t
a en
Nearly all individuals with Proteus syndrome have some
dermatologic manife~tations ~for review, see .Cohen et a~.
(2002d)~.~ese can ~ncludelinear verrucous epIdermal ~evI,
connectl:e tl~sue nevI?and cuta~eousvascular malformatIons.
Connec.tlvetI~sue~evl are es~clally tr~ublesomeas they can
causedIfficulties wIth shoefit, blomechanlcalchanges,and odor.
Evaluation
. An evaluation by a dermatologist is recommendedfor
all individuals with a confirmed or suspecteddiagnosis
. Hyperostoses of the external auditory canal should
.
be surgically reduced when they impair hearing or
causediscomfort.
Intrinsic lesionsof the airway such as hyperplasticnodules
that obstruct respiration should be excised.
.
of Proteus syndrome. Ongoing care by a dermatologist
(or plastic surgeon) may be necessary for those with
symptomatic vascular malformations.
Acutely malodorous connective tissue nevi should be
cultured for bacterial and fungal growth.
IV~'lrc;)
Treatment
.
'"
.
.
. Skin careshouldconsIstof bnef bathm~wIth ml~dnonsoap
cleansersand thorough but gentle dryIng (a hair dryer on
low heat works well).
Moisturizers with minima] fragrances,colors, etc. may be
d l be all
use I r y.
. MalodQrousconnective tissue nevi need to be cleaned
thoroughly but gently, using cotton swabs to cleanse
the sulci.
. Aluminum chloride solution may be applied to the feet to
reduceperspiration.
. Infections should be treated with appropriate topical or
systemic antimicrobials.
Debu]king procedures to treat foot overgrowth have
frequent complications,especially if they involve the so]e.
of the foot (usually for a connectivetissue nevus).
.
'
.
Cardiovascular
A]though cardiac lesions are rare in Proteussyndrome,vascular
manifestationsareessentiallyuniversal.Theserangefrom trivia]
cutaneouscapillary vascular malformations to gigantic mixed
lesionswith capillary, venous,and lymphatic components.Some
are also mixed with lipomatous tissue. High-flow or arteria]
vascularmalformationsare not common in Proteussyndrome.
Evaluation
. of vascular malformatIons
.
Imagmg
other than pure cap-
.
illary vascular malformations (which do not require
imaging) can be accomplished with magnetic resonance
IftllVI';)
ftJ'U
MftJ'ftUClVICI'l
..;,;,
the disparatelocation of those tumors make screeningdifficult,
and the efficacy of suchscreeningis unknown. Insteadof routine
screening,prompt and vigorous evaluationof signsor symptoms
of malignancy is recommended.
E vaIuat Ion
"
. In lieu of screening,affected individuals with any signs
and symptoms of a malignancy should be promptly and
thoroughly evaluated for a tumor. Because of the wide
variety of tumors, specific recommendationscannot be
made, and physicians instead must use clinical judgment
to prompt such evaluations.
Treatment
.
..
. AggressIvetreatment of tumors (surgery, IrradIatIon, and
chemotherapy)is indicated, as there are no data to suggest
that tumors in Proteus syndrome have a worse prognosis
than in the genera]population.
Endocrine
Little is known about the involvement of the endocrine system
in Proteussyndrome.One personhas been reported with goiter
(Vi]joenet al., 1987),although it is not known if this is causally
related to the underlying diagnosisof Proteussyndrome.
Evaluation
. A suspicion of thyroid
function tests.
disease should prompt thyroid
imaging, ultrasound,and, in select cases,invasive studies
such as ]ymphangiography.
Treatment
.
Treatmentof the most commonlesion of Proteussyndrome
(the mixed lymphatic-venous-lipomatousmalformation)
should be reserved for caseswhere the lesion interferes
with function or has major cosmetic or disfigurement
implications.
. Surgery is the preferred treatment for these lesions.
However, it should be borne in mind that dissection
of malformations that include lymphatics may be chal]enging and postoperative weeping from the margins
.
IS common.
TreatmeQt
. Under- or overactivity should be treated in a standard
manner.
Dental
Dental abnormalities are common in Proteus syndrome due to
asymmetric overgrowth of the mandible and maxilla. Some
individuals have enlargedor malformed teeth.
.
Evaluation
. Laser treatment is unlikely to be beneficial for these
. Physical and radiographic examination by an orthodontist
lesions,although hemangiomasthat may occur in Proteus
syndromemay respondto laser treatment.
may be useful when it is clear that dental malalignment
is developing.
Neoplasia
Treatment
It is recognized that individuals with Proteus syndrome have
experienceda number of unusualtumors and that the rarity of
these tumors in the general population strongly suggests(but
doesnot prove) that tumor predispositionis part of the disorder
(Cohenet al., 2002d). However, the wide variety of tumors and
. Orthodontic treatment may be appropriate for some
individuals, although there is little experiencewith such
treatments(Becktor et al., 2002). The treatmentof dental
malocclusion in a progressively disfiguring condition can
be challenging.
ACKNOWLEDGMENTS
.--
the diagnosis of
This chapter is dedicatedto the memory of Alex Hoag, Kyle
Dullenkopf, and SeanEasly, three individuals who participated
in the National Institutes of Health study. I hope that the sorrow of their families can in some small way be mitigated by
the knowledge that their child's participation in the study has
directly and significantly benefited current and future affected
individuals with this disorder. I am indebted to them and to
all of the other individuals and families who have participated.
Early drafts of this chapterwere reviewedby M. Michael Cohen,
Jr., ThomasDarling, DouglasSchwartzentruber,Laura Tosi, and
Joyce Turner. The author gratefully acknowled es their critical
.
. solely responsible
.
Input,
but the author IS
for ~
ItS content. The
.
opinions expressedin this chapter
are thoseof. the author and are
not to be construed
official
recommendatIons
by the De partment of Health andas
Human
Services,
the National
Institutes of
Health,
nor any other institution
to which
he is affiliated.
Proteus syndrome. Ophthalmology 100:
334-338.
CohenMM Jr (1987)Theelephantmandid not haveneurofibromatosis.
ProcGreenwood
GenetCetr 6:]87-]92.
CohenMM Jr, HaydenPW (1979)A newlyrecognized
hamartomatous
syndrome.
In: Birth DefectsOriginalArticleSeries:Marchof Dimes,
Vol. XV O'Donnell11, Hall BD, eds., Alan R. Liss, New York,
pp.29]-296.
CohenMM Jr, Neri G, Weksberg
R (2002a)Hernihyperplasia
(hemihypertrophy):In: Overgrowth
Syndromes.
NewYork:OxfordUniversity
Press,pp. 32-37..
.
CohenMM Jr, Nen G, Weksberg
R (2002b)Kllppel-Trenaunay
syndrome, Perkes Weber syndrome,and Sturge-We~r s.yndrome:
In:
Overgrowth
pp. ]]]
-] 24. Syndromes. New York: Oxford UnIversity Press'
C 0 h en MM
Jr,
N en. G ,
.' Ov ergrow th
In
pp.
125-]29.
Wi e k sberg R
Syn d rames. N ew
CohenMM Jr, Nen,. G
In: Overgrowth
(2002c)
v.or: k
Wi ek sb erg R
MaffuccI .
syndrome:
O x,or
r d U DIversity
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.
Pt ess
'
(2002d)
Proteus
Syndromes. New York: Oxford
syndrome:
University
Press,
RESOURCES
pp.75-]]0.
Costa T, Fitch N, Azouz EM (]985) Proteus syndrome: Report of two
cases with pelvic lipomatosis. Pediatrics 76:984-989.
Proteus Syndrome
Foundation
6235 Whetstone Dr.
Gordon PL, Wilroy RS, Lasater OE, Cohen MM Jr (1995) Neop]asms
in Proteus syndrome. Am J Med Genet 57:74-78.
Colorado Springs, CO 80918
Telephone: 719-264-8445
Contact by email: [email protected]
Happle R (1987) Lethal genes surviving by mosaicism: A possible
explanation for sporadic birth defects involving the skin. JAm Acad
Dennatol ]6:899-906.
Web
Lublin
site:
http://www.proteus-syndrome.org/
M,
Newman
Proteus
T
S
d
F
d f
Why.n rom
ode oun a Ion,
racey
-Neal
46
Th C Itewo
ft
H . e rE
o S
TN3
U.t
d K"
rn e
d
109 om
asnngs,
Telephone:
ast ussex
4 3HH UK
01424433708
.
Conta~t by Emall: [email protected]
Web sIte: http://www.proteus-syndrome.org.uk/
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