KLIPPEL-TRENAUNAY SYNDROME
"Moodie, D., Driscoll, D., Salvatore, D., Peripheral Vascular Disease in
Children, In:Young, J., Olin, J., Bartholomew, J., Peripheral Vascular
Diseases, 2nd Edition, Mosby Yearbook Publishers, 1996, p541--552."
Klippel-Trenaunay Syndrome (KTS) consists
of a triad of cutaneous capillary hemangioma, bone and soft tissue hypertrophy, and venous
varicosities (1). The etiology of KTS is unknown but some authors have
suggested that it results from a mesodermal abnormality that occurs during
fetal development leading to the maintenance of microscopic arteriovenous
communications in the limb bud (2). Most commonly it is a sporadic event.
Although there have been a few cases reported in which more than one family
member supposedly had the syndrome other authors suggest that this may
have not been the case (3,4). It has been suggested that KTS could result
from the action of a mosaic gene abnormality that is lethal to the gamete
when present in all cells of the embryo (5). We have seen two patients with
intriguing associations. One patient has prolonged QT interval syndrome and
the other a translocation of chromosome 8 and 14. Whether these are
coincidental abnormalities or provide a clue to the location of a causative
gene is unknown
KTS should be distinguished from Parks-Weber
Syndrome. In Parks-Weber Syndrome there are clinically apparent and important arteriovenous
fistulae where as in KTS any arteriovenous fistulae that exist are microscopic
in size and unassociated with the typical clinical findings of arteriovenous
fistulae. The natural history of these syndromes are different. For example,
because patients with KTS do not have arteriovenous fistulae, high output
cardiac failure does not occur.
The manifestations of KTS are variable (fig 1-3). In a study of 144patients evaluated at the Mayo clinic (6), 132 had lower extremity
involvement, 37 had upper extremity involvement, 21 had pelvic and
abdominal involvement, 25 had involvement of the thorax and 7 had head
and neck involvement(Table 1). In the same study 110(76%) had
varicosities, 137(95%) had hemangiomas, and 134 (93%) had limb hypertrophy...
With occasional exceptions, the appearance of the baby shortly after birth will define the ultimate appearance of the child and young adult. The
exceptions to this include: a) the cutaneous capillary hemangioma (port wine
stain) may become lighter or darker; b) dark small nodular escrescence may
develop on the skin; c) as growth occurs the limb length discrepancy may
increase; d) some of the apparent increased mass may regress as baby fat
regresses; e) subcutaneous masses may appear; and f) venous varicosities and,
possibly dependent lymphedema will become more prominent with time.
Parents should be reassured, however, that unaffected extremities and organs
will not become affected the future.
CLINICAL MANIFESTATIONS
VENOUS VARICOSITIES AND MALFORMATIONS
The venous involvement in KTS can range from subtle abnormalities to
massive varicosities and absence of important deep venous structures. The
venous abnormalities usually involve the affected extremity and are apparent
as superficial varicose veins. Dilation of superficial varicose veins may be
unapparent in infancy but become apparent with increasing age. Not all
patients with KTS have superficial venous varicosities.
In addition to superficial varicosities, many patients have abnormalities of the deep venous system of the extremity. The deep venous
abnormalities can include dilation of the deep veins, absent venous valves,
hypoplasia of the veins, and complete absence of the deep venous system. It
is critically important to ascertain the status of the deep venous system if
one is considering removal of superficial varicosities since the superficial
venous system cannot be removed if the deep venous system is inadequate to
provide venous drainage of the extremity. Because of the venous
malformations some patients with KTS can develop thrombophlebitis.
Venous varicosities also can involve intraabdominal and intrapelvic organs. In Gloviczki's series, 10% of the patients manifest rectal bleeding and
3% had hematuria (6). Others have reported that 20% of their patients have
had rectal bleeding, 10% had hematuria and 33% had evidence of abnormal
intrapelvic veins(7). Venous or arteriovenous malformations have been
described in other locations in rare patients with KTS. These include bone,
spinal and intracranial locations.
In addition to the complete absence of the deep venous system of an extremity, absence of the inferior vena cava has been reported (8) and we
have observed absence of the internal jugular veins.
LYMPHATIC ABNORMALITIES
Many patients with KTS have abnormalities of the lymphatic system.
Since in no series of patients have these abnormalities been looked for in a
systematic fashion the incidence of lymphatic abnormalities is unknown. In
one series it was reported that 20% of patients have cutaneous vesicles which
leak lymph. However in our experience exudation of lymph is less common.
It frequently is unclear if the edema of an affected dependent extremity is a
result of venous insufficiency, abnormal lymphatic drainage or a
combination of the two. Some patients do develop soft tissue masses that are
reminiscent of cystic hygromas. These masses can occur on an effected
extremity or over the trunk, head, or neck
CAPILLARY HEMANGIOMAS AND OTHER CUTANEOUS LESIONS
There is a broad spectrum of cutaneous manifestations of KTS. Most
commonly there is a port wine stain which can be very light in color to deep
maroon. This lesion can be flat or elevated. The integrity of the skin over
the hemangioma may be excellent or poor. In some cases the capillary
hemangioma is raised considerably from the surface and may be verrucous
in nature. Some areas of the malformation may be prone to skin breakdown,
bleeding, and infection. In general the intensity of the color of the
hemangioma lessens as the child ages. However, some patients develop dark
(deep blue to black) 1-2 mm nodules on top of the hemangioma or, at times,
over seemingly unaffected portions of skin. These can be quite friable and
prone to spontaneous bleeding or bleeding after minor trauma. Cutaneous or
subcutaneous cavernous hemangiomas occur in 40% of patients(1). These
can produce a spongy feel to the skin and frequently are associated with lymphangiomas
Other cutaneous manifestations of KTS include phlebectasias,
hyperhidrosis, hyperthermia and hypertrichosis. Patients with KTS are prone
to cellulitis. It is unclear if these episodes are always secondary to bacterial
infection or to a local inflammatory response in response to pockets of lymph accumulation.
BONE AND SOFT TISSUE HYPERTROPHY
In Gloviczki's series, 95 of 144 patients had one extremity longer than
the other and 100 of 144 patients had a swollen or circumferentially
enlarged extremity (6). Most commonly a lower extremity is affected but in a
forth of the patients an upper extremity is involved. Usually the longer,
bigger extremity is also the extremity that exhibits the skin and vascular
changes but occasionally the extremity with skin and vascular involvement is
the shorter or smaller extremity. The bony hypertrophy may effect all the
bones in an extremity or be limited to one or two bones. Some patients may
have macrodactaly.
In addition to bony hypertrophy, many patients have soft tissue
hypertrophy. This can be quite limited; for example to a localized mass on
the back or chest, or can be quite widespread; for example involving an entire
arm or leg. The soft tissue hypertrophy is usually fatty and contains
variable amounts of venous structures.
Other limb findings that have been described in KTS include syndactyly, clinodactyly, polydactyly, split hand deformity, metatarsal and
phalangeal agenesis, osteolysis, congenital dislocation of the hip, and
peripheral neuropathy (1).
HEAD, CENTRAL NERVOUS SYSTEM AND EYE INVOLVEMENT
Patients with KTS can have macrocephaly and, less frequently,
microcephaly. Intracranial angiomas, arteriovenous malformations, and
intraspinal angiomas have been described. More than 40 cases of KTS have
been described in association with Sturge-Weber syndrome(9).
Ophthalmologic findings reported in association with KTS include:
conjunctival telangiectasia, retinal varicosities, choroidal angioma, glaucoma,
coloboma iridis, heterochromia iridis, intraorbital varix, and enophthalmos(1,10).
ADDITIONAL FINDINGS AND PROBLEMS
COAGULOPATHY
Some patients with KTS exhibit evidence of an intravascular
coagulopathy. This usually is mild but in some patients can be relatively
severe and result in bleeding after minor trauma or major bleeding associated
with surgical procedures. This coagulopathy probably represents a form of
Kasabach-Merritt syndrome and may be manifest by thrombocytopenia,
reduced fibrinogen, and the presence of fibrin split products(11). It is prudent
to assess patients' coagulation status prior to planned surgical procedures
PULMONARY EMBOLI
There have been several instances of fatal and nonfatal pulmonary
emboli in patients with KTS. It is unclear at this point, which patients with
KTS are at risk for this complication. Some episodes have been associated
with bed rest following a surgical procedure. One author has recommended
that patients with KTS receive anticoagulation therapy when admitted to a
hospital or, long-term anticoagulation therapy for those who have had a
documented thrombotic event (7).
SYNCOPE
Patients with large venous capacitance in the legs can be prone to lightheadedness and syncope when standing.
MANAGEMENT ISSUES
COMPRESSION THERAPY
Most patients with lower extremity involvement experience some
degree of lower extremity edema. This usually is not manifest until after the
child begins walking and gravitational forces become a factor. It is
important to remember that an extremity may be enlarged because of
increased bony and soft tissue mass as well as edema. Compression of the
extremity with elastic support will acutely lessen the edema but there is no
data that chronic compressive therapy will result ultimately in less bony or
soft tissue mass. Also, compression will not affect the ultimate length of the
leg. Patients with a major component of lymphedema and those with severe
venous insufficiency seem to derive the most benefit from chronic
compressive therapy. Compressive therapy also should be used for patients
with edema and recurrent cellulitis. It may reduce the frequency of episodes
of cellulitis. Compression may or may not be useful for patients with friable
skin lesions that tend to bleed. In some cases the compression garment will
protect the sites and lessen the bleeding but in other cases, the garment may
irritate the skin and increase the bleeding episodes. Compression therapy
may slow the progression of lower extremity varicose veins. Compression
therapy also is useful for patients with upper extremity involvement who
have problems with edema.
We do not favor compression therapy for young children. In general
young children will not tolerate wearing a compression garment, they will
rapidly outgrow the garment and the parents will just become frustrated.
In general a compression garment should extend from the tip of the toes to well above the involved site.
REMOVAL OF VARICOSE VEINS
Unsightly or painful superficial varicose veins can be removed in
selected patients. It is critical that the status and integrity of the deep venous
system be established before superficial veins are removed. If the deep venous
system is inadequate, the superficial veins should not be removed.
EPIPHYSIODESIS
Epiphysiodeses are done to assure relatively equal leg lengths at full
maturation. This procedure is necessary only if the projected limb length
discrepancy exceeds 2.0 cm. It is important that this operation be done at
the appropriate time. Parents need to be reassured that the operation need
not be done during early childhood. Most epiphysiodeses are done between
10 and 14 years of age. For limb length discrepancies less that 2.0 cm, shoe
lifts can be uses.
Intentional destruction of growth plates also can be done to control excessive growth of digits.
AMPUTATION AND RAY RESECTION
Amputation of digits, and portions of an extremity should only be
undertaken to improve function of the extremity and to manage otherwise
uncontrollable infection or bleeding. Many of these children manage to
obtain excellent function from an extremity that is quite enlarged and
malformed. An important dictum in managing these patients is to operate
to improve function rather than for cosmesis and never to sacrifice function
to obtain improved cosmesis.
Patients with discordant foot size may have difficulty fitting the foot
into a shoe. We have found that ray resection is a very satisfactory
procedure to reduce excessive foot width
DEBULKING PROCEDURES
The potential complications of debulking procedures should be
considered carefully before undertaking this type of treatment. The potential
drawbacks of debulking procedures include: 1. the bulk can return, 2. the
bulk is traded for a scar, 3. the debulking procedure may interrupt the
venous and lymphatic drainage in an extremity with compromised drainage
to begin with , 4. wound infection, and 5. poor skin healing with resultant
chronic lymphatic ooze. In general the more proximal on a extremity a
debulking procedure is considered , the greater are the risks for interfering
with venous and lymphatic drainage. Conversely, debulking procedures on
digits, the hands, and feet are tolerated better than those on more proximal
locations. As noted above one must always consider function above form
when contemplating surgical procedures for patients with KTS.
LASER THERAPY
Laser therapy can be used to reduce the discoloration of capillary
hemangiomas. Before embarking on this treatment it must be remembered
that the procedure is painful. Also frequently it is the parent that opts to
have the lesion treated but it is the child who must undergo the discomfort.
It may preferable to wait until the child is old enough to participate in the
decision to have this treatment.
ANTIBIOTICS
Antibiotics are used to treat cellulitis. For patients who have recurrent
cellulitis, maintaining the patient on prophylactic antibiotics may be
helpful.
GASTROINTESTINAL BLEEDING
Gastrointestinal bleeding can occur in patients with perirectal or
pericolonic varicose veins. Bleeding can range from minimal to life
threatening. As with all cases of GI bleeding the source of bleeding needs to
be defined. If the bleeding is secondary to varicose veins and is not life
threatening, treatment should consist of stool softeners and iron replacement.
Surgery may be necessary to deal with massive recurrent bleeding.
REFERENCES
1. STICKLER, G. KLIPPEL-TRENAUNAY SYNDROME, IN NEUROCUTANEOUS
DISEASES, A PRACTICAL APPROACH GOMEZ, M.,ED ,
BUTTERWORTHS, BOSTON, 1987.
2. BASKERVILLE, P., ACKROYD, J., BROWSE, N., THE ETIOLOGY OF THE KLIPPEL-
TRENAUNAY SYNDROME, ANNALS OF SURGERY,202:624-627,1985
3. AELVOET,G, JORENS, P., ROELEN, L., GENETIC ASPECTS OF THE KLIPPELL-
TRENAUNAY SYNDROME, BRITISH JOURNAL OF DERMATOLOGY, 126:603-
607,1992
4. JORGENSON, R., DARBY, B., PATTERSON, R., TRIMMER,K., PRENATAL
DIAGNOSIS OF THE KLIPPEL-TRENAUNAY-WEBER SYNDROME, PRENATAL
DIAGNOSIS, 14:989-992,1994
5. HAPPLE, R., LETHAL HENES SURVIVING BY MOSAICISM: A POSSIBLE
EXPLANATION FOR SPORADIC BIRTH DEFECTS INVOLVING THE SKIN, JOURNAL
OF THE AMERICAN ACADEMY OF DERMATOLOGY, 16:899- 906,1987.
6. GLOVICZKI, P., STANSON, A., STICKLER, G., JOHNSON, C., TOOMEY, B.,
MELAND, N., ROOKE, T., CHERRY, K., KLIPPEL-TRENAUNAY SYNDROME:
THE RISKS AND BENEFITS OF VASCULAR INTERVENTIONS, SURGERY,
110:469-479.
7. KLIPPEL-TRENAUNAY SYNDROME IN DISEASES OF THE VEINS, PATHOLOGY,
DIAGNOSIS AND TREATMENT, BROWSE, N., BURNAND, K., THOMAS, M.,
ED, EDWARD ARNOLD, BALTIMORE, 1988
8. STEWART, G., FARMER,G., STURGE-WEBER AND KLIPPEL TRENAUNAY
SYNDROMES WITH ABSENCE OF INFERIOR VENA CAVA, ARCH DISEASE
CHILDHOOD(ENGLAND) 65:546-547, 1990.
9. DEUTSCH, J., WEISSENBACHER, G., ET AL, COMBINATION OF THE SYNDROME
OF STURGE-WEBER AND THE SYNDROME OF KLIPPELL-TRENAUNAY, KLIN
PAEDIATR, 188:464-471,1976.
10. BROD, R., SHIELDS, J., SHIELDS, C., OBERKIRCHER, O., SABOL, L., UNUSUAL
RETINAL AND RENAL VASCULAR LESIONS IN THE KLIPPEL-TRENAUNAY-
WEBER SYNDROME, RETINA, 12:355-358, 1992
11. D'AMICO, J., HOFFMAN, GL., DYMENT, PL., KLIPPEL-TRENAUNAY
COAGULATION AND MASSIVE OSTEOLYSIS, CLEVELAND CLINIC
QUARTERLY, 44:181-188, 1977
Table 1. Anatomic involvement in 144 patients with KTS
(adapted from Gloviczki et al, Ref #4)
Patients
Location n %
Lower extremity 132 92
Unilateral 103 72
Right 53 37
Left 50 35
Bilateral 29 21
Lower extremity only 106 74
Lower and upper extremities 26 18
Upper extremity 37 26
Upper extremity only 11 8
Pelvis or abdomen 21 15
Thorax 25 17
Head and neck 7 5
Table 2. Signs and symptoms in 144 patients with KTS
(adapted from Gloviczki et al, Ref #4)
Patients
Location n %
Varicosity 110 76
Atypical (lateral) 66 46
Suprapubic 2 1
Usual distribution 46 32
Hemangioma 137 95
Capillary 89 62
Lymphangioma 12 8
Limb Hypertrophy 134 93
Longer extremity 96 66
Swollen extremity 100 69
Pain 46 32
Cosmetic problem only 35 24
Bleeding from hemangioma 28 19
Thrombophlebitis 18 12
Cellulitis 13 9
Ulcers 11 8
Verrucae 9 6
Rectal Bleeding 14 10
Macroscopic hematuria 4 3
Paraparesis 4 3
Deep venous thrombosis 6 4
Pulmonary embolization 4 3
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