Genetics of Klippel-Trenaunay-Weber

Syndrome
Background
Klippel-Trenaunay syndrome (KTS) is defined by the presence of a combined
vascular malformation of the capillaries, veins, and lymphatics; congenital venous
abnormalities; and limb hypertrophy.

Isolated reports of cases of limb hypertrophy were published in the 19th century, but the
combination of a congenital vascular nevus of an extremity, venous varices on the affected side,
and limb hypertrophy was not recognized as a consistent and unique syndrome until a 1900
article by Klippel and Trenaunay. A few years later, Frederick Parkes Weber published a report of
similar patients in whom enlarged arteries and veins, rather than just venous abnormalities, were
present. Patients with limb hypertrophy, cutaneous capillary malformations, and venous and
arterial malformations sometimes receive a diagnosis of Klippel-Trenaunay-Weber syndrome.
Parkes Weber syndrome (PWS) is closely associated with and similar to Klippel-Trenaunay
syndrome, except that an arteriovenous malformation (AVM) occurs in association with a
cutaneous capillary malformation and skeletal or soft tissue hypertrophy.
Sturge-Weber syndrome is defined by the presence of a meningeal angioma, cutaneous capillary
malformation of the face, and glaucoma; this is often accompanied by hemiparesis and
hemiatrophy contralateral to the meningeal angioma.[1]
Although each of these syndromes is distinct, overlap does rarely occur. This article focuses on
Klippel-Trenaunay syndrome and Parkes Weber syndrome.

Pathophysiology
Klippel-Trenaunay syndrome is characterized by a combined type of vascular malformation of
the skin, abnormalities of the venous and lymphatic systems, and limb enlargement. Lymphatic
vesicles appear on the surface of the capillary malformation; the lymph may also ooze at times.
In addition, the abnormal venous system may produce protrusions of veins on the surface of the
skin, called venous flares. Varicose veins appear in early childhood, and lateral venous anomalies
are seen in 80% of cases.

Limb hypertrophy is due to the presence of vascular, venous, and lymphatic abnormalities but
also to the hypertrophy of soft tissue and bone. The hypertrophy is often asymmetrical and often
involves the digits. Ninety-five percent of cases involve the lower extremity.
Because the vascular abnormalities in Klippel-Trenaunay syndrome are not associated with
arterial malformations, flow through the malformations is slow. The combination of low-flow
vascular abnormalities and lymphatic involvement makes the skin lesions appear bluish or
purplish.
In contrast, Parkes Weber syndrome is characterized by the presence of arteriovenous fistulas,
and flow through the cutaneous malformations is fast, giving the lesions a pink color. Cardiac
hypertrophy or high-output congestive heart failure occurs.

Epidemiology
Frequency
United States
Klippel-Trenaunay syndrome and Parkes Weber syndrome are rare sporadic conditions with no
racial or geographic predisposition. Parkes Weber syndrome is much less common than KlippelTrenaunay syndrome.

Mortality/Morbidity
See the list below:

Klippel-Trenaunay syndrome and Parkes Weber syndrome have a mortality rate of 1%.

All patients have significant morbidity.

o Hypertrophy of the extremities or digits can be extreme, requiring amputation.
o Lymphatic involvement with lymph vesicles may lead to poor wound healing.
o Although superficial vein abnormalities are common, the deep vein can also be
involved with thrombosis.
o Pulmonary embolism may occur in 10% of patients, particularly after surgery.[2]
o Pain may also be a feature of Klippel-Trenaunay syndrome.

o One half of patients can be treated solely using medical means.

Race
See the list below:

No racial predilection is noted.

Sex
See the list below:

No sex predilection is observed.

Age
See the list below:

The cutaneous vascular malformation is apparent at birth.

The venous varicosities and limb hypertrophy may not be apparent initially.

The average age of presentation of children to a medical center is 4 years

History
The cutaneous vascular malformation in both Klippel-Trenaunay syndrome (KTS) and Parkes
Weber syndrome (PWS) is apparent at birth and may increase in size over the first few years.
Natural involution of the cutaneous vascular malformation occurs in as many as 20% of patients.
The vascular malformation in Klippel-Trenaunay syndrome is typically low flow and causes
some trapping of platelets, with mild to moderate depression of the platelet count. When an
arteriovenous malformation (AVM) is present as in Parkes Weber syndrome, congestive heart
failure may result from high output. Spinal AVMs, while rare, have been reported in a case
series.[3]
Varicosities can produce venous stasis, which, in turn, can produce pain, bleeding,
thrombophlebitis, and pulmonary emboli. Patients also commonly have lymphatic abnormalities
that can produce lymphedema and susceptibility to infection and cellulitis.
Limb hypertrophy, which occurs over a few years and may not initially be apparent, results from
a combination of factors, including lymphatic obstruction, dilated veins, increase in soft tissue,

and bone hypertrophy. The hypertrophy may preferentially involve the digits. This leads to leg
length discrepancy and an unsteady gait.

Physical
Cutaneous vascular malformation and skin
The cutaneous vascular malformation in Klippel-Trenaunay syndrome is a flat blue or purplish
capillary hemangioma (so-called port-wine stain). The combination of low flow and lymphatic
involvement produces the blue or purple color. The cutaneous vascular malformations have been
classified by Milliken. In Klippel-Trenaunay syndrome, the vascular malformations are a
combined type with flat endothelium. Although raised cavernous or mixed hemangiomas have
been reported in patients with Klippel-Trenaunay syndrome or Parkes Weber syndrome, they are
pathologically distinct from vascular malformations.
The cutaneous lesion is usually confined to part of an extremity; however, in 17-21% of patients,
the entire limb or one side of the body is affected.
In addition to the vascular abnormality, the skin may be hyperpigmented or thickened and have
varicose veins, cherry red varicosities (venous flares), and lymphatic vesicles.

Limb hypertrophy
In the vast majority of children, one leg is affected. In 5-11% of patients with Klippel-Trenaunay
syndrome, an arm is affected, and in 13-19% of patients, an arm and leg are both affected.
Lengthening of an extremity occurs in approximately 70% of patients, and an increase in
thickness of the extremity occurs in at least 50%. Usually, hypertrophy and vascular lesions
occur in the same extremity; only rarely do they occur in different limbs. Hypertrophy is due to a
combination of muscular hypertrophy, thickened skin, and increase in vascular tissue. Bone
overgrowth and lymphedema also contribute to increased size. The labia or scrotum may be
hypertrophied when the venous abnormalities extend into the pelvis. The breasts may be affected
by severe involvement of an upper extremity.

Venous abnormalities
Typically, superficial lateral venous anomalies start along the foot and extend upwards. In at least
one third of patients, the venous abnormalities extend the full length of the leg. Deep vein
abnormalities (occlusion by fibrous bands, agenesis, atresia) have been reported in some patients.
The frequency of these abnormalities is not clear because they are best demonstrated with
surgical exploration (which is usually not recommended).

Parkes Weber syndrome

Parkes Weber syndrome is defined by the presence of an AVM in addition to a cutaneous
hemangioma and segmental hypertrophy. Similar to Klippel-Trenaunay syndrome, Parkes Weber

syndrome more commonly affects the lower extremities. Patients with Parkes Weber syndrome
have a higher incidence of severe complications than patients with Klippel-Trenaunay syndrome.
The largest series reported was by Robertson.[4] Of 28 patients, 3 required amputations, 6 had
signs of cardiac enlargement, and 5 had significant leg length discrepancy requiring surgery.
Ulcerations and severe lymphedema are also believed to occur frequently. Robertson believed
that a positive bradycardiac reaction (compression of the artery feeding the AVM produces
slowing of the pulse) indicated a poor prognosis.

Lymphatic system
Abnormalities of the lymphatic system, such as a decreased number of lymph trunks and nodes,
are present in 70% of patients with Klippel-Trenaunay or Parkes Weber syndrome. As many as
23% of patients have lymphedema, cutaneous lymphatic vesicles, and weeping of lymph.

Miscellaneous
Other points to keep in mind include the following:

Pain and fatigability are common complaints

At least one episode of thrombophlebitis occurs in 19-53% of patients; venous

thrombosis can lead to pulmonary emboli

Deep vascular involvement (dilated veins) of the chest, abdomen, and pelvis may occur
in one third of patients; pelvic vein involvement may cause hematuria or rectal bleeding

Hemangiomas of the GI tract or kidney may also occur and cause bleeding and
compromise organ function

Klippel-Trenaunay syndrome is a pure low-flow condition. Parkes Weber syndrome, due

to presence of significant arteriovenous fistulas, results in combined high-flow vascular
malformation, causing high-output cardiac failure. In order to clinically differentiate
Klippel-Trenaunay syndrome from Parkes Weber syndrome, it is important to remember
that the cutaneous capillary malformation in Parkes Weber syndrome is more diffuse and
pinker than in Klippel-Trenaunay syndrome. In addition, skin ulcerations are much more
common in Parkes Weber syndrome ; they can be radiologically differentiated by
magnetic resonance (MR) projection angiography. [5]

Coagulopathy ( Kasabach-Merritt syndrome) is marked by anemia, thrombocytopenia,

prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT),
reduced fibrinogen levels, and fibrin split products

Rarely, ocular lesions and angiomas of the brainstem, cerebellum, and spinal cord are
complications found in patients with Klippel-Trenaunay syndrome; one patient has been
described with portosystemic encephalopathy due to intrahepatic portohepatic venous

shunts; [6] cases of mental retardation are rare; other congenital malformations,
particularly bone dysplasias, occur in 9-29% of patients; a few patients with features of
Klippel-Trenaunay syndrome and Sturge-Weber syndrome have been reported

Causes
The etiologies of the Klippel-Trenaunay and Parkes Weber syndromes are both still the subject of
hypothesis. Most of the mutations of Klippel-Trenaunay syndrome are sporadic, and the idea that
this disorder has a familial transmission is not yet proven. Autosomal dominant transmission of
the gene with variable expressivity was considered long ago,[7] but family members can have
isolated vascular nevi or varicose veins without having the disease itself.[8]
Translocations involving chromosomes 5 and 11 and 8 and 14 have been reported.[9, 10] As
proposed by Chen et al, the mutation on chromosome 5q13.3 causes defective AGGF1
expression.[9] In addition, it has been proposed that bone morphogenetic protein is a trigger for
AGGF1.[11] Ring chromosome 18 has also been reported in association with Klippel-Trenaunay
syndrome.
One group proposed that a mutation in the angiogenic factor VG5Q is the cause of angiogenesis
in Klippel-Trenaunay syndrome, but the reported mutation was subsequently identified as a
nonspecific polymorphism.[12]

Differential Diagnoses

Sturge-Weber Syndrome

Laboratory Studies
See the list below:

For the most part, patients with Klippel-Trenaunay-Weber syndrome are monitored for
symptoms.

Thrombocytopenia can occur and is diagnosed after an appropriate platelet cell count has
been obtained.

Imaging Studies
See the list below:

Ultrasonography
o Color duplex ultrasonography appears to be a reliable means of detecting
arteriovenous malformations (AVMs) in patients older than 1 year.
o Obtain color duplex ultrasonography in any child with evidence of cardiac
enlargement.
o Color duplex ultrasonography may be indicated as a screening procedure.

Radiography: When limb hypertrophy appears to be greater than 1.5 cm, scanography is
performed to assess timing of epiphysiodesis.

MRI
o MRI and magnetic resonance arteriography (MRA) provide information regarding
the extent of the vascular lesions, particularly deep-seated pelvic or thoracic
vascular lesions.
o MRI of the pelvis or chest is indicated if venous abnormalities extend the length
of the extremity.

Angiography
o Arteriography is primarily indicated when spinal cord or brain involvement is
suspected.
o Venography is rarely indicated.

Nuclear medicine: Lymphoscintigraphy may be indicated in children with significant

limb asymmetry to assess the lymphatic system and the risk of infection.

Medical Care
See the list below:

Most patients with Klippel-Trenaunay syndrome (KTS) can be conservatively treated

with compression stockings or pneumatic pumps. Compression stockings decrease
edema, act as a barrier for minor trauma, and reduce venous insufficiency.

In most series, patients with thrombophlebitis have been acutely treated without longterm prophylactic anticoagulants. However, aspirin is probably indicated in all patients.

Monitor cardiac status in all patients with arteriovenous malformations (AVMs).

Surgical Care
See the list below:

Servelle reported successful surgical intervention (resection or ligation of abnormal blood

vessels) in more than 700 patients with Klippel-Trenaunay syndrome.[13] Most medical
centers have tried to avoid surgical intervention. Surgical treatment can be complicated
by infection, lymph seepage, and skin breakdown. In a series by the Mayo Clinic,
surgical ligation and stripping of varicose veins produced improvement in only 40% of
patients.[14] Venous varicosities recur after surgery in 90% of patients. Intravenous
sclerotherapy has been proposed as an alternative to surgical intervention in KlippelTrenaunay syndrome and to embolization in Parkes Weber syndrome. Reports have
detailed the use of a sclerosant in microfoam.

Clinicians at all centers agree that a leg length discrepancy of more than 2 cm warrants
epiphysiodesis. Hypertrophied digits with severe deformity and infection may require
amputation.

Consultations
See the list below:

Psychologist: Psychological support is important because of the cosmetic effects of

Klippel-Trenaunay syndrome and Parkes Weber syndrome. A lay support group, the
Klippel-Trenaunay Syndrome Support Group, is available.

Activity
See the list below:

Patient activities are as tolerated

Antiplatelet agents
Class Summary
These agents inhibit platelet function by blocking cyclooxygenase production and subsequent
aggregation.

View full drug information

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Inhibits prostaglandin synthesis preventing formation of platelet-aggregating thromboxane A2.

May be used in low dose to inhibit platelet aggregation and improve complications of venous
stases and thrombosis.

Corticosteroids
Class Summary
These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and
varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisolone (Pediapred)

Used to treat coagulopathy. Decreases inflammation by suppressing migration of

polymorphonuclear leukocytes and reducing capillary permeability.

A 14 years old boy who was normal when born and till 7 yrs of age developed
dilated tortuous vein in the left leg.

WIKIPEDIA

KlippelTrnaunay syndrome
KlippelTrnaunay syndrome (KTS or KT), formerly KlippelTrnaunayWeber
syndrome[1] and sometimes angioosteohypertrophy syndrome and
hemangiectatic hypertrophy,[2] is a rare congenital medical condition in which
blood vessels and/or lymph vessels fail to form properly. The three main features
are nevus flammeus (port-wine stain), venous and lymphatic malformations, and
soft-tissue hypertrophy of the affected limb.[2] It is similar to, though distinctly
separate from, the less common Parkes-Weber syndrome.

Classification
There is disagreement as to how cases of KTS should be classified if there is an arteriovenous
fistula present. Several authorities have suggested that the term Parkes Weber syndrome is
applied in those cases.[3][4][5] ICD-10 currently uses the term "KlippelTrnaunayWeber
syndrome".

Signs and symptoms

The birth defect is diagnosed by the presence of a combination of these symptoms (often on
approximately of the body, though some cases may present more or less affected tissue):

One or more distinctive port-wine stains with sharp borders

Varicose veins

Hypertrophy of bony and soft tissues, that may lead to local gigantism or shrinking.

An improperly developed lymph system

In some cases, port-wine stains (capillary port wine type) may be absent. Such cases are very
rare and may be classified as "atypical KlippelTrenaunay syndrome".
KTS can either affect blood vessels, lymph vessels, or both. The condition most commonly
presents with a mixture of the two. Those with venous involvement experience increased pain
and complications.
Those with large AVMs are at risk of formation of blood clots in the vascular lesion, which may
migrate to the lungs (pulmonary embolism). If there is large-volume blood flow through the

lesion, "high-output heart failure" may develop due to the inability of the heart to generate
sufficient cardiac output.[5]

Genetics
The birth defect affects men and women equally, and is not limited to any racial group. It is not
certain if it is genetic in nature, although testing is ongoing.[6] There is some evidence that it may
be associated with a translocation at t(8;14)(q22.3;q13).[7] Some researchers have suggested
VG5Q has an association.[8]

Treatment
KTS is a complex syndrome, and no single treatment is applicable for everyone. Treatment is
decided on a case-by-case basis with the individual's doctors.
At present, many of the symptoms may be treated, but there is no cure for KlippelTrenaunay
syndrome.[9]

Surgical
Debulking has been the most widely used treatment for the syndrome, and has been used for
decades. Progress has been made in this method over the course of the past couple decades, but it
is still an invasive procedure, and has many complications. As other choices now exist for KTS
patients, this method is generally reserved as a last resort.
Mayo Clinic has reported the largest experience in managing KTS with major surgery. In 39
years at Mayo clinic the surgery team evaluated 252 consecutive cases of KTS, of which only
145 (57.5%) could be treated by primary surgery.[10] The immediate success rate for treating
varicose veins was only 40%, excision of vascular malformation was possible in 60%, debulking
operations in 65%, and correction of bone deformity and limb length correction (epiphysiodesis)
had 90% success. All the procedures demonstrated high recurrence rate in the follow-up. Mayo
clinic studies demonstrate that primary surgical management of KTS has limitations and nonsurgical approaches need to be developed in order to offer a better quality of life for these
patients. Major surgery including amputation and debulking surgery does not seem to offer any
benefit on a long-term basis.

Nonsurgical
Sclerotherapy is a treatment for specific veins and vascular malformations in the affected area. It
involves the injection of a chemical into the abnormal veins to cause thickening and obstruction
of the targeted vessels. Such treatment may allow normal blood flow to resume. It is a nonsurgical medical procedure and is not nearly as invasive as debulking. Ultrasound guided foam
sclerotherapy is the state of the art new treatment which could potentially close many large
vascular malformations.[11][12] Debulking operations can result in major deformities and have a
high potential for recurrence and nerve injuries.

Compression therapies are finding more use as of the last ten years. The greatest issue with KTS
syndrome is that the blood flow and/or lymph flow may be impeded, and will pool in the affected
area. This can cause pain, swelling, inflammations, and in some cases, even ulceration and
infection. Among older children and adults, compression garments can be used to alleviate
almost all of these, and when combined with elevation of the affected area and proper
management, can result in a comfortable lifestyle for the patient without any surgery.
Compression garments are also used lately after a debulking procedure to maintain the results of
the procedure. For early treatment of infants and toddlers with KTS, custom compression
garments are impractical because of the rate of growth. When children may benefit from
compression therapies, wraps and lymphatic massage may be used. While compression garments
or therapy are not appropriate for everyone, they are relatively cheap (compared to surgery), and
have few side-effects. Possible side-effects include a slight risk that the fluids may simply be
displaced to an undesirable location (e.g., the groin), or that the compression therapy itself
further impedes circulation to the affected extremities.[citation needed]

History
The condition was first described by French physicians Maurice Klippel and Paul Trnaunay in
1900; they referred to it as naevus vasculosus osteohypertrophicus.[13][14] The German-British
physician Frederick Parkes Weber described cases in 1907 and 1918 that were similar but not
identical to those described by Klippel and Trnaunay.[15][16]