OVERVIEW: What every practitioner needs to know

Are you sure your patient has Klippel-Trenaunay-Weber syndrome? What are the typical findings for this disease?

Klippel-Trenaunay-Weber (KTW) syndrome is the traditional eponym applied when a person has findings of Klippel-Trenaunay syndrome (KTS) together with an arteriovenous malformation (AVM) or arteriovenous fistula as is found in Parkes-Weber syndrome (PWS). However, there are substantial inconsistencies and disagreement over the findings and diagnostic criteria for KTS and KTW.

Existing studies have used different definitions of KTS when describing the epidemiology and prognosis. Some authors recommend abolishing the terms KTS, KTW, and PWS altogether because of the controversy that exists regarding the overlapping findings of these conditions. There have been recent attempts to redefine the diagnostic criteria of KTS, but they have yet to be formally adopted.

Given the existing confusion over the diagnostic criteria for KTS (and hence KTW), it is perhaps not entirely helpful here to attempt to present a set of findings that will lead to a definitive diagnosis of KTS/KTW. Instead, it is likely more useful to discuss some general and historical features that may point to a spectrum of disorders that include KTS/KTW.

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At its most basic, KTS is considered an overgrowth disorder that is associated with lymphatic, venous, or capillary congenital malformations. The most commonly agreed upon triad of findings considered to represent KTS includes (1) a localized vascular nevus on a body part, (2) hypertrophy of affected tissues, and (3) varicosities in that same body part. Because of the hamartoma-like nature of the vascular malformations, KTS is typically included in the phacomatosis family of disorders. In addition, some authors believe that KTS is associated with spinal or other AVMs, and thus KTS and KTW are also listed as neurocutaneous disorders.

Vascular Abnormalities

Vascular abnormalities that have been listed as occurring in KTS include capillary malformations (such as port wine stains), lymphatic malformations, venous malformations, and AVMs. The port wine stains are typically present at birth and are most common on the lower limbs, but they can also occur on the upper limbs, trunk, or rarely the face. These typically do not cross the midline. Because AVMs can (rarely) be found in KTS in addition to port wine stains, KTS/KTW is sometimes thought to be related to Sturge-Weber syndrome, with its facial port wine stains and intracranial capillary-venous malformation of the pia and arachnoid matter.

Typical venous anomalies in KTS include venous hypoplasia and persistence of fetal veins. The overall decreased venous drainage and subsequent congestion that results is thought to cause the varicosities that can be seen on the skin surface. Varicosities of the affected limb are one of the original features proposed by Klippel and Tenaunay. Although the actual underlying venous malformations are present at birth, the varicosities can be present at birth or may appear in infancy or occasionally later.

Lymphatic malformations can include localized hyperplasia, hypoplasia, or aplasia and are closely associated with the venous malformations. The lymphatic abnormalities typically result in decreased lymphatic flow.

Limb Overgrowth and Undergrowth

Overgrowth of the affected limb is also a cardinal manifestation of KTS. The overgrowth is in the same limb that displays the cutaneous and venous/lymphatic manifestations. Overgrowth in the form of increased limb circumference is likely related to edema and lymphedema associated with congestion and increased pressures associated with the venous and lymphatic abnormalities. Through unclear mechanisms, there can also be increased growth of underlying musculature and bones, leading to significant limb length discrepancies. However, there can also be limb undergrowth, presumably from ischemia or other consequences of reduced blood flow to affected limbs, especially in deeper tissues.

Significant morbidity in KTW can come from pain associated with the various clinical features. A review by Lee et al lists nine complications of KTW (chronic venous insufficiency, cellulitis, superficial thrombophlebitis, deep vein thrombosis, calcification of vascular malformations, growing pains, intraosseous vascular malformations, arthritis, and neuropathic pain) along with suggestions for alleviating the pain in each condition.

What other disease/condition shares some of these symptoms?

The vascular lesions in KTS are considered slow-flow lesions. The presence of a high-flow lesion such as an AVM may lead some to use the KTW label. There are several additional conditions that are either historically associated with KTS or confused with KTS. CLOVE syndrome (Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi) can be distinguished from KTS by the presence of spinal or paraspinal AVMs, and is also typically associated with scoliosis and sometimes seizures.

Cobb syndrome consists of a spinal AVM together with a port wine stain in the vascular territories affected by the AVM and is perhaps most similar to a noncranial version of Sturge-Weber syndrome. The appearance of overgrown limbs seen in KTS may be mistaken for Proteus syndrome, which is a progressive syndrome characterized by abnormal growth of skin and bone affecting one or more limbs, including the hands and feet.

What caused this disease to develop at this time?

The vascular malformations that lead to the clinical features of KTS are present at birth, even though the signs and symptoms themselves may not appear until later. The cause of KTS is unknown.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of KTS or KTW is a clinical diagnosis (albeit with clinical criteria that vary among authors) and there are no genetic or molecular tests that are useful as an aid in diagnosis.

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging (MRI) of an affected body part, together with vascular imaging with MRI or ultrasonography may be helpful in elaborating a pattern of disease findings. The presence of an AVM, if suspected, should also be evaluated with appropriate imaging techniques.

Confirming the diagnosis

As discussed, the clinical criteria used in diagnosing KTS or KTW is highly variable. An approach such as proposed by Oduber et al is attractive (see references).

If you are able to confirm that the patient has this disease, what treatment should be initiated?

KTS cannot be cured, and treatment is aimed at alleviating symptoms. Varicose veins are typically treated with compression stockings with as much pressure as can be tolerated. However, stockings in general are poorly tolerated by most children. Port wine stains can be treated for cosmetic reasons with laser therapy. AVMs, if present in KTW, should be treated (i.e., with embolization or surgery) on a case-by-case basis, depending on the specific consequences of the particular AVM.

What are the adverse effects associated with each treatment option?

The range of treatments used in KTS/KTW and the adverse affects are two broad to detail here but include debulking of gross tissues, surgical excision of malformations, surgical correction of limb-length discrepancies, and sclerotherapy or other treatment for varicosities. However it should be noted that KTS is a lifelong progressive disease, and treatments (together with any adverse consequences) are related specifically to each individual clinical finding, that is, the treatment of the finding is independent and not typically altered by the establishment of the diagnosis of KTS.

What are the possible outcomes of this disease?

There is a wide range of outcomes in KTS and KTW. In addition to the cosmetic and functional limitations of a limb imposed by hypertrophy and overgrowth, there are several additional potential associated findings that affect outcomes. Complications of high-flow lesions such as the AVMs found in KTW are the most serious and include congestive heart failure.

Venous malformations and congestion increase the risk of deep venous thrombosis, which then also increases the risk of pulmonary embolism. It is currently not known whether anticoagulation improves outcomes in KTS. Venous stasis and congestion lead to increased risk of skin breakdown and normal blood flow, which can lead to increased risk of cellulitis.

What causes this disease and how frequent is it?

KTS is a rare sporadic disorder, in which some occasional familial cases may occur. There is no known preference for sex or race. The causes of KTS and KTW are unknown.

How do these pathogens/genes/exposures cause the disease?

There are several different hypotheses as to the cause of the malformations seen in KTS, but none has good experimental evidence, and none seems to completely explain all the findings of KTS.

How can this disease be prevented?

There is currently no known way to prevent KTS/KTW.

What is the evidence?

Oduber, CE, van der Horst, CM, Hennekam, RC. “Klippel-Trenaunay syndrome: diagnostic criteria and hypothesis on etiology”. Ann Plast Surg. vol. 60. 2008. pp. 217-23. (This article proposes new criteria for the diagnosis of KTS, along with strict definitions of associated clinical manifestations. In addition, this reference is an additional well-written source that explains and illustrates the history and complexity of the diagnostic controversies surrounding KTS/KTW. There is also a discussion of the various proposed mechanisms to explain the cause of KTS.