In 1900, M. Klippel and P. Trénaunay [1] described a disease characterized by a triad of physical features: cutaneous vascular naevi, varices and venous malformations, hypertrophy of one extremity: the Klippel–Trénaunay syndrome (KTS). Owing to their color, the naevi (capillary malformations) are universally recognized as port-wine stains. This classic triad is not present in all KTS patients (Table 27.1).

Table 27.1 Physical features in KTS
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Currently, KTS is defined [5] as the association of: (1) combined malformations of the capillary, venous, and lymphatic systems; (2) varicosities of unusual distribution (in particular, the lateral venous anomaly, observed during infancy and childhood); (3) limb enlargement.

Vascular naevi in none of the about 1500 cases reported in the literature involved the cranio-facial region [5], as at a glance differentiation from Sturge–Weber syndrome.

Describing the characteristics observed in a large series of patients, Gloviczki and Driscoll [6] pointed to the main features of the disease: capillary malformations (port-wine stains); soft tissues and bone hypertrophy (occasionally hypotrophy) of one limb (usually lower limb); atypical, mostly lateral, varices. They recognized that KTS derives from the involvement of capillary, venous, and lymphatic systems without any significant arteriovenous shunting.

The lack of a-v shunts was categorically asserted by Lindenauer [2], as a mark of differentiation from Parkes Weber syndrome (PWS). Further observations [3, 7] confirmed the absence of significant a-v communications; these may be present, but deprived of any functional relevance [8,9,10,11].

Limb overgrowth is a typical feature in most cases of KTS; however, hypotrophy has been recorded [2, 4, 11].

Whereas varicosities may be absent, malformations in the venous system are the rule: these may be of different types consisting on segmental defects of deep veins and/or persistence of veins pertaining to the embryonic system. Servelle [3] demonstrated and successfully treated, with a 14-year follow-up, the compression of the popliteal vein by a fibrous band in a 16-year-old girl with KTS. The same author, who collected the largest world experience in this field, extensively used phlebography to study the patients, demonstrating obstructive lesions of lower limb deep veins at different levels: popliteal 51%, superficial femoral 16%, iliac 3.3%: the lesion consisted on agenesis in 8% of the patients and hypoplasia in 21%. Lindenauer [2] observed, through phlebography, absence of deep vein at popliteal and thigh level. Vein abnormalities are considered the prime cause of KTS by some authors [12, 13]. Baskerville et al. [8, 9] assert that only a minority of patients have true absence of deep veins and that the principal defect is superficial and/or deep veins reflux: they observed absence of valves in the deep veins in 47% of 33 patients and in 68% a large lateral venous channel, mainly valveless, representing a birth-mark. The rarity of deep vein atresia had been already reported [14, 15]. At Mayo Clinic [16], a severe involvement of lower limb veins was observed consisting on complex reflux patterns, diffuse valvular incompetence with impairment of the calf muscle pump and chronic venous hypertension. In the same institutional review, atypical veins (lateral and persistent sciatic) were very frequent. The persistence of the venous sciatic system produces an overload of the internal iliac vein, causing secondary varices in the rectum, bladder, and vagina [3].

The involvement of the lymphatic system is a common component of KTS [3, 5, 6], sometimes manifesting as lymph oozing from the surface of capillary malformations sometimes as lymphangitis or true lymphedema. Studying by RM lymphography 31 KTS patients with lymphedema, Liu et al. [17] observed aplasia or hypoplasia of the lymphatics in 20 and hyperplasia in 11.

KTS may be defined as a slow-flow vascular malformation with a good prognosis; however, severe complications can manifest, represented by hemorrhage from the rectum or the genitourinary system [10]. Hemorrhage can derive from secondary varicosities [3] but is in general attributed to angiomatous lesions [18]. Whereas colon involvement is scantily reported [19], urogenital manifestations are not rare [20,21,22]. In a review of the Mayo Clinic experience 1970–2005 [23], genitourinary involvement was observed in 41/218 patients (19%) and severe hemorrhage requiring hospitalization occurred in 19 cases. Another relevant complication of KTS is the augmented risk of pulmonary embolism [24], up to 10% in children [25].

According to Cohen [5], KTS affects lower limb in 95% of the cases and upper limbs in 5%; involvement of the trunk alone is extremely rare [2, 3, 25].

KTS is considered a sporadic disease and its origin is unknown. Examples of familiarity are very rare [2, 26]. The most credited etiological hypothesis is that of a mesodermal defect during fetal development [2] producing the persistence [27] or the delayed regression [8] of the embryonic vascular system represented by a reticular network. Tijan et al. [28] identified in a mutation of the VG5Q gene a susceptibility to develop KTS; this hypothesis was contested by other researchers [29], but supported, albeit modified, by others: Hu et al. [30], studying 177 KTS patients and 477 controls, observed that two single nucleotide polymorphism of the AGGF1 (VG5Q) gene were significantly associated with susceptibility for KTS, proposing a two-hit mechanism for development of KTS, according to the concept of paradominant inheritance [31]. This molecular mechanism is still on the stage even if not universally accepted [32].

In 1918, F. Parkes Weber [33] described the syndrome which bears his eponym, relying on three main features: (1) capillary malformations; (2) arteriovenous communications; (3) overgrowth of a limb deriving from abnormal growth of bone and soft tissues. Already in 1907 [34], he had reported on patients who could have been classified as KTS patients, without any mention of arteriovenous communications. The substantial difference which characterizes PWS with respect to KTS is the presence of functionally relevant a-v fistulae, which progress relentlessly with time, eventually causing ulcerations, cardiac failure, and amputation [10]. Currently, MR projection angiography looks a very reliable diagnostic tool for the evidentiation of a-v fistulae in order to separate KTS from PWS [35]. This is important, as PWS, being a fast flow vascular malformation, implies a prognosis substantially worse than KTS, notwithstanding the potential complications associated with the latter [2]. Already in 1956, Robertson [36], reviewing 28 cases of PWS, observed six cases of cardiac enlargement and three major amputations. In spite of these objective considerations, cases of “KTS” with a-v fistulae were repeatedly reported [37,38,39] and in 1962 Mullins et al. [40] proposed the term Klippel–Trénaunay–Weber syndrome (KTWS), asserting that there is no prognostic or therapeutic meaning in maintaining the differentiation into two specific entities. In effects, prognosis of PWS is really worse than that of KTS, and, after all, Parkes Weber described patients with enlarged arteries and veins, capillary and venous malformations, a-v communications, and enlargement of a limb; moreover, a lymphatic component is rarely observed [32] and the lateral venous anomaly has never been observed [5].

However, the term KTWS is frequently used [41,42,43], even when the patient should be undoubtedly classified as affected with PWS [44].

After the initial observations of Eerola et al. [45], a mutation of the gene RASA1 has been found both in cases of CM-AVM (capillary malformation-arteriovenous malformation) and PWS [46], apparently linked to the condition of high-flow a-v malformation; this mutation is lacking in KTS [47].

Arterial aneurysms have been reported both in KTS and PWS. In some cases, it is difficult to assess a specific etiology or to rule out a coincidental occurrence with other vascular diseases. Peculiar microscopy findings seem to characterize some cases of aneurysm in KTS. Nakamura et al. [18] described aneurysm of the transverse cervical artery due to the weakening of the arterial wall by invasion from a surrounding hemangiomatous lesion. Particularly intriguing is the histology in the case of popliteal aneurysm reported by Akagi et al. [48]: disrupted and disordered elastic fibers in an extremely thinned media. The authors suggest that this picture could represent a specific arterial lesion of KTS. On the other side, some of the aneurysms observed in KTS are clearly atherosclerotic (as the aortic aneurysm reported by Kaladji et al. [49] and the popliteal aneurysm operated on for acute ischemia by Komai [50]). The genesis of aneurysmal lesions in PWS could be correlated with the overload and the increased turbulence consequent to a-v fistulae; diffuse dilation of all the arteries of the involved limb has been described [51].

Aneurysms observed in KTS involved the renal artery [20, 52] and cerebral arteries [53,54,55]. In PWS (or KTWS) were reported aneurysms at different sites: cerebral arteries [56,57,58]; renal artery [59]; brachial artery [60]; iliac and femoral arteries [61].

Details of aneurysms of the popliteal artery observed in KTS and PWS are illustrated in Table 27.2.

Table 27.2 Popliteal artery aneurysm in KTS and PWS
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