Nosological Consideration of Arterial Aneurysms Associated with Klippel–Trenaunay Syndrome

Klippel–Trenaunay syndrome (KTS) is a rare slow-flow combined vascular malformation characterized by capillary-lymphatic-venous lesions with soft tissue overgrowth of the limbs. We report the case of a 37-year-old female KTS patient with a deep femoral arterial aneurysm. We finally diagnosed that the aneurysm had resulted from a fundamental defect in the arterial wall structure. We discuss whether the use of “aneurysm associated with KTS” is accurate and how to better classify this type of capillary-venous lesion in 17 reported KTS patients with arterial aneurysms. In this review, we describe nosological problems of arterial aneurysms associated with KTS.


Case Report
A 37-year-old woman presented with capillary malformation and hypertrophy of the right lower limb, which had been present since birth, and she was diagnosed with lymphatic hypoplasia. There was no significant family history. She initially presented with high fever due to cellulitis at the age of 12 years, which recurred several times per year thereafter. Overgrowth of the affected limb progressed de- Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the credit of the original work, a link to the license, and indication of any change are properly given, and the original work is not used for commercial purposes. Remixed or transformed contributions must be distributed under the same license as the original. spite conservative treatment with the regular use of a compressive elastic support and automatic massage device. She was referred to us with a diagnosis of KTS associated with a deep femoral artery aneurysm.
Physical examination demonstrated enlargement of the right limb both in girth (4, 24, and 28 cm longer than the left at the foot, calf, and thigh, respectively) and length (5 cm longer than the left). The right toes with lymphatic verrucae were enlarged, especially the big toe, and pale pink capillary malformation was observed in the fifth toe (Fig. 1A).
Varicose veins were observed in the right leg. There were areas of skin pigmentation due to dermatitis related to hyperhidrosis on the popliteal fossa and buttock of the affected leg. Left lumbar scoliosis was observed due to excessive enlargement of the right lower leg.
There were no abnormal findings on chest X-ray or echo-cardiogram. Radionuclide lymphoscintigraphy revealed increased radiotracer accumulation in soft tissue below the right calf, but no lymph nodes were observed in the right groin (Fig. 1B). Abnormal dilated superficial veins and marked lymphedema were noted on plain computed tomography (CT) ( Fig. 2A). CT angiography demonstrated dilated and calcified iliofemoral arteries, a deep femoral artery aneurysm in the right groin (arrow), and earlier venous filling in the right lower leg (Fig. 2B). Axial CT revealed a deep femoral arterial aneurysm in the right groin, atrophy of the muscles, and typical findings of lymphedema of the thigh (Fig. 2C). Blood gas analysis results from the right common femoral vein were as follows: PH, 7.3; PvO 2 , 40 mmHg; PvCO 2 , 46 mmHg; HCO 3 , 24 mEq/L; Baseexcess, -2 mmol/L; and SvO 2 , 81%.   Simple ligation with aneurysmectomy was performed because we were able to confirm pulsatile backflow even by clamping the proximal neck of the aneurysm. The postoperative course was uneventful. Follow-up CT angiography performed in 2018 showed no aneurysmal dilatation in the arterial system of the right lower extremity.
Histological findings of the aneurysm included atherosclerotic degeneration with calcification and hyalinization in the intima and media, and fibrous changes in the adventitia. An organized thrombus and coagula were observed in the lumen. On Elastica van Gieson staining, elastic fiber fragmentation was noted in the aneurysmal wall (Figs.  3A and 3B). Detecting whether the changes of the arterial wall structure were congenital was difficult.
Arterial aneurysms in arterial dysplasia have been reported in several studies. Our patient developed a deep femoral aneurysm in the affected limb. The main arterial system of the affected limb is smoothly dilated, and the branch angle and the shape of the deep femoral artery were abnormal. Increased skin temperature, calcified dilated iliofemoral arteries, and early venous filling on contrast CT angiography of the affected limb suggest the presence of micro-arteriovenous fistulae. Lindenauer 25) and Baskerville 26) noted microscopic arterio-venous (AV) communication in KTS patients, but CLVM in KTS associated with chronic cellulitis and CVM in KTS with chronic knee synovitis due to repeated intra-articular hemorrhage have been observed. Based on Doppler analysis, venous blood gas analysis, and high values of fibrinogen and Ddimer, we thought that early venous filling resulted from clinically nonfunctioning arteriovenous communication. Thus, we considered our case to be slow-flow combined malformation and that smoothly calcified iliofemoral arteries may not have resulted from arteriovenous shunting, but from the hyper-hemodynamic state for maintaining nutrition to the affected giant limb and hypercholesterolemia.
In addition to the findings of the main arterial trunk,   the branch angle of the ectatic deep femoral artery was morphologically abnormal, and we finally concluded that the bifurcation angle and the shape of the dilated deep femoral artery in our case were congenital in nature and that the aneurysm may have resulted from increased shear stress due to hyper-hemodynamic blood supply to the lower limb and hyperlipidemia. Lee 27) proposed the following hypothesis regarding the pathogenesis of these aneurysms: arterial malformation (AM) is one of the many combined vascular malformations, and its truncular lesion is the result of developmental arrest in the latter stage of embryogenesis based on the Hamburg Classification ( Table 4). 28) It often remains as aplasia/hypoplasia/hyperplasia. Depending upon the severity, location, and postnatal hemo-arteriodynamics, this lesion will progress to an aneurysmal condition or remain ectatic, which is not uncommon. Based on this fundamental defect in the arterial wall structure, it will become more susceptible to pathological change (e.g., atherosclerosis).
In 6 of 18 cases, including ours, arterial aneurysms developed in the affected lower limbs with KTS. [14][15][16][17]23) In 12 cases, aneurysms were found in areas other than the extremities ( Table 3). [8][9][10][11][12][13]18,19,21,23) There is no clear taxonomic definition of KTS with morphologically abnormal congenital arteries such as aplasia, hypoplasia, hyperplasia, and dysplasia. In the International Society for the Study of Vascular Anomalies (ISSVA) classification, combined vascular malformations are classified into two categories: the slow-flow type and fast-flow type. Both CVM and CLVM with arterial dysplasia are defined as the high-flow type. We think that these types should be categorized by the rheology of the venous system. Thus, CVM and CLVM with arterial dysplasia should be categorized into the slow-flow type. If CVLM and arterial dysplasia are present in the same limb, referring to it as KTS is confusing. Therefore, the term arterial aneurysm associated with KTS may be inaccurate. Furthermore, considering the hemodynamics of the affected limb, it should not be classified into the fast-flow type. If arterial dysplasia is present in other parts of the body, calling it an arterial aneurysm associated with KTS is accurate. Lee also stated that aneurysm formation is due to a fundamental defect in the arterial wall structure and that the old name-based nosology/term, such as KTS, caused further confusion; this old term failed to fulfill its mandate as a proper classification for combined vascular malformations. He recommended to discourage its further use. 27) Thus, our case with arterial dysplasia, but without hemodynamically significant arteriovenous malformation, was subcategorized as the slow-flow type, and it is better to be included as a low-flow type capillary-lymphaticvenous-arterial malformation (CLVAM) in the ISSVA classification (Tables 1 and 2).
Lastly, in 4 9,17,19,22) of 17 previous reports, a composite hybrid term Klippel-Trenaunay-Weber syndrome was used, perhaps because of arterial involvement in KTS patients. We think that this vague and meaningless term should be abandoned. Diffuse (ectasia) * Both forms may exist together, may be combined with other various malformations (e.g., capillary, arterial, AV shunting, venous, hemolymphatic, and/or lymphatic), and/or may exist with hemangioma.

Conclusion
We presented a case with a smoothly dilated main arterial system in the affected limb, and abnormal branch angle and shape of the deep femoral artery. We considered the former change to have been secondary for maintaining nutrition to the affected giant limb, and the later change of the deep femoral artery may have been due to a fundamental defect in the arterial wall structure. Therefore, our case was subcategorized as the slow-flow type and termed CLVAM without arteriovenous malformations. In cases with arterial dysplasia in the affected limb, referring to them as KTS is inaccurate. We consider it necessary to reconsider the confusing use of the term aneurysm associated with KTS, especially when in the affected limb, and that the new syndrome CLVAM should be added to the slow-flow type in the ISSVA classification considering both morphological and functional findings.

Informed Consent
The patient signed an informed consent on Dec. 29, 2014, acknowledging the publication of her data, including images and information that may reveal her identity.