Journal of Vascular Surgery
Volume 45, Issue 3 , Pages 561-567, March 2007

Hemodynamic impairment, venous segmental disease, and clinical severity scoring in limbs with Klippel-Trenaunay syndrome

Presented at the Eighteenth Annual Meeting of the American Venous Forum, Miami, Fla, Feb 22-26, 2006.

  • Konstantinos T. Delis, MD, PhD, FRCSI

      Affiliations

    • Division of Vascular Surgery, Mayo Clinic, Rochester, Minn
    • ,
  • Peter Gloviczki, MD

      Affiliations

    • Division of Vascular Surgery, Mayo Clinic, Rochester, Minn
    • Corresponding Author InformationReprint requests: Peter Gloviczki, MD, Division of Vascular Surgery, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905
    • ,
  • Paul W. Wennberg, MD

      Affiliations

    • Division of Vascular Medicine, Mayo Clinic, Rochester, Minn
    • ,
  • Thomas W. Rooke, MD

      Affiliations

    • Division of Vascular Medicine, Mayo Clinic, Rochester, Minn
    • ,
  • David J. Driscoll, MD

      Affiliations

    • Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minn

Received 24 March 2006; accepted 10 November 2006. published online 03 February 2007.

Article Outline

Background

Klippel-Trenaunay syndrome (KTS) is a complex congenital anomaly featuring two or more of the following: (1) capillary malformations (port-wine stains), (2) soft tissue or bony hypertrophy (or both), and (3) varicose veins or venous malformations. With the purpose of determining the actual significance of venous impairment in patients with KTS, we quantified the venous valvular competency and calf muscle pump function and examined their effect on clinical severity.

Methods

Included were patients with near-normal function of affected limb(s) and minimal/small foot hypertrophy. Excluded were those with deep venous hypoplasia, aplasia or thrombosis, lymphedema, limb length discrepancy (>2.5 cm), peripheral arterial (ankle-brachial index <1.0), or cardiac disease and walking impairment. Venous duplex scanning, ascending venography, magnetic resonance imaging, strain gauge plethysmography, and a bone scanogram were performed. We studied eight men and seven women aged 15 to 51 years (median, 24 years). The KTS involved 17 limbs (unilateral in 13 patients and bilateral in 2). Contralateral limbs in patients with unilateral KTS acted as controls (n = 13). Venous clinical severity was graded according to the CEAP and venous clinical severity score (VCSS), and reflux complexity was classified according to the venous segmental disease score. Outflow obstruction (outflow fraction at 1 and 4 seconds; OF1 and OF4, respectively), reflux (venous filling index), calf muscle pump function (ejection fraction), and hypertension (residual volume fraction) were determined in both limbs with strain gauge plethysmography. Data, reported as median and interquartile range, were analyzed with the Mann-Whitney test.

Results

Varicose veins or venous malformations occurred in the medial, posterior, or anterolateral limb segments of the ankle (7/17, 7/17, and 9/17), calf (10/17, 8/17, and 12/17), knee (9/17, 8/17, and 8/17), and thigh (10/17, 6/17, and 8/17, respectively). Venous malformations occupied the subcutaneous space (17/17) and extended into the subfascial space in 6 (35.3%) of 17 limbs. Abnormal reflux (>0.5 seconds) was distributed in the great (64.7%; 11/17) and small (5.9%; 1/17) saphenous veins and the common femoral (23.5%; 4/17), femoral (41.1%; 7/17), popliteal (29.4%; 5/17), perforator (70.6%; 12/17), and axial calf (35.3%; 6/17) veins. There was no difference in the OF1 and OF4 between the affected limbs and the controls. Limbs with KTS had a fivefold greater venous filling index (0.133-0.46 mL · 100 mL−1 · s−1; 0.258 mL · 100 mL−1 · s−1) than the controls (0.034-0.055 mL · 100 mL−1 · s−1; 0.046 mL · 100 mL−1 · s−1; P < .0001), and this was linked to a higher venous segmental disease score (3 [2-4] vs 0 [0-1]; P < .0001). Limbs with KTS had half the ejection fraction (20.8%; 12.3%-24%) of the controls (39.3%; 30.9%-64.6%) and twice as high a residual venous fraction (77% [69.6%-84.5%] vs 40.9% [20.6%-60%]; both P < .004). Patients complained of swelling (100%; 15/15), aching (100%; 15/15), pain (93.3%; 14/15) and heaviness (100%; 15/15), tiredness (66.7%; 10/15), and tightness (33.3%; 5/15) of the limb(s) with KTS. Limbs with KTS had a worse (1) venous clinical severity by 11 VCSS points (11 [8-12] vs 0 [0-1]) and (2) clinical status by 3 CEAP classes (C3 [C3-C4] vs C0 [C0-C2]) than the control limbs (both P < .0001).

Conclusions

Venous disease in limbs with KTS is a major source of morbidity in affected patients. Limbs with KTS are characterized by complex reflux patterns, severe valvular incompetence, calf muscle pump impairment, and venous hypertension, thus explaining the advanced clinical severity (VCSS) and CEAP grade.

 

Klippel-Trenaunay syndrome (KTS) is a complex congenital anomaly, defined as a combination of (1) capillary malformations (port-wine stains) often located at the lateral aspect of the affected limb and, less often, at sites other than the hypertrophied limb; (2) soft tissue and/or bony hypertrophy; and (3) varicose veins or venous malformations, frequently in the presence of persistent posterolateral embryologic veins.1, 2, 3, 4, 5 The presence of two or more of these criteria allows the diagnosis of KTS.3 Deep venous abnormalities (hypoplasia, aplasia, and valvular incompetence) and lymphatic impairment also may occur.1, 2, 3, 4, 5, 6

Capillary malformations (port-wine stains) occur in 98% of patients, varicosities or venous malformations are present in 72%, and some form of limb hypertrophy is reported in 67%.3 All three features of KTS are present in approximately 63% of patients, and the remaining 37% have two of the three diagnostic features.3 KTS is unilateral in 85% of patients, bilateral in 12.5%, and crossed-bilateral in 2.5%, and in 10% both the upper and lower extremities are affected.1 Atypical veins, including lateral veins and persistent sciatic vein, occur in more than two thirds of patients.3 Aneurysmal dilatation of deep and superficial veins also is common in KTS, may result either from congenital weakness of the vascular walls or the presence of a high ambulatory venous pressure, and increases with age and disease progression.3, 4, 7

Because of the complex nature of KTS, affected patients are best treated initially in a center with an experienced multidisciplinary team that includes a primary health care provider, expert surgeons, and ancillary staff.4, 5 Yet KTS may have a relatively benign course. Up to 50% of affected patients may not have clinically significant or debilitating complaints and may require nothing but elastic support.1, 2, 3, 4, 5, 6 Treatment of KTS continues to be primarily nonoperative.1, 2, 3, 4, 5 Some patients with patent deep veins may benefit from excision and stripping of varices (7.5%; 3/40), partial varicectomy (10%; 4/40), and angioma resection (20%; 8/40); these bring about a significant clinical improvement with a view to a reoperation in the future if recurrence ensues.1 With the purpose of determining the actual significance of venous impairment in patients with KTS, we quantified the venous valvular competency and calf muscle pump function in the affected limbs and examined their effect on venous clinical severity. We determined the distribution of venous abnormalities and the sites of venous valvular incompetence in limbs with KTS and quantified the global venous hemodynamics in relation to the clinical symptoms and signs of venous disease.

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Methods 

This was a retrospective, institutional review board–approved, controlled study based on a standardized protocol of comprehensive investigations set in place prospectively, reported in fine detail, stored digitally, and retrieved instantly via a state-of-the-art computerized database system. The diagnosis of KTS was made independently by at least three expert vascular specialists. Included were patients with near-normal function of the affected limb(s) and minimal/small foot hypertrophy. Excluded were patients with deep venous hypoplasia, aplasia or thrombosis, lymphedema (on clinical examination with or without lymphoscintigraphy), length discrepancy of the limbs more than 2.5 cm, peripheral arterial disease (ankle-brachial index <1.0), cardiac disease, walking impairment, or incomplete investigational records. Comprehensive assessment included venous duplex sonography, ascending venography, magnetic resonance imaging, strain gauge plethysmography (SGP), and a bone scanogram. Thirty-six consecutive patients with KTS were considered initially; however, 15 (8 men and 7 women) met the study criteria. Their median age was 24 years (range, 15-51 years). KTS was diagnosed in 17 limbs. KTS was unilateral in 13 patients and bilateral in 2. Limbs unaffected by KTS in patients with unilateral KTS were used as the controls (n = 13). Detailed data of the study patients are shown in Table I.

Table I. Study patients and diagnostic features of limbs affected by Klippel-Trenaunay syndrome
VariableKTSControl
No. study patients15—⁎
Male:female ratio8:7—⁎
Age (y)24; IQR, 19-33.5; range, 15-51—⁎
No. study limbs1713
Right:left ratio6:119:4
Unilateral:bilateral KTS15:213:0

Bony hypertrophy
Longer by ≤2.5 cm11 limbs
Equal4 limbs
Shorter by ≤2 cm2 limbs
Port-wine stain12 limbs
Varicose or embryonic veins17 limbs
ThighMedial 10/17
Posterior 6/17
Anterolateral 8/17
KneeMedial 9/17
Posterior 8/17
Anterolateral 8/17
CalfMedial 10/17
Posterior 8/17
Anterolateral 12/17
AnkleMedial 7/17
Posterior 7/17
Anterolateral 9/17

KTS, Klippel-Trenaunay syndrome; IQR, interquartile range.

⁎See Methods.

The distributions of the varicose veins or venous malformations in the foot, calf, and thigh and their depth in the subcutaneous or intramuscular tissues among subjects affected by KTS were noted. The severity of venous disease was determined according to the CEAP classification 8, 9 and the venous clinical severity score (VCSS).10 Reflux complexity was expressed by using the venous segmental disease score (VSDS).10

Global venous hemodynamic assessment of the lower limb was performed with SGP, as previously described.11, 12, 13 Assessment included the following parameters:

1.The venous filling index (VFI; calculated from the tangential of the refilling venous volume curve [first second], in milliliters per 100 mL/s), mirroring the amount of venous reflux.11, 14, 15, 16, 17, 18, 19, 20

2.The ejected volume (calf venous volume ejected with a single calf muscle contraction, in milliliters per 100 mL).

3.The ejection fraction (EF; ejected volume divided by the total calf venous volume times 100, in percentages), an estimate of the calf muscle pump ejection capacity.11, 14, 15, 16, 17, 18, 19, 20

4.The residual volume fraction (RVF; residual calf venous volume immediately after 10 optimal calf muscle contractions divided by the total calf venous volume times 100, in percentages), a noninvasive equivalent of the ambulatory venous pressure.11, 14, 19, 20

5.The outflow fraction (OF; percentage of calf venous outflow at 1 [OF1] and 4 [OF4] seconds from the release of a thigh cuff inflated at 50 mm Hg on recumbency in relation to the total calf venous volume), reflecting the status of venous outflow.11, 14, 20, 21

Calculation of venous global hemodynamics with SGP was performed as previously described,11, 14, 20 corresponding to that reported for venous hemodynamics obtained with air plethysmography.11, 14, 18, 19, 20

The study patients had (1) their clinical notes examined in detail, (2) stratification of chronic venous disease (CVD) according to the CEAP clinical classes (C-class)8, 9, 11 and the VCSS,10 (3) clinical assessment of the lower limb arteries with determination of the resting ankle-brachial index,22 (4) lower limb venous duplex investigation to determine the sites of venous reflux,11, 23 (5) magnetic resonance imaging of both limbs and the abdomen to ascertain the anatomic distribution of venous abnormality, with multiplanar ascending iliocavography if doubt existed on the patency and luminal intactness of the proximal deep venous system,24, 25 (6) global venous hemodynamic assessment of the lower limbs with SGP,11, 12 and (7) a bone scanogram to determine the exact difference in the length of the two limbs in unilateral KTS. Investigations were scheduled and performed within one or two consecutive days. Venous reflux exceeding 0.5 seconds was considered abnormal.11, 23 Outward perforator vein flow exceeding 0.5 seconds upon release of manual compression of the limb applied distal to the anatomic location of the perforator under study was also taken as abnormal.23 Limbs were stratified according to the presence of superficial, deep, and perforator incompetence and their combinations.

Analysis of the data was performed by using nonparametric statistics. Comparisons of quantitated nonpaired data on global venous hemodynamics and the clinical status of CVD between the affected and the control limbs were conducted with the Mann-Whitney test. The 95% confidence interval (CI) of the point estimate (PE; Mann-Whitney test) and select proportions is also quoted. Differences in proportion were assessed with the χ2 test. A P value of <.05 was considered significant. Data are expressed as median and interquartile range (IQR).

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Results 

Port-wine stain was present in 70.6% (12/17; 95% CI, 46.4%-94.7%) of affected limbs. It was located on the thigh in six limbs (35.3%), in the calf in three (17.6%), and in both in three (17.6%). The anatomic distribution of varicose veins or venous malformations in the lower extremity is reported in Table I. Venous malformations occurred in the subcutaneous space (17/17) and extended into the subfascial space in 6 (35.3%) of 17 limbs. Abnormal reflux involved all 3 venous systems (superficial, perforator, and deep) in 11 affected limbs (64.7%; 95% CI, 39.4%-90%) and involved 2 systems in the remaining 6 limbs (35.3%), of which 4 (23.5%) had superficial and deep reflux and 2 (11.8%) had superficial and perforator reflux. The overall likelihood of deep venous reflux in limbs with KTS was 88.2% (15/17), of perforator reflux was 76.5% (13/17), and of superficial reflux was 100% (17/17). In contrast, none of the control limbs had triple venous system incompetence; 3 limbs had dual-system incompetence (3/13, 23%; 2 had superficial and perforator reflux, and 1 had superficial and deep reflux), and an additional 3 had single-system incompetence (3/13, or 23%; all had superficial reflux) (Table II). Reflux in affected limbs was distributed in the great (64.7%; 11/17) and small (5.9%; 1/17) saphenous veins and the common femoral (23.5%; 4/17), femoral (41.1%; 7/17), popliteal (29.4%; 5/17), perforator (70.6%; 12/17), and axial calf (35.3%; 6/17) veins. A large lateral embryonic vein (with reflux) was present in 35.3% (6/17) of limbs with KTS. Determined with the VSDS, venous reflux complexity in limbs with KTS (median, 3; IQR, 2-4) was significantly worse (P ≤ .0001; PE, 2; 95% CI, 1-3.5) than in the control limbs (median, 0; IQR, 0-2).

Table II. Venous reflux, CEAP, VCSS, and VSDS stratification in study limbs
VariableKTSControlP value
Study limbs1713
Venous reflux
Superficial (total)17(100%)6(46.2%)<.01
Deep (total)15(88.2%)1(7.7%)<.01
Perforator (total)13(76.5%)2(15.4%)<.01
Reflux patterns <.01
S + D + P11(64.7%)0
S + D4(23.5%)1(7.7%)
S + P2(11.8%)2(15.4%)
S03(2.3%)
CEAP clinical classification <.0001
007(53.8%)
102(15.4%)
204(30.8%)
312(70.6%)0
43(17.6%)0
500
62(11.8%)0
VCSS stratification <.0001
009(69.2%)
>0 to 504(30.8%)
>5 to 108(47.1%)0
>109(52.9%)0
VSDS stratification <.0001
008(61.5%)
>0 to 27(41.2%)5(38.5%)
>2 to 47(41.2%)
>43(17.6%)

VCSS, Venous clinical severity score; VSDS, venous segmental disease score; KTS, Klippel-Trenaunay syndrome; S, superficial; D, deep; P, perforator.

The venous outflow of affected limbs (OF1, 34.9% [26.5%-36.38%]; OF4, 73.89% [60%-81.4%]) was similar to that of the control limbs (OF1, 33.6% [31.48%-35.8%]; OF4, 73.4% [63%-81.4%]; P > .5). The median amount of venous reflux (VFI) was 5.6 times higher in affected limbs than in control limbs (P ≤ .0001; PE, 0.2 mL/100 mL/s; 95% CI, 0.095-0.345 mL/100 mL/s), whereas the ability of the calf muscle pump to eject venous volumes (EF) of the latter was twice as high as that of affected limbs (P < .0007; PE, 24.3%; 95% CI, 10.6%-46.6%). The level of venous hypertension (RVF), estimated noninvasively with the RVF, was significantly higher in affected limbs than in the control limbs (P < .0035; PE, 34.5%; 95% CI, 11.6%-51.5%). A detailed account of the venous hemodynamic performance of affected limbs as compared with the control group is shown in Fig 1, Fig 2 and Table II.

Patients with KTS complained of heaviness (100%; 15/15), aching (100%; 15/15), pain (93.3%; 14/15), swelling (100%; 15/15), easy tiredness (66.7%; 10/15), and tightness (33.3%; 5/15) of the affected limb. This, in relation to the reported hemodynamic impairment in affected limbs, resulted in an overt deterioration of the venous clinical severity. The CEAP clinical classification was a median of three clinical classes worse for the affected than for the control limbs (P ≤ .0001; PE, 3 classes; 95% CI, 2-3). Similarly, the VCSS was highly significantly worse in affected limbs (P < .0001; PE, 10; 95% CI, 8-12). A detailed demonstration of these differences is provided in Fig 3.

  • View full-size image.
  • Fig 3. 

    The CEAP clinical class, venous clinical severity score (VCSS), and venous segmental disease score (VSDS) in 17 limbs with Klippel-Trenaunay syndrome and 13 control limbs.

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Discussion 

Complications related to venous abnormalities, such as (1) chronic venous insufficiency, (2) cellulitis, (3) superficial thrombophlebitis, (4) deep vein thrombosis, (5) calcification of vascular malformations, and (6) intraosseous vascular malformation, are listed among the nine common causes of real and debilitating pain in patients with KTS; the other common remaining causes are (7) arthritis, (8) neuropathy, and (9) unabated tissue growth.5 Because venous functional abnormality is fundamental in determining the clinical presentation of KTS, and in the absence of pertinent data, we quantified the venous valvular incompetence and calf muscle pump impairment in correlation with the symptoms and clinical severity of CVD. The involvement of different systems (two or more) in KTS,1, 2, 3, 4, 5, 6 resulting in gross overlap of presenting symptoms and subjective complaints, compelled us to include in the study patients who did not have lymphedema or marked length discrepancy (>2.5 cm) of the limbs. Similarly, because those with absent or hypoplastic proximal lower limb deep venous trunks form the minority in KTS6, 26 and to strengthen the homogeneity and clinical significance of our findings, we opted to exclude the few patients in whom the iliofemoral and popliteal veins could not be imaged or appeared less well developed on investigation.

The data of this study have shown that limbs with KTS have a high propensity for triple (ie, superficial, deep, and perforator reflux combined; 64.7% of limbs [11/17]) and dual (35.3% of limbs [6/17]) venous system incompetence. The propensity for both triple and dual venous system incompetence in limbs with KTS is similar to that for limbs with clinical classes CEAP 4 to 6,23, 27 reported recently at 63.6% and 36.4%, respectively.27 As for limbs with skin changes and ulceration, none of the affected limbs in KTS had single venous system incompetence.27 Believed to be critical for the manifestation of advanced grades of CVD, reflux in the femoropopliteal axis, found in a third of affected limbs, is certainly a strong indicator of the gravity of hemodynamic impairment in these limbs.28, 29 Deep reflux occurred most often in the femoral (41.1%; 7/17) and axial calf (35.3%; 6/17) veins, followed by the popliteal (29.4%; 5/17) and the common femoral (23.5%; 4/17) veins. The preponderance of abnormal venous reflux in the axial deep veins of limbs with KTS corresponds to that in legs with venous leg ulceration (CEAP 5-6).29 Demonstrated totally in 88% of affected limbs, the likelihood of deep venous incompetence in KTS exceeded that both in postthrombotic limbs 5 years after iliofemoral thrombosis treated with anticoagulation (reported in 81%)14 and in limbs with CEAP classes 5 or 6 (noted in 60%).23

The occurrence of superficial vein incompetence in affected limbs (100%), encountered twice as often as in the control limbs, was practically not different from that reported for limbs with venous ulceration (91%),29, 30 yet the likelihood of superficial incompetence varied little with increasing clinical severity of CVD from C2 to C6.23 The presence of reflux in the great saphenous vein trunk in more than two thirds of affected limbs (64.7%; 11/17) is in keeping with CVD31; however, the small saphenous vein was a relatively uncommon site of incompetence (5.9%; 1/17). Perforator reflux was a frequent finding (76.5%; 13/17), occurring, though, more often in limbs with KTS than in limbs complicated with venous ulceration.23, 29 This complexity of venous valvular incompetence in KTS, confirmed objectively with the VSDS system, was far greater than that reported previously in CVD.32 The complexity of venous valvular incompetence paralleled the amount of venous reflux in limbs with KTS, estimated at a VFI median of 0.258 mL/100 mL/s (IQR, 0.133-0.46 mL/100 mL/s); this was at least fivefold greater than that of the control limbs. Venous reflux in approximately a third of the KTS limbs (29.4%; 5/17) was 10-fold or greater than the median reflux of the controls (0.0458 mL/100 mL/s). When compared with the control group, this level of venous reflux in affected limbs is equivalent to that in limbs with advanced CVD and triple venous system incompetence or multiple incompetent perforators (three or more).27 This amount of venous reflux in affected limbs is also greater than that in limbs with complicated iliofemoral venous thrombosis both before and after successful endovenous stenting.13

Large varicose veins or venous malformations occurred most often in the anterolateral aspect of the calf (12/17) and ankle (9/17) and the medial aspect of the calf (10/17) and thigh (10/17); however, these lesions were located in any part of the ankle (≥7/17), calf (≥8/17), or thigh (≥6/17). As far as their anatomic depth was concerned, the diseased venous structures in limbs with KTS occupied the subcutaneous space in all cases (17/17) but extended through the fascia into the subfascial tissues in just over a third of the affected limbs (6/17; 35.3%). Large lateral embryonic veins, noted in more than a third of the study limbs with KTS (35%), are reported to occur in up to 55% of affected patients.3, 4

The large amount of venous reflux in limbs with KTS was associated with a significant impairment in the calf muscle pump function; their ability to eject venous volumes up into the thigh during calf muscle contraction was almost half (EFmedian, 20.8%) of that of near-normal limbs acting as controls (EFmedian, 39.3%). All affected limbs but one had an EF that was lower than the IQR of that in the near-normal control limbs. EF is impaired in 60% of limbs with CVD (CEAP 2-3), in 76% of limbs with healed ulcers, and in 90.5% of limbs with active ulcers.32 With calf muscle pump function impairment, the residual venous volume in the calf immediately after muscle contraction increases if venous valvular incompetence is present, thus causing the ambulatory venous pressure to increase.33 Because of the deficiency of the calf muscle pump in limbs with KTS acting against high volumes of refluxing venous blood, it was not surprising to find that the RVF, a noninvasive estimate of venous hypertension, was excessively increased, being approximately twice as high as that of the control limbs. The RVF, which is the common denominator of the power of the calf muscle pump against the refluxing venous blood,33 is impaired in 63% of limbs with varicose veins with or without edema (RVF, 32%-37.6%) and in 92% of legs with active ulcers (RVF, 49%-61%).32

Subjectively, patients with KTS complained of swelling (100%; 15/15), heaviness (100%; 15/15), aching (100%; 15/15), and pain (93.3%; 14/15) of the affected limbs. Two thirds (66.7%; 10/15) experienced tiredness of their limb(s), and half as many mentioned tightness (33.3%; 5/15). Objective quantification of the venous clinical severity, made possible with the VCSS introduced by Rutherford et al,10 revealed a median score of 11 (IQR, 8-12) in limbs with KTS. This is almost twice as high as that of limbs with prior iliofemoral deep vein thrombosis (6; range, 1-16),14 when the control ones had a median score of 0 (IQR, 0-1).

Considering the severity of venous hemodynamic impairment, the pattern of complexity of venous valvular incompetence, and the advanced state of venous severity, the CEAP clinical stratification of affected limbs was rather mild. In terms of clinical signs, venous disease in most of the evaluated study limbs with KTS was complicated mainly by edema (C3; 12/17, 70.6%) or skin changes (C4; 3/17, or 17.6%). Only two limbs with KTS had ulcers (C6; 2/17, or 11.8%).

Young age and fairly consistent support of the affected limbs with high-grade elastic compression probably accounted for the milder venous disease course in KTS. Patients with KTS in this series had a median age of 24 years (IQR, 19-33.5 years)—more than three decades younger than the median age of patients with primary or secondary CVD seeking medical attention,14, 27, 29, 31 including patients with venous ulcers.30 However, all but four limbs with KTS had been cared for with some form of elastic compression, with more than 40% having had comprehensive management with optimally selected elastic compression hosiery. Attenuation of venous hemodynamic impairment34, 35 with amelioration of pertinent complications in CVD with elastic compression36 is increasingly appreciated. In effect, the magnitude of reflux complexity and hemodynamic impairment, parallel to an older age, and incomplete elastic compression support seemed essential for determination of the clinical severity of venous disease in KTS. Deep venous hypoplasia, aplasia or thrombosis, lymphedema, length discrepancy of the limbs secondary to bone overgrowth, and foot hypertrophy—all possible features in KTS—may generate various grades of physical impairment and disability, with yet-unaccounted repercussions in quality of life.

Vascular morphogenesis is crucial during embryonic development, determining biological function as much in normal physiologic conditions (eg, wound healing) as in pathologic (eg, atherosclerosis and cancer) processes.37, 38 Research in vascular morphogenesis has led to the identification of the gene VG5Q (formally named AGGF1) in patients with KTS.37, 38 Tian et al37 reported 2 genetic defects of gene VG5Q in patients with KTS: a chromosomal translocation, t(5;11), which increases VG5Q transcription, and the mutation E133K, identified in 5 KTS patients, but not in 200 matched controls. The VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, whereas suppression of VG5Q expression inhibits vessel formation. The E133K mutation substantially enhances the angiogenic effect of VG5Q. VG5Q is strongly expressed in blood vessels, is secreted with the initiation of vessel formation, and binds to endothelial cells, thus promoting cell proliferation.37 Increased angiogenesis is probably a pivotal molecular mechanism in the pathogenesis of KTS. A substantial number of angiogenesis-related genes (ie, TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1, and PTEN) have been identified in vascular anomalies; however, more insight is required on the involved molecular mechanisms, which may lead to the development of therapeutic strategies for treating KTS.

In conclusion, venous disease is a major source of morbidity in patients with KTS. The study findings establish the presence of complex reflux patterns, severe venous incompetence, calf muscle pump impairment, and venous hypertension in limbs with KTS, thus explaining the advanced venous clinical severity (VCSS). In light of this, comprehensive elastic compression support, physical therapy, and excision of symptomatic varicose veins or venous malformations in selected cases are thus encouraged by the study findings.

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Author contributions 


Conception and design: KTD

Analysis and interpretation: KTD, PG, PWW, TWR, DJD

Data collection: KTD, PW, TR

Writing the article: KTD

Critical revision of the article: KTD, PG, PWW, TWR, DJD

Final approval of the article: KTD, PG, PWW, TWR, DJD

Statistical analysis: KTD

Obtained funding: KTD

Overall responsibility: KTD, PG, PWW, TWR, DJD

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References 

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 Competition of interest: none.

PII: S0741-5214(06)02084-2

doi:10.1016/j.jvs.2006.11.032

Journal of Vascular Surgery
Volume 45, Issue 3 , Pages 561-567, March 2007

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