Gloviczki K-T Syndrome –  Rochester 2010 – Dr. Peter Gloviczki, Mayo Clinic, July 2010 presentation

Dr. Matthew Monsein –  2010 Pain Management presentation Dr. Matthew Monsein, Courage Center Pain Rehabilitation, Minneapolis

(An Adobe Reader file)

Online Registration

The Klippel Trenaunay Support Group

is pleased to host

Dr. Matthew Monsein

Dr. Denise Adams

Vascular Malformation Clinic at the Gonda Vascular Center

Rochester, Minnesota

beginning at 1:00 P.M.

Friday, July 23, 2010

Carla Sosenko

at the **Clarion Inn (formerly Holiday Inn South)

Also scheduled:

The syndrome is characterized by a localized or diffuse capillary malformation (portwine stain) that overlies a venous malformation and/or lymphatic malformation with associated soft tissue and bone hypertrophy (excessive growth). The portwine stain is typically substantial, varicose veins are often quite numerous, and bone and soft tissue hypertrophy is variable. The affected limb is either larger or smaller than the unaffected limb. Hypertrophy occurs most commonly in the lower limbs, but may affect the arms, the face, the head or internal organs. Additionally, a wide range of other skeletal and skin abnormalities sometimes coexists.

We provide families, adults with K-T, and professionals with links to information and opportunities to learn from each other.  K-T Support Group activities include bi-annual meetings of patients and their families (with medical advisors available to those who wish it) and maintaining a confidential group roster (distributed only to group members). A periodic newsletter of shared experiences is distributed. Campaigns to seek out new members and to make the medical community aware of the group are undertaken, as are distribution of literature and information to members and the medical community. Pertinent medical literature related to K-T is shared. Phone support among members is available. Membership privacy is respected.

The K-T Support Group encourages contributions from members and others interested in Klippel-Trenaunay Syndrome. All activities are funded by and dependent upon these contributions which are the Group’s sole means of financial support. Donations are greatly appreciated and put to maximum use in furthering support and informational services. No one is refused admission to the Group for financial reasons, however.

Affiliations and Tax Status

The K-T Support Group is an Associate member of the National Organization of Rare Disorders (NORD). The   K-T Support Group has received notification from the Internal Revenue Service of official status as a non-profit, tax-exempt organization. This means that any gifts or contributions made from the date of incorporation (August 31,1998) will qualify as contributions to a tax exempt organization (i.e a Section 501 (c) (3) organization) for federal income tax purposes.).

Networking

As a service to members, we maintain an email discussion group. To request information about joining either the discussion group or the K-T Support Group, please click here to contact the Information Coordinator.

If you are not a member of the K-T Support Group, register by completing our online application:

Click here to Register

Network with us on Facebook!  To participate at our Facebook site, KT.org, send a request to support@k-t.org.

Share on Facebook at

Cases of K-T vary widely from person to person and each person must be treated on an individual basis.  Any opinions/statements expressed on this site are for general information only. The opinions/statements made are not the opinions/statements of the K-T Support Group. The K-T Support Group does not recommend treatment for specific individuals and in all cases recommends that you consult your physician or local treatment center before pursuing any course of treatment.

The K-T Support Group joins NORD and EURORDIS in promoting the 3rd annual Rare Disease Day.

Please join us to help share the message that rare diseases are an important public health concern, and that additional research is needed to develop new treatments for these diseases.

A new program called Disease Detectives, based on the real-life experiences of William Gahl, MD, and the National Institutes of Health Undiagnosed Diseases Program, will air on Rare Disease Day, in honor of the global observance.

Some of the events scheduled to bring awareness to this year’s Rare Disease Day include:

The K-T Support Group is an Associate member of the National Organization of Rare Disorders (NORD). The K-T Support Group has received notification from the Internal Revenue Service of official status as a non-profit, tax-exempt organization. This means that any gifts or contributions made from the date of incorporation (August 31,1998) will qualify as contributions to a tax exempt organization (i.e a Section 501 (c) (3) organization) for federal income tax purposes.).

The K-T Support Group encourages contributions from members and others interested in Klippel-Trenaunay Syndrome. All activities are funded by and dependent upon these contributions which are the Group’s sole means of financial support. Donations are greatly appreciated and put to maximum use in furthering support and informational services. No one is refused admission to the Group for financial reasons, however.

kT-Shirts Order Form

Help support the K-T Support Group by purchasing a kT-shirt! We are offering quality, all cotton Tees embroidered with the K-T Support logo and web address. All proceeds will go to the support group to support mail costs, meeting expenses, and other group support costs. Order your shirt TODAY!

Evaluation and Management of Pain in Patients with Klippel-Trenaunay Syndrome: A Review

Adriana Lee, MD*, David Driscoll, MD*,  Peter Gloviczki, MD , Ricky Clay, MD, William Shaughnessy, MD, Anthony Stans, MD

^* Pediatric and Adolescent Medicine
Orthopedic Surgery
Divisions of Pediatric Cardiology
Vascular
Plastic Surgery, Mayo Clinic School of Medicine, Gonda Vascular Center, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Klippel-Trenaunay syndrome (KTS) is a rare disorder that consists of a triad of capillary vascular malformation, venous malformations and/or varicose veins, and soft tissue and/or bony hypertrophy. Pain is a real and debilitating problem in these patients. We have observed 9 common causes of pain in KTS: (1) chronic venous insufficiency, (2) cellulitis, (3) superficial thrombophlebitis, (4) deep vein thrombosis, (5) calcification of vascular malformations, (6) growing pains, (7) intraosseous vascular malformation, (8) arthritis, and (9) neuropathic pain. The management of pain in patients with KTS depends on its cause. These patients are best evaluated initially in a center with an experienced multidisciplinary team that includes a primary health care provider, surgeons, and ancillary staff. The ongoing care of a patient with KTS often depends on a local provider who is more readily accessible to the patient but may not have the expertise of a large center to manage the complications of KTS. The purpose of this communication is to review the common causes of pain in these patients to provide local health care providers and patients and their families with appropriate management strategies.

Klippel-Trenaunay syndrome (KTS) is a rare disorder that comprises the triad of (1) capillary vascular malformation, (2) varicose veins and/or venous malformation, and (3) soft tissue and/or bony hypertrophy.1–4 It is a mixed malformation with soft tissue and bony malformations and is associated with predominantly venous, lymphatic, and capillary vascular malformations, with involvement of usually 1 of the lower limbs. Chronic lymphedema will frequently aggravate the clinical presentation. The manifestations of KTS are protean, and, in many patients, pain is a frequent and debilitating problem. We previously5 reported that 38% of patients had significant pain, and Baskerville et al6 found that 88% of their patients had pain. The lower extremity is most often affected in KTS, and pain is a great problem in these patients compared with those whose upper extremity is affected.

Over the past 25 years, we have collectively had the opportunity to evaluate and treat >300 patients with KTS.5,7–13 On the basis of this experience, we have observed several different patterns and causes of pain. It has become clear that to deal appropriately with pain in patients with KTS, one first must define the exact cause of the pain. The purpose of this communication is to share our experiences so that patients with this rare problem receive the best possible care.

At Mayo Clinic Rochester, we use a multidisciplinary approach to the evaluation and treatment of patients of all ages with vascular anomalies, including KTS. The core of this team includes a pediatrician/family physician or internist and vascular, orthopedic, and plastic surgeons. In addition, the expertise of vascular internists of the Gonda Vascular Center, radiologists, physiatrists, pain management specialists, and dermatologists are employed. Periodically, formal reviews of our experience are conducted and published. The basis of this communication is the cumulative experience of this multidisciplinary team.

We believe that there are 9 common causes of pain in KTS. Some patients may have only 1 cause of pain, but others may have several causes of pain.

Chronic Venous Insufficiency
Venous abnormalities are a hallmark of KTS. Superficial varicosities; persistent large superficial embryonic veins, usually in the lateral position in the leg; and deep venous valvular incompetence, aneurysmal dilation, hypoplasia, or aplasia are common. Varicose veins become more prominent and problematic with increasing age. Ambulatory venous hypertension is a well-defined entity because of increasing venous pressure after exercise as a result of valve incompetence or outflow obstruction. The discomfort that results from generalized venous congestion is poorly understood, but clearly, varicosities and venous malformations are more painful when distended with venous blood. The discomfort associated with venous incompetence is usually described as a “dull, achy” sensation and typically is more noticeable as the day progresses because of venous pooling of blood.

Varicose veins have been thought to result from primary valvular incompetence. Recent theories propose that decreased elasticity of vein walls cause dilation of the walls, leading to separation of the valve leaflets.14 Others have shown that varicosities can result even without valvular incompetence.15 Persistence of embryonic veins that normally regress during gestation is clearly a major cause of varicosities in KTS. Another plausible explanation that has been proposed for increased venous congestion is inefficient calf pump function. However, Baskerville et al6 compared foot volumetry in normal patients and KTS patients and found no significant differences in reduction of foot volumes during exercise to suggest inefficient calf pump in limbs of patients with KTS.

Chronic venous congestion can lead to pigmentation, eczema, lipodermatosclerosis, varicosity, atrophy blanche, corona phlebectatica, and, ultimately, breakdown of the skin and ulcerations. It has been found that the severity of the skin ulceration correlates with the degree of ambulatory venous hypertension.16,17 Patients with ambulatory venous pressure <40 mm Hg had a lower incidence of skin ulcers than patients with ambulatory venous pressure >80 mm Hg.18

The mainstay of treatment of this type of pain and discomfort is external compression of the venous system. It can be treated with elastic or nonelastic compression garments. It usually is best to use a closed-toe compression garment. The length of the garment is dictated by the extent of leg involvement. However, we have found that if the entire leg is involved, then a full-length pantyhose-type garment works best. This type of garment is least likely to drift downward while worn and also can provide compression to the groin and buttocks. The greatest pressure that the patient can tolerate should be used. Most patients can tolerate compression of 40 to 50 mm Hg. However, some patients cannot tolerate this level of pressure and will need compression of 30 mm Hg. Foot and leg overgrowth can present a challenge to fitting appropriately a support garment and a challenge to the patient to put on the garment. In some patients, it will be impossible to design a garment that can be applied because of a very large foot. These patients will have to be instructed in methods of wrapping the extremity with compression bandages. In rare cases of complete deep vein obstruction, patients with large superficial veins do not tolerate compression garments. Duplex evaluation of the venous anatomy in these patients is very important.

Frequent elevation of the extremity during the day is very important in reducing pain and the development of stasis ulcers. At all times, when it is possible to elevate the affected extremity, it should be done. We frequently recommend elevating the foot of the bed for good drainage of the venous system during the night. In severe cases, a patient may have to alter his or her occupation from a job that requires prolonged standing to one that allows the patient to sit and, preferably, elevate the leg.

In selected cases, surgical intervention, sclerotherapy, or endovascular laser ablation may be indicated in patients who are symptomatic with pain and edema. Asymptomatic patients are usually managed conservatively because of the high (50%) recurrence rate of varicosities.9 In the highly selected group of patients who are considered for surgical procedures, a thorough assessment of the venous anatomy should be performed with duplex scanning, contrast phlebography, MRI, and magnetic resonance phlebography. Duplex scanning and ascending and descending phlebography are used to assess valvular incompetence of the deep, superficial, or perforator veins; discover deep venous anomalies and obstructions; and assess collateralization, respectively. Frequently, the abnormalities seen in KTS include persistence of embryonic veins, agenesis, hypoplasia, valvular incompetence, or aneurysms of deep veins.

The most common surgical treatment in patients with KTS is stripping of the veins and avulsion or excision of varicosities and vascular malformations. The primary goal of imaging is to confirm patency of the deep venous system before these procedures are performed. In a very rare subset of patients, removal of the tortuous but patent superficial venous system leads to venous hypertension if deep venous reconstruction is not also performed. Although most surgical procedures for varicosities are uncomplicated, it is often impossible to remove all varicosities because of the extent of involvement. Fifty percent of patients who have surgery will have some form of recurrent varicosities. Despite this, patients report subjective improvement in symptoms and an overall clinical improvement as reflected by a reduction in the clinical severity score after surgery.9 Recurrent varicosities can and have been reoperated on if the benefits outweigh the risks of the procedure. Sclerotherapy of cavernous venous malformation with alcohol and foam sclerotherapy of the venous malformations have been used by others, with mixed results.

Cellulitis
Patients with KTS are prone to cellulitis, and whether this is attributable to an actual bacterial infection or an inflammatory response as a result of venous stasis, localized lymph accumulation, or thrombosis is not always clear.19 Chronic lymphedema is clearly a major cause of cellulitis and lymphangitis. In our series,5 13% of patients had infectious cellulitis. These patients may be more susceptible to infection because of poor skin integrity or from venous pooling. Thus, it is imperative for patients to maintain excellent skin hygiene. Maintaining strict hygiene can be challenging because of hyperhidrosis associated with KTS that is accentuated by the use of stockings, shoes, etc. Particularly for patients with significant foot and toe involvement, thorough washing of leg, foot, and toes may be challenging. We encourage patients to wash the affected body parts thoroughly with soap and water twice a day. If the patient prefers showers to bathtubs, then we suggest that he or she place a stool in the shower so that he or she can sit and wash thoroughly between the toes. It is imperative that patients wear clean stockings every day and allow their shoes and feet to dry between shoe changes. These patients should avoid going barefoot.

For some patients, use of a compression garment will reduce the incidence of cellulitis, but in others, it may increase the risk for cellulitis because of the associated hyperhydrosis or because of abrasions of keratohemangiomas by the stocking. One must experiment with this to know which is best for individual patients.

If there is new-onset erythema, local discomfort, and warmth, then cellulitis always must be suspected. It is imperative to treat these patients with antibiotics as soon as the diagnosis is apparent.

Usually, patients who have had recurrent cellulitis are able to recognize the heralding symptoms of cellulitis up to 24 hours before the infection is clinically apparent. For these patients, we suggest that they have a 10-day supply of an appropriate antibiotic at home so that they can begin taking antibiotics at the first sign or symptom of cellulitis. In rare patients, this may not be enough to prevent serious recurrent cellulitis, and one must consider prophylactic antibiotics. We think that it is best in these situations to consult with an infectious disease expert to plan the most appropriate course of treatment for these rare situations.

Growing Pains
Growing pains are normal in healthy children. Children with KTS are just as likely to have growing pains as are healthy children. The muscles are affected more so than the joints, and the area is usually normal on examination with no evidence of erythema, skin ulceration, mass, or swelling. Compared with pain caused by other factors, that of growing pains is relieved by simple comforting measures such as holding, stroking, and massaging of the limb.

Thrombophlebitis
Inflammation of the superficial veins is common in KTS and, in our series,5 occurred in 15% of patients. Aseptic inflammation probably results from venous stagnation in the lower extremity varicose veins. This type of pain is best treated with simple analgesics and antiinflammatory agents along with compression and elevation. If recurrent, then vein stripping, ligation, or injection sclerotherapy may be helpful. This should be undertaken only in a select group of patients in whom an intact deep venous system has been demonstrated. In patients with large embryonic veins or when the saphenous junctions are involved, anticoagulation should be considered.

When left untreated, superficial thromboses usually are a self-limiting problem. In 7 to 14 days, the pain subsides and a small knot may be palpable (the organized thrombus). These clots may calcify and become “phleboliths” that are apparent on radiographs. Treatment, if used, consists of nonsteroidal antiinflammatory agents and mild analgesics.

When a calcified phlebolith is on a weight-bearing surface (Fig 1), such as the plantar aspect of the foot, it can be painful when downward pressure is applied on the foot. Adding a pad to the insole will usually relieve this type of pain.

Deep Vein Thrombosis
Deep vein thrombosis (DVT) is more common in patients with KTS than in those with normal varicose veins.20 In our series, 11 (4%) of 252 patients had documented DVT.5 It is important to diagnose and treat immediately any DVT with anticoagulation or, selectively, with thrombolytics if the DVT involves the large iliofemoral veins. Pain is a usual presentation, in addition to swelling and cyanotic discoloration of the leg.

Intraosseous Vascular Malformations
Rarely, patients with KTS can have intraosseous vascular malformations.21 Although rare, they usually occur in long bones (Fig 2), but we have reported 1 patient13 who had multiple osteolytic lesions of the calvarium (Fig 3). These lesions cause intense pain. When they involve long bones, there is an increased risk for fracture. A variety of analgesics can be tried, but in most cases, surgical removal of the malformation may be necessary. If the lesions cannot be removed, then management of the pain can be challenging. Some of these patients may require long-term opiates for pain control.

Calcified or Scarified Vascular Malformations
Calcified vascular malformations can be a source of pain if located around structures that are mobile, such as the ankle joint (Fig 4). We have seen this occur in natural calcification of a vascular malformation. We have also seen it as a result of sclerotherapy of a vascular malformation. If well localized, then surgical removal may relieve this type of pain.

Arthritis
In a study of 27 patients with purely venous malformations occurring within the extremities, it was found that 81% (13 of 16) of lower limb cases and 36% (4 of 11) of upper limb cases involved arthritis of the knee and elbow joint, respectively. In 7 of the 16 lower limb cases in this study, patients had to undergo surgical treatment for severe functional impairment, which consisted of synovectomy and excision of the venous mass.22 In our experience, arthritis occurs in a very small number of patients with KTS, but in those patients, it is a major problem. Usually it involves the knee, but we have also treated patients with ankle involvement. MRI of the affected joint will establish the presence of intra-articular vascular malformation. Proliferative vascular synovitis and an associated joint effusion is the usual accompanying findings on MRI.

Destruction of cartilage occurs probably from recurrent hemarthrosis when the vascular malformation is within a joint (Fig 5). Alternatively or in addition, the presence of the vascular malformation may create a chronic synovitis. Patients with this have pain and, as a result, keep the knee flexed, and they can develop a flexion contracture.

Treatment includes analgesics and maneuvers to prevent the flexion contracture. This may involve physical therapy, passive stretching, and bracing. Synovectomy may be useful but is unproved at this time. If the flexion contracture is severe enough to prevent walking and the leg cannot be straightened, then amputation may be necessary to control the pain and allow the patient to walk (with a prosthesis).

Neuropathic Pain
Neuropathic pain results from damage or dysfunction of neuronal pathways and is a shooting, burning, aching (or a combination) pain that is poorly responsive to conventional analgesics. It often occurs in areas with altered sensation. We have evaluated 4 patients who have KTS with neuropathic pain. Their pain is disabling and associated with hyperesthesia. All 4 patients are adults, and all have KTS involving the leg. Three of the 4 had extensive surgical procedures on the leg, and in 2 of these, the pain occurred after the surgical procedures. We speculate that neuropathic pain can result from damage to nerves at the time of operation. Also, we think that this pain can result from effects of the venous abnormality on the nerve that shares the neurovascular bundle. It may result from direct compression of the nerve and/or abnormal venous pressure of the nutrient vascular system of the nerve.

The management of neuropathic pain is difficult as such pain responds poorly to conventional analgesics and less well to opioids. In the past 30 years, antidepressants and anticonvulsants have been the 2 major classes of drugs used to treat neuropathic pain.23–25 Their mechanism of action relies on inhibition of excitatory pathways or enhancement of inhibitory pathways. Drugs such as carbamazepine, phenytoin, lamotrigine, and felbamate inhibit the excitatory sodium channels, whereas valproic acid increases the inhibitory pathways of -aminobutyric acid. In this manner, the excess firing of neuronal pathways that lead to pain is dampened. The choice of which agent to use is a matter of trial and error as not one has been shown to be more efficacious than another. We tend to introduce 1 agent at a time at a low starting dose, titrate up to desired effect, and if not beneficial after a trial period of 2 to 3 weeks, we substitute another agent. More than 1 drug is sometimes necessary to control the pain. The short-term use of steroids (Prednisone) can also be used for acute neuropathic pain.

KTS occurs in 1 of 20000 to 40000 live births. The manifestations of KTS are protean and historically has been confused with other overgrowth syndromes such as Proteus syndrome and Parkes Weber syndrome. The absence of clinically significant arteriovenous shunting distinguishes KTS from Parkes Weber syndrome.26

The triad of capillary malformations (port wine stain), varicosities or venous malformations, and limb hypertrophy has been found to occur in 98%, 72%, and 67% of patients, respectively, in our series5 of 252 patients. All 3 features were present in 63% of patients, and 37% had 2 of the 3 features, which illustrates that not all patients with KTS have all 3 features of the triad, and patients can receive a diagnosis of KTS with only 1 or 2 features. The cause of KTS is still unclear. Several theories have been proposed, including (1) Servelle’s theory of a primary obstruction of the venous system resulting in venous hypertension and therefore development of abnormal venous pathways and tissue overgrowth; (2) failure of regression of the lateral limb bud vein; and (3) alteration of the tight balance between angiogenesis and vasculogenesis, which is controlled by numerous genes, among other theories.27–30 KTS is a mixed malformation whereby soft tissue and bony malformation is associated with predominantly venous, lymphatic, and capillary vascular malformations, with involvement of usually 1 of the lower limbs.

Although pain is such a prevalent morbidity factor and affects up to 88% of patients with KTS, the causes of pain have not been well documented up until now. We have observed that there are 9 most common causes of pain in these patients: (1) chronic venous insufficiency, (2) cellulitis, (3) thrombophlebitis, (4) DVT, (5) calcification of vascular malformations, (6) growing pains, (7) intraosseous vascular malformation, (8) arthritis, and (9) neuropathic pain. Common complications that accompany KTS and also may contribute to pain include pregnancy-associated complications, coagulation abnormalities, and the psychological effects of the visible overgrowth.

Perhaps chronic venous insufficiency accentuates and predisposes to the other causes of pain. If that is the case, then controlling the venous insufficiency and improving venous drainage might reduce pain of a variety of causes. Although the true pathophysiology of venous insufficiency is not yet fully understood at this point, mechanisms that incorporate external compression, limb elevation, exercise, and even a pump to improve venous drainage may be beneficial.

Because it is such a rare condition and because of its protean manifestations, most health care providers are uncomfortable treating patients with KTS. Hence, most patients become frustrated by their inability to find local health care providers who can help them deal with the many complications associated with KTS. For patients in whom pain significantly affects their quality of life, it is important to have local health care providers who can work with the patients on an ongoing basis to manage chronic pain. Because there are numerous causes of pain in KTS, the first step in management is to define the exact cause of the pain. One also must recognize that individual patients may have >1 source of pain, and treatment strategies must be designated to deal with all of the types of pain in an individual patient. A multidisciplinary team that has experience with KTS may best perform the initial evaluation of these patients. However, a local health care provider is best in providing ongoing care. We hope that this review will be useful to achieve this.

Accepted Aug 11, 2004.

Reprint requests to (D.D.) Division of Pediatric Cardiology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905

No conflict of interest declared.

1. Meine JG, Schwartz RA, Janniger CK. Klippel Trenaunay Weber syndrome. Pediatr Dermatol. 1997;60 :127 –132

2. You CK, Rees J, Gillis DA, Steeves G. Klippel Trenaunay syndrome: a review. Can J Surg. 1983;26 :399 –403

3. Guidera KJ, Brinker MR, Kousseff BG, et al. Overgrowth management in Klippel-Trenaunay-Weber and Proteus syndromes. J Pediatr Orthop. 1993;13 :459 –466

4. Berry SA, Peterson C, Mize W, et al. Klippel-Trenaunay syndrome. Am J Med Genet. 1998;79 :319 –326

5. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stans AW, Clay RP, Gloviczski P. Klippel Trenaunay syndrome: spectrum and management. Mayo Clin Proc. 1998;73 :28 –36

6. Baskerville PA, Ackroyd JS, Thomas ML, Browse NL. The Klippel Trenaunay syndrome: clinical, radiological and hemodynamic features and management. Br J Surg. 1985;72 :232 –236

7. Telander RL, Kaufman BH, Gloviczki P, Stickler GB, Hollier LH. Prognosis and management of lesions of the trunk in children with Klippel-Trenaunay syndrome. J Pediatr Surg. 1984;19 :417 –422

8. Gloviczki P, Hollier LH, Telander RL, Kaufman B, Bianco AJ, Stickler GB. Surgical implications of Klippel-Trenaunay syndrome. Ann Surg. 1983;197 :353 –362

9. Noel AA, Gloviczki P, Cherry KJ, Rooke TW, Stanson AW, Driscoll DJ. Surgical treatment of venous malformations in Klippel-Trenaunay syndrome. J Vasc Surg. 2000;32 :840 –847

10. Cherry KJ, Gloviczki P, Stanson AW. Persistent sciatic vein: diagnosis and treatment of a rare condition. J Vasc Surg. 1996;23 :490 –497

11. Gloviczki P, Stanson AW, Stickler GB, et al. Klippel-Trenaunay syndrome: the risks and benefits of vascular interventions. Surgery. 1991;110 :469 –479

12. McGrory BJ, Amadio PC, Dobyns JH, Stickler GB, Unni KK. Anomalies of the fingers and toes associated with Klippel-Trenaunay syndrome. J Bone Joint Surg Am. 1991;73 :1537 –1546

13. Sorom A, Driscoll DJ, Stanson AW. Klippel-Trenaunay syndrome: a rare cause of severe headache. Int Angiol. 2002;11 :7 –8

14. Travers JP, Brookes CE, Evans J, et al. Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content. Eur J Vasc Endovasc Surg. 1996;11 :230 –237

15. Rose SS, Ahmed A. Some thought on the etiology of varicose veins. J Cardiovasc Surg. 1986;27 :534 –543

16. Araki CT, Back TL, Padberg FT, et al. The significance of calf pump function in venous ulceration. J Vasc Surg. 1994;20 :872 –877

17. Labropoulos N, Ginannoukas AD, Nicolaides AN, et al. The role of venous reflux and calf muscle pump function in nonthrombotic chronic venous insufficiency. Correlation with severity of signs and symptoms. Arch Surg. 1996;131 :403 –406

18. Nicolaides AN, Zukowski AJ. The value of dynamic venous pressure measurements. World J Surg. 1986;10 :919 –924

19. Quartey-Papafio CM. Lesson of the week: importance of distinguishing between cellulitis and varicose eczema of the leg. BMJ. 1999;318 :1672 –1673

20. Fowkes FJ, Price JF, Fowkes FG. Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg. 2003;25 :1 –5

21. Samlaska CP, Gagliardi JA. Diffuse venous malformation with intraosseous involvement. Hawaii Med J. 1994;53 :218 –221

22. Enjolras O, Ciabrini D, Mazoyer E, Laurian C, Herbereteau D. Extensive pure venous malformation in the upper or lower limb: a review of 27 cases. J Am Acad Dermatol. 1997;36 :219 –225

23. McQuay H. Neuropathic pain: evidence matters. Eur J Pain. 2002;6(suppl A) :11 –18

24. Dickenson AH, Matthews EA, Suzuki R. Neurobiology of neuropathic pain: mode of action of anticonvulsants. Eur J Pain. 2002;6(suppl A) :51 –60

25. Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical evidence. Eur J Pain. 2002;6(suppl A) :61 –68

26. Biesecker LG, Happle R, Mulliken JB, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84 :389 –395

27. Tian X, Liu M, Kadaba R, et al. Positional cloning of a novel angiogenic factor gene: VG5Q mutations cause susceptibility to KTS. Nature. 2004;427 :640 –645

28. Whelan AJ, Watson MS, Porter FD, Steiner RD. Klippel Trenaunay Weber syndrome associated with a 5:11 balanced translocation. Am J Med Genet. 1995;59 :492 –494

29. Ceballos-Quintal JM, Pinto-Escalante D, Castillo-Zapata I. A new case of Klippel-Trenaunay-Weber (KTW) syndrome: evidence of autosomal dominant inheritance. Am J Med Genet. 1996;63 :426 –427

30. Servelle M. Klippel and Trenaunay’s syndrome. 768 operated cases. Ann Surg. 1985;201 :365 –373

KLIPPEL-TRENAUNAY SYNDROME

“Moodie, D., Driscoll, D., Salvatore, D., Peripheral Vascular Disease in
Children, In:Young, J., Olin, J., Bartholomew, J., Peripheral Vascular
Diseases, 2nd Edition, Mosby Yearbook Publishers, 1996, p541–552.”

Klippel-Trenaunay Syndrome (KTS) consists of a triad of cutaneous capillary hemangioma, bone and soft tissue hypertrophy, and venous varicosities (1).  The etiology of KTS is unknown but some authors have suggested that it results from a mesodermal abnormality that occurs during fetal development leading to the maintenance of microscopic arteriovenous communications in the limb bud (2).  Most commonly it is a sporadic event. Although there have been a few cases reported in which more than one family member supposedly had the syndrome other authors suggest that this may have not been the case (3,4).  It has been suggested that KTS could result from the action of a mosaic gene abnormality that is lethal to the gamete when present in all cells of the embryo (5).  We have seen two patients with intriguing associations. One patient has prolonged QT interval syndrome and the other a translocation of chromosome 8 and 14. Whether these are coincidental abnormalities or provide a clue to the location of a causative gene is unknown

KTS should be distinguished from Parks-Weber Syndrome.  In Parks-Weber Syndrome there are clinically apparent and important arteriovenous fistulae where as in KTS any arteriovenous fistulae that exist are microscopic in size and unassociated with the typical clinical findings of arteriovenous fistulae.  The natural history of these syndromes are different.  For example, because patients with KTS do not have arteriovenous fistulae, high output cardiac failure does not occur.

The manifestations of KTS are variable (fig 1-3).  In a study of 144patients evaluated at the Mayo clinic (6), 132 had lower extremity involvement, 37 had upper extremity involvement, 21 had pelvic and abdominal involvement, 25 had involvement of the thorax and 7 had head and neck involvement(Table 1).  In the same study 110(76%) had varicosities, 137(95%) had hemangiomas, and 134 (93%) had limb hypertrophy…

With occasional exceptions, the appearance of the baby shortly after birth will define the ultimate appearance of the child and young adult.  The exceptions to this include: a) the cutaneous capillary hemangioma (port wine stain) may become lighter or darker; b) dark small nodular escrescence may develop on the skin; c) as growth occurs the limb length discrepancy may increase; d) some of the apparent increased mass may regress as baby fat regresses; e) subcutaneous masses may appear; and f) venous varicosities and, possibly dependent lymphedema will become more prominent with time.  Parents should be reassured, however, that unaffected extremities and organs will not become affected the future.

CLINICAL MANIFESTATIONS

VENOUS VARICOSITIES AND MALFORMATIONS
The venous involvement in KTS can range from subtle abnormalities to massive varicosities and absence of important deep venous structures.  The venous abnormalities usually involve the affected extremity and are apparent as superficial varicose veins.  Dilation of superficial varicose veins may be unapparent in infancy but become apparent with increasing age. Not all patients with KTS have superficial venous varicosities.

In addition to superficial varicosities, many patients have abnormalities of the deep venous system of the extremity.  The deep venous abnormalities can include dilation of the deep veins, absent venous valves, hypoplasia of the veins, and complete absence of the deep venous system.  It is critically important to ascertain the status of the deep venous system if one is considering removal of superficial varicosities since the superficial venous system cannot be removed if the deep venous system is inadequate to provide venous drainage of the extremity.  Because of the venous malformations some patients with KTS can develop thrombophlebitis.

Venous varicosities also can involve intraabdominal and intrapelvic organs.  In Gloviczki’s series, 10% of the patients manifest rectal bleeding and 3% had hematuria (6).  Others have reported that 20% of their patients have had rectal bleeding, 10% had hematuria and 33% had evidence of abnormal intrapelvic veins(7).  Venous or arteriovenous malformations have been described in other locations in rare patients with KTS.  These include bone, spinal and intracranial locations.

In addition to the complete absence of the deep venous system of an extremity, absence of the inferior vena cava has been reported (8) and we have observed absence of the internal jugular veins.

LYMPHATIC ABNORMALITIES
Many patients with KTS have abnormalities of the lymphatic system.  Since in no series of patients have these abnormalities been looked for in a systematic fashion the incidence of lymphatic abnormalities is unknown.  In one series it was reported that 20% of patients have cutaneous vesicles which leak lymph.  However in our experience exudation of lymph is less common.  It frequently is unclear if the edema of an affected dependent extremity is a result of venous insufficiency, abnormal lymphatic drainage or a combination of the two.  Some patients do develop soft tissue masses that are reminiscent of cystic hygromas.  These masses can occur on an effected extremity or over the trunk, head, or neck

CAPILLARY HEMANGIOMAS AND OTHER CUTANEOUS LESIONS
There is a broad spectrum of cutaneous manifestations of KTS.  Most commonly there is a port wine stain which can be very light in color to deep maroon.  This lesion can be flat or elevated.  The integrity of the skin over the hemangioma may be excellent or poor.  In some cases the capillary hemangioma is raised considerably from the surface and may be verrucous in nature.  Some areas of the malformation may be prone to skin breakdown, bleeding, and infection.  In general the intensity of the color of the hemangioma lessens as the child ages.  However, some patients develop dark (deep blue to black) 1-2 mm nodules on top of the hemangioma or, at times, over seemingly unaffected portions of skin.  These can be quite friable and prone to spontaneous bleeding or bleeding after minor trauma.  Cutaneous or subcutaneous cavernous hemangiomas occur in 40% of patients(1).  These can produce a spongy feel to the skin and frequently are associated with lymphangiomas
Other cutaneous manifestations of KTS include phlebectasias, hyperhidrosis, hyperthermia and hypertrichosis.  Patients with KTS are prone to cellulitis.  It is unclear if these episodes are always secondary to bacterial infection or to a local inflammatory response in response to pockets of lymph accumulation.

BONE AND SOFT TISSUE HYPERTROPHY
In Gloviczki’s series, 95 of 144 patients had one extremity longer than the other and 100 of 144 patients had a swollen or circumferentially enlarged extremity (6).  Most commonly a lower extremity is affected but in a forth of the patients an upper extremity is involved.  Usually the longer, bigger extremity is also the extremity that exhibits the skin and vascular changes but occasionally the extremity with skin and vascular involvement is the shorter or smaller extremity.  The bony hypertrophy may effect all the bones in an extremity or be limited to one or two bones.  Some patients may have macrodactaly.
In addition to bony hypertrophy, many patients have soft tissue hypertrophy.  This can be quite limited; for example to a localized mass on the back or chest, or can be quite widespread; for example involving an entire arm or leg.  The soft tissue hypertrophy is usually fatty and contains variable amounts of venous structures.
Other limb findings that have been described in KTS include syndactyly, clinodactyly, polydactyly, split hand deformity, metatarsal and phalangeal agenesis, osteolysis, congenital dislocation of the hip, and peripheral neuropathy (1).

HEAD, CENTRAL NERVOUS SYSTEM AND EYE INVOLVEMENT
Patients with KTS can have macrocephaly and, less frequently, microcephaly.  Intracranial angiomas, arteriovenous malformations, and intraspinal angiomas have been described.  More than 40 cases of KTS have been described in association with Sturge-Weber syndrome(9).
Ophthalmologic findings reported in association with KTS include: conjunctival telangiectasia, retinal varicosities, choroidal angioma, glaucoma, coloboma iridis, heterochromia iridis, intraorbital varix, and enophthalmos(1,10).

ADDITIONAL FINDINGS AND PROBLEMS

COAGULOPATHY
Some patients with KTS exhibit evidence of an intravascular coagulopathy.  This usually is mild but in some patients can be relatively severe and result in bleeding after minor trauma or major bleeding associated with surgical procedures.  This coagulopathy probably represents a form of Kasabach-Merritt syndrome and may be manifest by thrombocytopenia, reduced fibrinogen, and the presence of fibrin split products(11).  It is prudent to assess patients’ coagulation status prior to planned surgical procedures

PULMONARY EMBOLI
There have been several instances of fatal and nonfatal pulmonary emboli in patients with KTS.  It is unclear at this point, which patients with KTS are at risk for this complication.  Some episodes have been associated with bed rest following a surgical procedure.  One author has recommended that patients with KTS receive anticoagulation therapy when admitted to a hospital or, long-term anticoagulation therapy for those who have had a documented thrombotic event (7).

SYNCOPE
Patients with large venous capacitance in the legs can be prone to lightheadedness and syncope when standing.

MANAGEMENT ISSUES

COMPRESSION THERAPY
Most patients with lower extremity involvement experience some degree of lower extremity edema.  This usually is not manifest until after the child begins walking and gravitational forces become a factor.  It is important to remember that an extremity may be enlarged because of increased bony and soft tissue mass as well as edema.  Compression of the extremity with elastic support will acutely lessen the edema but there is no data that chronic compressive therapy will result ultimately in less bony or soft tissue mass.  Also, compression will not affect the ultimate length of the leg.  Patients with a major component of lymphedema and those with severe venous insufficiency seem to derive the most benefit from chronic compressive therapy.  Compressive therapy also should be used for patients with edema and recurrent cellulitis.  It may reduce the frequency of episodes of cellulitis.  Compression may or may not be useful for patients with friable skin lesions that tend to bleed.  In some cases the compression garment will protect the sites and lessen the bleeding but in other cases, the garment may irritate the skin and increase the bleeding episodes.  Compression therapy may slow the progression of lower extremity varicose veins.  Compression therapy also is useful for patients with upper extremity involvement who have problems with edema.
We do not favor compression therapy for young children.  In general young children will not tolerate wearing a compression garment, they will rapidly outgrow the garment and the parents will just become frustrated.
In general a compression garment should extend from the tip of the toes to well above the involved site.

REMOVAL OF VARICOSE VEINS
Unsightly or painful superficial varicose veins can be removed in selected patients.  It is critical that the status and integrity of the deep venous system be established before superficial veins are removed.  If the deep venous system is inadequate, the superficial veins should not be removed.

EPIPHYSIODESIS
Epiphysiodeses are done to assure relatively equal leg lengths at full maturation.  This procedure is necessary only if the projected limb length discrepancy exceeds 2.0 cm.  It is important that this operation be done at the appropriate time.  Parents need to be reassured that the operation need not be done during early childhood.  Most epiphysiodeses are done between 10 and 14 years of age.  For limb length discrepancies less that 2.0 cm, shoe lifts can be uses.
Intentional destruction of growth plates also can be done to control excessive growth of digits.

AMPUTATION AND RAY RESECTION
Amputation of digits, and portions of an extremity should only be undertaken to improve function of the extremity and to manage otherwise uncontrollable infection or bleeding.  Many of these children manage to obtain excellent function from an extremity that is quite enlarged and malformed.  An important dictum in managing these patients is to operate to improve function rather than for cosmesis and never to sacrifice function to obtain improved cosmesis.         Patients with discordant foot size may have difficulty fitting the foot into a shoe.  We have found that ray resection is a very satisfactory procedure to reduce excessive foot width

DEBULKING PROCEDURES
The potential complications of debulking procedures should be considered carefully before undertaking this type of treatment.  The potential drawbacks of debulking procedures include: 1.  the bulk can return, 2.  the bulk is traded for a scar, 3.  the debulking procedure may interrupt the venous and lymphatic drainage in an extremity with compromised drainage to begin with , 4.  wound infection, and 5.  poor skin healing with resultant chronic lymphatic ooze.  In general the more proximal on a extremity a debulking procedure is considered , the greater are the risks for interfering with venous and lymphatic drainage.  Conversely, debulking procedures on digits, the hands, and feet are tolerated better than those on more proximal locations.  As noted above one must always consider function above form when contemplating surgical procedures for patients with KTS.

LASER THERAPY
Laser therapy can be used to reduce the discoloration of capillary hemangiomas.  Before embarking on this treatment it must be remembered that the procedure is painful.  Also frequently it is the parent that opts to have the lesion treated but it is the child who must undergo the discomfort.  It may preferable to wait until the child is old enough to participate in the decision to have this treatment.

ANTIBIOTICS
Antibiotics are used to treat cellulitis.  For patients who have recurrent cellulitis, maintaining the patient on prophylactic antibiotics may be helpful.

GASTROINTESTINAL BLEEDING
Gastrointestinal bleeding can occur in patients with perirectal or pericolonic varicose veins.  Bleeding can range from minimal to life threatening.  As with all cases of GI bleeding the source of bleeding needs to be defined.  If the bleeding is secondary to varicose veins and is not life threatening, treatment should consist of stool softeners and iron replacement.  Surgery may be necessary to deal with massive recurrent bleeding.

REFERENCES

1.  STICKLER, G.  KLIPPEL-TRENAUNAY SYNDROME, IN NEUROCUTANEOUS
        DISEASES, A PRACTICAL APPROACH  GOMEZ, M.,ED ,
        BUTTERWORTHS, BOSTON, 1987.

2.  BASKERVILLE, P., ACKROYD, J., BROWSE, N., THE ETIOLOGY OF THE KLIPPEL-
        TRENAUNAY SYNDROME, ANNALS OF SURGERY,202:624-627,1985

3.  AELVOET,G, JORENS, P., ROELEN, L., GENETIC ASPECTS OF THE KLIPPELL-
        TRENAUNAY SYNDROME, BRITISH JOURNAL OF DERMATOLOGY, 126:603-
        607,1992

4.  JORGENSON, R., DARBY, B., PATTERSON, R., TRIMMER,K., PRENATAL
        DIAGNOSIS OF THE KLIPPEL-TRENAUNAY-WEBER SYNDROME, PRENATAL
        DIAGNOSIS, 14:989-992,1994

5.  HAPPLE, R., LETHAL HENES SURVIVING BY MOSAICISM: A POSSIBLE
        EXPLANATION FOR SPORADIC BIRTH DEFECTS INVOLVING THE SKIN, JOURNAL
        OF THE AMERICAN ACADEMY OF DERMATOLOGY, 16:899- 906,1987.

6.  GLOVICZKI, P., STANSON, A., STICKLER, G., JOHNSON, C., TOOMEY, B.,
        MELAND, N., ROOKE, T., CHERRY, K., KLIPPEL-TRENAUNAY SYNDROME:
        THE RISKS AND BENEFITS OF VASCULAR INTERVENTIONS, SURGERY,
        110:469-479.

7.  KLIPPEL-TRENAUNAY SYNDROME IN DISEASES OF THE VEINS, PATHOLOGY,
        DIAGNOSIS AND TREATMENT, BROWSE, N., BURNAND, K., THOMAS, M.,
        ED, EDWARD ARNOLD, BALTIMORE, 1988

8.  STEWART, G., FARMER,G., STURGE-WEBER AND KLIPPEL TRENAUNAY
        SYNDROMES WITH ABSENCE OF INFERIOR VENA CAVA, ARCH DISEASE
        CHILDHOOD(ENGLAND) 65:546-547, 1990.

9.  DEUTSCH, J., WEISSENBACHER, G., ET AL, COMBINATION OF THE SYNDROME
        OF STURGE-WEBER AND THE SYNDROME OF KLIPPELL-TRENAUNAY, KLIN
        PAEDIATR, 188:464-471,1976.

10. BROD, R., SHIELDS, J., SHIELDS, C., OBERKIRCHER, O., SABOL, L., UNUSUAL
        RETINAL AND RENAL VASCULAR LESIONS IN THE KLIPPEL-TRENAUNAY-
        WEBER SYNDROME, RETINA, 12:355-358, 1992

11. D'AMICO, J., HOFFMAN, GL., DYMENT, PL., KLIPPEL-TRENAUNAY
        COAGULATION AND MASSIVE OSTEOLYSIS, CLEVELAND CLINIC
        QUARTERLY, 44:181-188, 1977

Patients
    Location                      n     %

Lower extremity                 132    92
    Unilateral                  103    72
        Right                    53    37
        Left                     50    35
    Bilateral                    29    21
    Lower extremity only        106    74
    Lower and upper extremities  26    18
Upper extremity                  37    26
    Upper extremity only         11     8
Pelvis or abdomen                21    15
Thorax                           25    17
Head and neck                     7     5

Patients
    Location                      n     %

Varicosity                      110    76
    Atypical (lateral)           66    46
    Suprapubic                    2     1
    Usual distribution           46    32
Hemangioma                      137    95
    Capillary                    89    62
    Lymphangioma                 12     8
Limb Hypertrophy                134    93
    Longer extremity             96    66
    Swollen extremity           100    69
Pain                             46    32
Cosmetic problem only            35    24
Bleeding from hemangioma         28    19
Thrombophlebitis                 18    12
Cellulitis                       13     9
Ulcers                           11     8
Verrucae                          9     6
Rectal Bleeding                  14    10
Macroscopic hematuria             4     3
Paraparesis                       4     3
Deep venous thrombosis            6     4
Pulmonary embolization            4     3

]]> http://k-t.org/?feed=rss2&p=43 0