Publication date: 2013-03-12
Version: 3.0
Klippel-Trenaunay syndrome (sometimes shortened KTS) is a congenital disorder characterised by skin abnormalities (port-wine stains, naevus flammeus), venous and/or lymphatic vascular malformations, soft tissue enlargement, and localised skeletal anomalies.
The syndrome was first described in 1900 by French neurologists Maurice Klippel and Paul Trenaunay. Another older name for the condition is angioosteohypertrophy syndrome (angio=vessel, osteo=bone, hypertrophy=cell, tissue, or organ enlargement).
The port-wine stains are caused by capillary malformations, and may present in isolation or in combination with other vascular anomalies. Other vascular malformation disorders, sometimes confused with Klippel-Trenaunay syndrome, include Sturge-Weber syndrome (see separate information in the Rare Disease Database of the Swedish Board of Health and Welfare), Parkes-Weber syndrome, Servelle-Martorell syndrome and Proteus syndrome.
Parkes-Weber syndrome is a more severe disorder than Klippel-Trenaunay syndrome, characterised by a large number of abnormal connections between the arteries and veins (arteriovenous malformations). In both these conditions the vascular malformations usually affect an arm or a leg, but in Parkes-Weber syndrome the skin marks are lighter and there is local warmth. Parkes-Weber syndrome is not associated with lymphatic vascular malformations, coagulation disorders or pulmonary thrombosis. Deep vein thrombosis is also very rare.
Servelle-Martorell syndrome is another vascular malformation disorder, affecting capillaries, veins, and sometimes lymph vessels. The arm or leg with vascular malformations will be smaller than the other arm or leg.
The symptoms of Proteus syndrome resemble those of Klippel-Trenaunay syndrome, but in Proteus syndrome soft tissue or skeletal hypertrophy is more marked.
The international estimated incidence of Klippel-Trenaunay is 2-5 per 100,000 newborns, meaning that in Sweden approximately 2-5 children are born with the syndrome every year. It is equally common in girls and boys.
Although the aetiology of the disease remains unknown, it is believed that the syndrome results from a mutation in a gene regulating vascular growth in tissues. The mutation probably occurs during early foetal development. The specific gene mutation has not yet been identified.
As the vascular malformations and soft tissue hypertrophy only affect restricted parts of the body, and the degree of severity varies, it is likely that the mutation is only present in some tissues of the body.
Although the cause of Klippel-Trenaunay is most likely genetic, it is very unusual for several cases to occur within a family.
Vascular malformations associated with Klippel-Trenaunay syndrome are congenital and affect small superficial blood vessels in the skin and the veins (the vessels transporting blood to the heart), which become enlarged (varicose veins). In most cases the lymph vessels are also affected, leading to tissue swelling (lymphatic oedema) and/or fluid retention. The most conspicuous signs of the disease are port-wine stains of various sizes, caused by capillary malformations. Some anomalies associated with Klippel-Trenaunay syndrome may not be evident at birth, and can remain undetected for years. The condition does not spread to other parts of the body.
Newborns with the syndrome may have localised soft tissue swelling, for example on the back or chest, or one arm or leg may be enlarged (hypertrophy) with superficial port-wine stains. Hypertrophy may progress until puberty. This will sometimes result in leg length discrepancy, which may lead to asymmetrical loading of the spine and consequent scoliosis. Toes and fingers are sometimes enlarged.
The vascular malformations commonly affect one arm or leg, which often becomes enlarged both in terms of length and circumference. The face, abdominal wall and internal organs may also be affected, and in rare cases, one entire side of the body.
The number of capillaries is usually normal, but may be increased in some cases. The affected vessels are dilated, probably as a result of damage to the nerves that control them and they develop a rough surface that may increase the blood flow, thereby altering skin colour. Port-wine stains range from light red to deep reddish-brown, and they may be smooth or slightly elevated. With time, they may either darken or fade. Sometimes they develop small vesicles (small blisters) that may bleed, or the skin may become dry, or eczema develop. Superficial vessels may be affected by inflammation (thrombophlebitis). Although these lesions are benign, they may be aesthetically displeasing. Other symptoms such as varicose veins, cellulite, heat sensations and increased sweating may occur and cause discomfort.
Venous malformations vary in size, ranging from superficial abnormalities to extensive varicose veins and malformations in the deep venous system. These may cause oedemas, and which may also ulcerate and bleed. Approximately 20 per cent of all cases are associated with blood clots forming within a vein (venous thrombosis), associated with an increased risk of blood clot in the lung (pulmonary embolism). Lymph vessel malformations may also occur and cause soft-tissue swelling and fluid retention.
Sometimes, particularly during pregnancy, swelling increases and may give rise to sensations of pressure, hyperthermia, and pain. Physical activity and heavy work often exacerbate the symptoms, but owing to the circulation problems it is still important to be as physically active as possible.
Lymphatic vascular malformations may become infected. In rare cases, blood vessels of the internal organs, for example the urinary tract, genital tract or intestinal wall, are affected. Bleeding may result, indicated by blood in faeces or urine, or as heavy menstrual bleeding.
Klippel-Trenaunay syndrome is generally not associated with abnormal connections between veins and arteries (arteriovenous malformations). Many individuals with the syndrome have a marginal vein on the surface of the arm or leg, a remnant of embryonic vessels that have failed to regress. With age, the marginal vein becomes enlarged, thereby causing a decrease in size of the normal deep veins in the arm or leg. Marginal veins are dilated and thickened, and small arteries empty blood into them in order to compensate for poor circulation in the leg or arm. This may result in increasing problems, such as large superficial veins, bleeding, thromboses, and slow blood flow (venous stasis).
Other, very rare symptoms associated with Klippel-Trenaunay syndrome include finger or toe fusions (syndactyly) or supernumerary fingers or toes (polydactyly).
Symptoms vary considerably among individuals, ranging from mild, barely noticeable, to severely debilitating. Varicosities and hypertrophy associated with the syndrome may affect both fine and gross motor skills. Hypertrophy may affect daily life activities, both on the practical and the psychological levels. For example, it may be difficult to find clothes and shoes that fit properly.
The diagnosis is based on clinical evidence. At least two of the following criteria must be fulfilled:
- Skin anomalies (birthmarks or port-wine stains)
- Venous and or lymphatic malformations
- Localised soft tissue and/or skeletal hypertrophy
There is no cure for Klippel-Trenaunay syndrome, and treatment focuses on alleviating symptoms and compensating for disabilities. Owing to the wide variation in symptoms and degree of disability, treatment must always be adapted to the needs of the individual. Individuals with mild symptoms may not require treatment.
Magnetic resonance imaging (MRI) should be carried out to assess soft tissue abnormalities, which are often more extensive than suggested by clinical findings. Sometimes an ultrasound examination is carried out in order to identify venous and lymphatic vascular abnormalities.
Individuals who have had blood clots, and/or have wide-ranging venous malformations, extensive superficial veins, or heavy, prolonged menstrual periods, should undergo a coagulation assessment. Deep venous or pulmonary thrombosis and coagulation disorders are treated with long-term, sometimes lifelong anticoagulant therapy. This treatment is carried out in collaboration with a coagulation specialist, especially before or after surgery, and in association with embolization, a treatment method for occluding dilated veins.
An elastic garment may be used to relieve discomfort associated with soft tissue swelling. Compression therapy may also prevent the development of varicose veins, reduce the risk of vein inflammation, and protect affected skin from minor injuries that may cause bleeding. Raising the legs while sitting or lying down can relieve swelling as well as discomfort or pain.
Joint and skeletal pain due to swelling, as well as pain associated with skin anomalies and wounds can be alleviated with medication. Infections of the skin or dermis are treated with antibiotics, and if there are repeated infections prophylactic antibiotics may also be necessary.
Laser treatment can help lighten port-wine stain birthmarks, but it cannot remove them. Repetitive treatments are normally required to achieve the desired effect, and laser therapy is usually reserved for treating aesthetically displeasing lesions. Skin discolorations can also be concealed with covering makeup.
Localised varicose veins may be removed surgically, but the intervention must always be preceded by an evaluation of the status of the deep venous system.
Limited varicose abnormalities can be treated with sclerotherapy, which is the process of injecting the veins with a sclerosing solution that causes scarring on the inside of the vessels. The scars obstruct the blood flow, and as a result the veins occlude. Beta blockers can be used to treat major lymphatic abnormalities that cause bleeding.
Localised soft tissue swelling causing discomfort as well as limited hypertrophy of an extremity may be an indication for surgery.
Orthopaedic assessment and treatment are often essential, for example if one leg is longer than the other. To keep this discrepancy from increasing, further bone growth can be prevented by surgery. This operation is usually carried out between the ages of 10 and 13. A customized shoe lift can be used to prevent asymmetrical loading of the spine and gait abnormalities. Physiotherapy is beneficial to retain mobility in the affected limb, and a physiotherapist may design an individualised exercise programme. Sometimes a change of routines, aids, and home adaptations may be needed to optimise mobility and function. An occupational therapist may provide practical assistance.
The Swedish KTS network (see under "Organizations for the disabled/patient associations") provides practical advice and support. For example:
Compression stockings should be medical grade, and preferably custom-made by an occupational therapist, a nurse or an orthopaedic technician. Use of these stockings decreases leg pressure and the risk of dizziness caused by poor circulation. Apart from preventing injury, they also lower the risk of spontaneous bleeding and blood clots, as well as relieving swelling.
It is important to keep the skin soft and well moisturised. Skin creams should be neutral, as having superficial vascular malformations is often associated with sensitivity to scented products. There is an over-the-counter cream that relieves bruises, vascular inflammation and superficial blood clots, but it cannot be used on open sores.
Vascular malformations are associated with a risk of hypersensitivity to plasters and surgical tape.
Physical activity increases muscle mass and improves circulation. All activities should be adapted to the individual, and the affected part of the body should not be overloaded.
A few Swedish health care teams specialise in blood and lymph vascular disorders. These teams consist of physicians, occupational therapists, and physiotherapists with specialised knowledge and experience in the field of vascular anomalies and who continuously follow current research:
The Vascular Centre, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00. Coordinator: Anni Tovi, email: ann-christin.tovi@karolinska.se.
Multidisciplinary Vascular Malformation Group, Dermatology Clinic, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00. Contact: Associate Professor Agneta Troilius.
Plastic Surgery Clinic, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00. Contact: Peter Wroblewski, MD, email: peter.wroblewski@vgregion.se
Assessment and treatment of limb hypertrophy is carried out at paediatric orthopaedic clinics and/or hand surgery clinics.
Chief physician Paul Tordai, Department of Hand Surgery, Aleris Specialist Care, Sabbatsberg Hospital, Olivecronas väg 1, SE-113 24 Stockholm, Sweden. Tel: +46 8 690 63 00, email: paul.tordai@aleris.se.
Chief physician Metin Tovi, Vascular Unit, ENT Clinic, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, email: metin.tovi@karolinska.se.
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The Swedish KTS network: www.svenskaktsnatverket.se. Contact: Marie Weis, email: marie.weis@svenskaktsnatverket.se, tel: +46 70 32 32 239, or Ingela Park, email: ingela.park@svenskaktsnatverket.se, tel: +46 73 52 10 202.
There is a US Klippel-Trenaunay Syndrome Support Group: www.k-t.org.
The Proteus and KT Family Network UK: www.proteus-uk.org.
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An information leaflet on Klippel-Trenaunay syndrome that summarises the information in this database text is available free of charge from the Publications Department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2012-5-22). Address: SE-106 30 Stockholm, Sweden. Fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se, or tel: +46 75 247 38 80. Postage will be charged for bulk orders.
Klippel-Trenaunays syndrom. Brochure in Norwegian (2010). Order from: Frambu, Senter for sjeldne funksjonshemninger, Sandbakkveien 18, NO-1404 Siggerud, Norway. Tel: +47 64 85 60 00, fax: +47 64 85 60 99, email: info@frambu.no. The text can also be printed out from www.frambu.no.
Klippel-Trenaunays syndrom. Brochure in Danish (2007). Order from: Center for Små Handicapgrupper, Bredgade 25 F, 5 sal, DK-1260 Köpenhamn K, Danmark. Tel: +45 339 140 20, fax: +45 339 140 19, email: csh@csh.dk. The text can also be printed out from www.csh.dk.
The websites of the Klippel-Trenaunay Syndrome Support Group and the Klippel-Trenaunay Foundation have information in English: www.k-t.org.
Funayama E, Sasaki S, Oyama A, Furukawa H, Hayashi T, Yamamota Y. How do the type and location of a vascular malformation influence growth in Klippel-Trenaunay syndrome? Plast Reconstr Surgery 2011; 127: 340-346.
Hu Y, Li L, Seidelmann SB, Timur AA, Shen PH, Driscoll DJ et al. Identification of association of common AGGF1 variants with susceptibility for Klippel-Trenaunay syndrome using the structure association program. Ann Hum Genet 2008; 72: 636-643.
Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trenaunay Syndrome: Spectrum and Management. Mayo Clinic Proc 1998; 73: 28-36.
Karuppal R, Raman RV, Valsalan BP, Gopakumar TS, Kumaran CM, Vasu CK. Servelle-Martorell syndrome with extensive upper limb involvement: a case report. J Med Case Rep 2008; 2: 142.
Kihiczak GG, Meine JG, Schwartz RA, Janniger CK. Klippel-Trenaunay syndrome: a multisystem disorder possibly resulting from a pathogenic gene for vascular and tissue overgrowth. Int J Dermatol 2006; 45: 883-890.
Liu NF, Lu Q, Yan ZX. Lympathic malformation is a common component of Klippel-Trenaunay syndrome. J Vasc Surg 2010; 52: 1557-1563.
Oduber C, Bliek J, van der Horst C, van Steensel M, Hennekam R. Monozygotic twins discordant for vascular malformations and dysregulated growth. Eur J Med Genet 2010; 53; 14-18.
Redondo P, Bastarrika G, Aguado L, Martinez-Cuesta A, Sierra A, Cabrera J et al. Foot and hand malformations related to deep venous system anomalies of the lower limb in Klippel-Trénaunay syndrome. J Am Acad Dermatol 2009; 61: 621-628.
Tian XL, Kadaba R, You S, Liu M, Timur AA, Yang L et al. Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature 2004; 427: 640-645.
OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: klippel-trenaunay syndrome
The Swedish Information Centre for Rare Diseases produced and edited this information material.
The medical expert who wrote the draft of this information material is chief physician Paul Tordai, Aleris Specialist Care, Sabbatsberg, Stockholm.
The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.
An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.
Publication date: 2013-03-12
Version: 3.0
Publication date of the Swedish version: 2012-09-10
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.