Klippel-Trénaunay syndrome

Author: Vladimir Popa-Nimigean, Medical Student, School of Clinical Medicine, University of Cambridge, Cambridge, UK. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. October 2018. 


What is Klippel-Trénaunay syndrome?

Klippel-Trénaunay syndrome (KTS) is a rare congenital vascular bone syndrome that is characterised by a triad of symptoms and features:

The syndrome is also called Klippel-Trénaunay-Weber syndrome, angio-osteohypertrophic syndrome, and haemangiectactic hypertrophy.

Klippel Trenaunay syndrome

Who gets Klippel-Trénaunay syndrome?

Klippel-Trénaunay syndrome is a rare disease, affecting 1:20,000–40,000 children. It affects males and females equally and it occurs in all races [1]. While it mostly occurs sporadically, some inherited cases have been reported [3].

What causes Klippel-Trénaunay syndrome?

While the exact cause of Klippel-Trénaunay syndrome is not clear, several genes and pathways have been identified in its pathogenesis. Notably, PIK3CA gene mutations have been detected in some cases of Klippel-Trénaunay syndrome. PIK3CA encodes for a subunit of the PI3K enzyme, which is involved in cell proliferation and migration. Gain of function mutations can lead to tissue hypertrophy in the bone, soft tissue, and blood vessels [2,4].

The angiogenic gene VG5Q has also been implicated in Klippel-Trénaunay syndrome [5].

What are the clinical features of Klippel-Trénaunay syndrome?

Capillary vascular naevus

One or more port-wine stains (capillary vascular malformations) are present in the overwhelming majority of patients with Klippel-Trénaunay syndrome and this is usually the first noticeable feature [1,2,6]. Commonly, the capillary malformation occurs over the affected hypertrophic limb, but it can also be present at other sites. Rarely, the affected area can blister and bleed [2].

Venous malformations

Varicose veins are a common feature of Klippel-Trénaunay syndrome They tend to be larger than normal varicose veins and they can be painful. Varicose veins may not be present initially. They usually become noticeable in later infancy, childhood or adolescence. Deep veins can also be affected, increasing the risk of developing deep vein thrombosis (DVT) [1–3,6].

Additionally, the formation of veins may be atypical, resulting in lateral veins or persistent sciatic veins for example. Bleeding can also occur, which may result in bleeding from the rectum or blood in the urine [6–9].

Malformations in Klippel-Trénaunay syndrome are of slow-flow vessels, and fast-flow arteriovenous malformations are not present. Bruits tend to be absent on examination [8].

Limb hypertrophy

Limb hypertrophy affects the lower limb in most cases (about 95%), with the remainder affecting the upper limb. Limb enlargement is disproportionate, with the width of the leg enlarging more than length, as the skin and muscles tend to become thicker than other sites. The average difference in limb length is around 2 cm. The length discrepancy can cause uneven walking, unstable gait or pain. The child might appear to have scoliosis [1–3,6,9].

What are the complications of Klippel-Trénaunay syndrome?

The possible complications of Klippel-Trénaunay syndrome include:

  • Deep vein thrombosis (DVT) due to malformations of deep veins
  • Pulmonary embolism
  • Cellulitis
  • Lymphoedema
  • Internal bleeding
  • Less commonly, syndactyly or polydactyly [1,2].

How is Klippel-Trénaunay syndrome diagnosed?

The diagnosis of Klipper-Trénaunay syndrome is made clinically when the classical triad of port-wine stain, varicose veins and limb hypertrophy are present. While a diagnosis of Klipper-Trénaunay syndrome can be suspected in a newborn when a port-wine stain is present, confirmation comes later when and the other symptoms become more apparent [1,2,3].

Possible diagnostic tests include:

  • Magnetic resonance imaging (MRI)
  • Magnetic resonance angiography (MRA)
  • Computer tomography (CT) or CT venography
  • Colour duplex ultrasonography
  • Ultrasound during pregnancy [3,10].

What is the differential diagnosis for Klippel-Trenaunay syndrome?

Conditions that can be mistaken for Klippel-Trenaunay syndrome are listed here.

  • Parkes-Weber syndrome; this is characterised by fast-flow arteriovenous malformations and fistulae [8].
  • Proteus syndrome; in which there are usually no obvious deformities/features at birth. Proteus syndrome presents later with progressive and more generalised musculoskeletal deformities [11].
  • Macrodistrophia lipomatosa; in this form of limb hypertrophy, there is absence of soft-tissue vascular malformations and lack of limb length discrepancy [12].

What is the treatment for Klippel-Trénaunay syndrome?

There is no specific cure for Klippel-Trénaunay syndrome and generally, most patients can be managed conservatively. Specific treatments and procedures can also be used to reduce symptoms and prevent complications [1,6,10].

Conservative management

Compression stockings are often used to control symptoms of varicose veins, alleviate pain and swelling, and prevent complications such as bleeding, in which case dressings and leg elevation and rest are recommended [1,10].

If the difference in leg lengths is small (less than 2 cm), shoe raisers might be recommended to allow the child to walk more easily and prevent compensatory scoliosis. Physiotherapy can also help reduce swelling in the affected limb [1,10].

Ligation and stripping

Ligation of the veins (or tying them off) can be used to treat varicose veins in conjunction with vein stripping. See leg vein therapies. This treatment is not advised in children [1,7,10].

Sclerotherapy

Sclerotherapy refers to the injection of a sclerosing agent into the veins in order to collapse them. It is used to treat complications arising due to varicose veins so they are no longer noticeable on the surface of the skin. It can be used in children after detailed scans of the veins in the leg have been made. Several sclerotherapy sessions months apart are usually required [1,7,10].

A variation of this procedure is foam sclerotherapy, which involves injecting a foaming agent (in addition to the sclerosing one) into the veins [7].

Laser therapy

Laser therapy can be used to treat or manage the port-wine stains, although to a limited extent. It is also used to treat small varicose veins and as an adjuvant for sclerotherapy or endovascular ablation (see below) [7,10].

Endovascular thermal ablation

Problematic varicose veins can be closed off by using high-frequency radio waves to create local heat in the affected vein. This is generally associated with fewer risks and faster recovery when compared to ligation and stripping [7].

Epiphysiodesis

If the asymmetry between the affected and unaffected legs is larger than 2 cm, epiphysiodesis can be performed to slow down the growth in the affected leg. The procedure involves prematurely fusing the growth plates and needs to be timed correctly in order to match the lengths of the legs by the end of the growth phase [6,7].

Similarly, the normal leg can also be lengthened surgically to achieve matching size [1].

What is the outcome for Klippel-Trénaunay syndrome?

Patients with Klippel-Trénaunay syndrome tend to do very well. While it is not a life-threatening condition and most patients end up having normal lives, ongoing care is required, best provided by a multidisciplinary team of dermatologists, vascular and orthopaedic surgeons, and general surgeons [1,10]. Some people may require counselling to adjust to the cosmetic aspects of the disease. [3].

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References

  1. The Birthmark Unit, Great Ormond Street Hospital for Children. Klippel-Trenaunay syndrome. July 2015. Available at: https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/klippel-trenaunay-syndrome (accessed 27 September 2018)
  2. NIH U.S. National Library of Medicine. Klippel-Trenaunay syndrome. September 2018. Available at: https://ghr.nlm.nih.gov/condition/klippel-trenaunay-syndrome (accessed 27 September 2018)
  3. Edens AC, Klippel-Trenaunay syndrome. October 2017. MedLine Plus
  4. Vahidnezhad H, Youssefian L, Uitto J. Klippel-Trenaunay syndrome belongs to the PIK3CA -related overgrowth spectrum (PROS). Exp Dermatol 2016; 25(1): 17–9. DOI: 10.1111/exd.12826. PubMed
  5. Tian X-L, Kadaba R, You S-A, 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(6975): 640–5. DOI: 10.1038/nature02320. Journal
  6. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trénaunay Syndrome: Spectrum and Management. Mayo Clin Proc 1998; 73(1): 28–36. DOI: 10.1016/S0025-6196(11)63615-X. PubMed
  7. Cleveland Clinic, Klippel-Trenaunay syndrome (KTS). January 2016. Available at: https://my.clevelandclinic.org/health/diseases/17152-klippel-trenaunay-syndrome-kts
  8. Mendiratta V, Koranne RV, Sardana K, Hemal U, Solanki RS. Klippel Trenaunay Parkes-Weber syndrome. Indian J Dermatol Venereol Leprol; 70(2): 119–22. PubMed
  9. Cohen MM. Klippel-Trenaunay syndrome. Am J Med Genet 2000; 93(3): 171–5. Available from: http://doi.wiley.com/10.1002/1096-8628%2820000731%2993%3A3%3C171%3A%3AAID-AJMG1%3E3.0.CO%3B2-K
  10. 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(8): 883–90. DOI: 10.1111/j.1365-4632.2006.02940.x. PubMed
  11. EL-Sobky TA, Elsayed SM, EL Mikkawy DME. Orthopaedic manifestations of Proteus syndrome in a child with literature update. Bone Reports 2015; 3: 104–8. DOI: 10.1016/j.bonr.2015.09.004. PubMed Central
  12. Abdulhady H, El-Sobky T, Elsayed N, Sakr H. Clinical and imaging features of pedal macrodystrophia lipomatosa in two children with differential diagnosis review. J Musculoskelet Surg Res 2018; 2(3): 130. DOI: 10.4103/jmsr.jmsr_8_18. Journal

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