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Vascular

Klippel-Trenaunay syndrome

KTS affects blood vessel development and can lead to various medical challenges, primarily impacting limbs. It is caused by changes in the PIK3CA gene that occur after conception, meaning it is not typically inherited.

Somatic / Mosaic Vascular Tier C OMIM:149000
Rare
Prevalence
Population estimate
1
Associated genes
PIK3CA

Overview

Klippel-Trenaunay syndrome (KTS) is a rare condition that affects the development of blood vessels, bones, and soft tissues. It is typically present at birth, though some features may become more apparent over time [PMID:33678564]. Individuals with KTS usually have a combination of three main features: a red birthmark (capillary malformation), abnormal veins (venous malformation), and overgrowth of a limb, most often a leg. The condition's severity can vary significantly among affected individuals, even within the same family, though KTS is usually caused by changes that occur after conception.

KTS is considered a segmental overgrowth syndrome, meaning that the overgrowth typically affects only one part of the body, rather than the entire body. While the lower limbs are most commonly affected, overgrowth can also occur in the upper limbs, trunk, or, less frequently, internal organs. The condition requires a multidisciplinary approach to management due to its varied presentation and potential complications.

Symptoms & clinical features

The primary symptom of KTS is a red or purple birthmark, known as a capillary malformation (often called a 'port-wine stain'). This birthmark is typically flat, irregular in shape, and present on one limb, though it can also appear on the trunk or face. It may darken with age and can sometimes cause discomfort, bleeding, or be prone to infection.

Another key feature is the presence of venous malformations, which are abnormal, dilated veins. These can be superficial (close to the skin surface) or deep. Superficial venous malformations may appear as bluish, swollen areas, while deep malformations can lead to pain, swelling, and an increased risk of blood clots (thrombosis) [PMID:33678564]. Lymphatic malformations, which involve the lymphatic system, can also occur, causing swelling (lymphoedema).

Limb overgrowth is the third characteristic feature, usually affecting one leg or arm. This can lead to differences in limb length (leg length discrepancy), which may cause issues with mobility and posture. The overgrowth can involve bone, soft tissue, or both. Pain, reduced mobility, and recurrent infections are common concerns associated with KTS symptoms. Some individuals may also experience bleeding from vascular malformations or develop ulcers.

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Affected organs

KTS primarily affects the skin, blood vessels, and musculoskeletal system. The skin is impacted by capillary malformations, which are visible birthmarks. The vascular system is significantly involved, with abnormalities in both capillaries and veins, which can occur superficially or deep within tissues [PMID:24606708]. The lymphatic system may also be affected, leading to lymphatic malformations and swelling.

The musculoskeletal system, particularly the limbs, shows overgrowth of bone and soft tissue. This overgrowth is usually localised to one side of the body. In some cases, internal organs can be affected by vascular malformations, though this is less common. This can potentially lead to complications depending on the organ involved, such as the bladder or intestines.

Multiple body systems
Multiple body systems
Systemic involvement
Cellular impact
Cellular impact
Mechanism at cellular level

Risks & severity

The severity of KTS can vary widely, from mild cases with minimal symptoms to more severe presentations with significant complications. The lifetime risks associated with KTS largely depend on the extent and location of the vascular malformations and overgrowth. Complications can include chronic pain, recurrent cellulitis (skin infection), bleeding from fragile vascular lesions, and impaired mobility due to limb length discrepancy or massive overgrowth.

Individuals with KTS have an increased risk of developing blood clots, particularly in the abnormal veins [PMID:33678564]. This can lead to deep vein thrombosis (DVT) and, in rare cases, pulmonary embolism. Lymphoedema can cause chronic swelling and discomfort. The age of onset for KTS symptoms is typically at birth, with features either present at that time or developing shortly thereafter. The overgrowth and vascular malformations can progress over time, requiring ongoing monitoring and management.

Genetic causes

Klippel-Trenaunay syndrome is understood to be caused by somatic variants in the PIK3CA gene. Somatic variants are genetic changes that occur in some cells after conception but are not present in every cell of the body. This means the variant is not inherited from a parent and cannot be passed on to future children.

The PIK3CA gene provides instructions for making a protein that is a key component of the PI3K (phosphatidylinositol 3-kinase) signalling pathway. This pathway plays a crucial role in regulating cell growth, division, and survival [PMID:24606708]. When a somatic variant occurs in PIK3CA, it can lead to overactivity of this pathway in specific cells or tissues, resulting in the abnormal cell proliferation and differentiation observed in KTS. These variants are typically gain-of-function, meaning they enhance the protein's normal activity.

  • PIK3CA
    phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
    The PIK3CA gene provides instructions for a crucial enzyme involved in fundamental cellular processes such as growth, division, and survival.

Inheritance pattern

Klippel-Trenaunay syndrome typically follows a somatic inheritance pattern. This means the genetic change (variant) in the PIK3CA gene happens in a body cell very early in development, after the egg has been fertilised, rather than being inherited from a parent's egg or sperm. As a result, only some cells in the body carry the variant, leading to a mosaic pattern of affected tissues.

Because the genetic changes are somatic and not present in the reproductive cells (sperm or eggs), KTS is generally not passed down from parent to child. It is considered a non-hereditary condition. Therefore, individuals with KTS usually do not have affected family members, and the risk of future children inheriting the condition is typically very low.

Diagnosis & testing

Diagnosis of Klippel-Trenaunay syndrome is primarily clinical, based on the presence of the characteristic triad of capillary malformations, venous malformations, and limb overgrowth [PMID:24606708]. Imaging studies, such as ultrasound, MRI, or CT scans, are often used to evaluate the extent of vascular malformations and limb overgrowth, helping to confirm the diagnosis and guide management.

Genetic testing for somatic PIK3CA variants can confirm the diagnosis, especially in atypical or complex cases. This testing often requires samples from affected tissues, rather than standard blood samples, due to the mosaic nature of the variants. Referral to an NHS Clinical Genetics service, often via a GP or specialist, is appropriate for individuals suspected of having KTS. Genetic counsellors within these services can provide further information about testing options and the implications of a diagnosis. The relevant NHS Genomic Medicine Service R-code for testing related to overgrowth syndromes, which may include KTS, is R207.

Management & lifestyle

Management of Klippel-Trenaunay syndrome is highly individualised and aims to address specific symptoms and prevent complications. It often involves a multidisciplinary team, including dermatologists, vascular specialists, orthopaedic surgeons, and physiotherapists. Treatment options for capillary malformations may include laser therapy to lighten the birthmark. Venous malformations might be managed with compression garments, sclerotherapy (injecting a solution to shrink the veins), or surgical removal in some cases.

Limb overgrowth and length discrepancy often require orthopaedic interventions, such as custom footwear, orthotics, or, in some instances, surgical procedures to equalise limb length. Physiotherapy can help maintain mobility and muscle strength. Regular monitoring for complications such as blood clots and infections is crucial. The NHS provides care through specialist centres, and a clinical genetics team can help coordinate investigations and referrals within the NHS Genomic Medicine Service framework. Genetic counsellors can also provide support and information regarding the condition.

UK care pathway

In the UK, individuals with suspected Klippel-Trenaunay syndrome are typically referred to specialist services within the NHS. This often begins with a GP referral to a paediatrician or a clinical genetics service. Clinical geneticists and genetic counsellors play a key role in confirming the diagnosis, explaining the genetic basis, and coordinating further investigations and management. Genetic testing for overgrowth syndromes, including KTS, is available through the NHS Genomic Medicine Service under R-code R207, which requires a referral from a clinician.

Management is usually provided by a multidisciplinary team in specialist centres, tailored to the individual's specific symptoms and needs. Genetic counsellors offer crucial support, helping families understand the condition, its implications, and available support networks. They can also discuss the non-inherited nature of KTS and provide appropriate family planning advice.

Frequently asked questions

Is Klippel-Trenaunay syndrome inherited?

No, Klippel-Trenaunay syndrome is typically not inherited. It is caused by genetic changes (variants) in the PIK3CA gene that occur after conception, meaning they are present in some body cells but not in the reproductive cells. This makes it a sporadic condition, and the risk of passing it on to children is usually very low.

What is the red birthmark in KTS?

The red birthmark seen in KTS is called a capillary malformation, often referred to as a 'port-wine stain'. It is caused by an abnormal collection of small blood vessels (capillaries) close to the skin surface. It is usually flat and can vary in size and colour.

Can KTS affect internal organs?

While KTS primarily affects the limbs, skin, and superficial blood vessels, in some cases, vascular malformations can occur in internal organs. This is less common but can lead to specific symptoms and complications depending on the organ involved.

How is limb length difference managed?

Limb length difference due to overgrowth in KTS is often managed by orthopaedic specialists. Treatments can include using shoe inserts or lifts to even out leg length, or, in some situations, surgical procedures to either slow the growth of the longer limb or shorten it, to improve mobility and posture.

What should I do if I suspect KTS in myself or my child?

If you suspect Klippel-Trenaunay syndrome, it is important to speak with your GP. They can provide a referral to a specialist, such as a paediatrician or a clinical geneticist, for a thorough evaluation and potential genetic testing within the NHS Genomic Medicine Service.

References

  1. John PR. Klippel-Trenaunay Syndrome. Techniques in vascular and interventional radiology. 2019. PMID: 31864529
  2. Turner VL, Kearns C, Wattamwar K. Klippel-Trenaunay Syndrome. Radiographics : a review publication of the Radiological Society of North America, Inc. 2022. PMID: 36190869
  3. Fang X, Kuang F, Lei S. Klippel-Trénaunay syndrome. Joint bone spine. 2022. PMID: 35114345
  4. Suda T, Katagiri A, Fujii H. Klippel-Trenaunay Syndrome. Internal medicine (Tokyo, Japan). 2023. PMID: 36171122
  5. Santino MFF, Lopes MJP. INVERSE KLIPPEL-TRENAUNAY SYNDROME. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2020. PMID: 33331597
  6. Bukhari S, Saati A. Upper-Extremity Klippel-Trenaunay Syndrome. Rhode Island medical journal (2013). 2024. PMID: 38687265
  7. Porres-Aguilar M, Auron M, de Leon MCG. Klippel-Trenaunay and pregnancy. Oxford medical case reports. 2021. PMID: 34729195
  8. Harna B, Tomar S. Klippel Trenaunay Syndrome. Indian journal of pediatrics. 2020. PMID: 32036598
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.