Introduction

Klippel-Trenaunay Syndrome (KTS) is a congenital condition (occuring before birth) that occurs due to defects in the formation of the blood vessels and lymph vessels. It is characterised by the presence of malformation of the capillaries, veins, lymphatics in varying proportions, with an overgrowth of the overlying soft tissues and/or bone, making the limb to grow bigger or longer than normal (limb hypertrophy).¹ It is also called capillary- venous- lymphatic malformation (CVLM) by the International society for the study of vascular anomalies (ISSVA). It is a rare condition, occuring in 2 - 5 in 100,000 population.^2,3

It was first described in 1900 by two French surgeons; Maurice Klipel and Paul Trenauny and the lesion derived its name from this. It is occasionally wrongly referred to as Parkes- Weber syndrome. However, this lesion is a different entity as the Parkes - Weber syndrome has an arterial component.⁴ 

The lower limbs are commonly affected and it is usually unilateral. It may occasionally be bilateral and affect other regions of the body such as the upper limb, trunk, pelvis. The right and left sides of the body are equally affected.⁵ The syndrome becomes more pronounced with age as it grows with the child.

The care of patients with KTS is multidisciplinary, involving specialists such as a paediatrician, plastic surgeon, dermatologist, vascular and orthopedic surgeons. The monitoring and follow up of these patients is for life. This syndrome currently has no cure.⁶ 

Understanding Klippel-Trenaunay syndrome

Klippel-Trenaunay syndrome has no known cause. It is sporadic and occasionally familial. It is thought to be due to an abnormal change or genetic mutation in the enzyme that encodes the phosphatidylinositol-4-5-bisphosphate 3 kinase catalytic subunit gene (PIK3CA). These genes are involved in pathways in the cell which coordinate normal cell growth and differentiation. This mutation affects other pathways, eventually leading to the dysregulation of the mTOR pathway.⁷

The limbs are commonly affected in KTS, mostly unilateral; with an incidence of 85%.⁸ Other organs, although rare, are also affected including;^3,9

The gastrointestinal tract

This is involved in the absorption and digestion of food; causing complaints such as passage of blood in stool or haematochesia

The genitourinary system

This is responsible for the production and removal of urine. It causes passage of blood in the urine or hematuria 

The central nervous system

It houses the brain and spinal cord; causing bleeding within the brain, presenting as headaches, convulsions, abnormally enlarged head or hydrocephalus

Musculoskeletal anomalies

This includes limb length discrepancies, hip dislocation.

The classical signs that lead to the diagnosis of KTS is the presence of a pink stain on the skin also referred to as port wine stain representing a capillary malformation, varicose veins and an overgrowth of soft tissue and/or bone. The presence of any two of these three signs is diagnostic of KTS.¹⁰

The capillary abnormality 

This is seen in 90-100% of cases. It is mainly superficial but may affect deeper structures.^1,11 

The venous abnormality

This is present in 70-100% of patients with KTS. The superficial and or deep veins are affected with their valves.^1,11

The lymphatic abnormality

This occurs in 15-15% of cases, appearing as the presence of fluid filled sacs which may be small or large with accompanying enlargement of the limb or underlying tissues.¹

Clinical presentation in children

The child could be brought to the hospital as a healthy child in the clinic or very ill in the emergency unit because of a complication. 

Capillary abnormalities 

This is the first sign of the disease, seen at birth or within the first year of life. It appears as port wine stains. 

The dilated veins 

These become visible as the child begins to walk. Their presence in the genitourinary and gastrointestinal systems can cause haematuria and hematochezia respectively, occasionally causing massive blood loss.

Lymphatic abnormalities

This appears as localised swelling or enlargement. Presentation differs based on severity. 

Limb anomaly 

The size of the extremity varies. It may initially be normal, becoming bigger than the unaffected limb with age. The affected limb may have a normal length, longer or occasionally shorter than the unaffected limb. Sometimes, this is not apparent until adulthood.

Complications 

This includes itching, pain, bleeding from trivial injury, recurrent ulceration, infections and limb heaviness, preventing ambulation without support or causing regression of milestones such as crawling when the child is due to walk. Cosmetic embarrassment due to the deformity.^1,10,11

Clinical presentation in adults

The symptoms progress from childhood into adulthood, growing in proportion with the growth of the child and at other times, out of proportion. In a few patients, the deformity becomes apparent in adulthood. 

Adults also present as stable patients in the clinic or very ill with complications at the emergency unit. 

Capillary abnormalities 

It appears as a worsening area of redness which now becomes raised, with accompanying enlargement of the underlying soft tissue and or bone.

Venous anomalies 

The dilated veins are more pronounced, and can cause bleeding in the stool or urine in adults if they are present in the bladder or gastrointestinal tract respectively. In comparison with children, haematuria is rare in adults.¹²

Pain may occur at sites due to formation of phleboliths in the veins. Blood can get thickened in the affected veins due to sluggish flow, forming blood clots that can get to the lungs causing pulmonary embolism.

In females, abnormally dilated uterine veins may cause bleeding from the vagina.¹³ This sometimes makes a cesarean section difficult. Furthermore, the risk of forming blood clots is higher in pregnant women with KTS.⁵

Lymphatic and limb anomalies 

There is enlargement of the limb or lymphedema, heaviness and inability to walk with the affected limb due to the increased weight of the limb. 

Complications 

This includes cellulitis, venous ulcers, dermatitis, anaemia from recurrent bleeding, psychological issues, joint disease with limitation of movement.¹⁴

Diagnosis: similarities and differences by age

The diagnosis of Klippel Trenaunay syndrome is clinical.^10,11 Both in adults and children, a thorough history and physical examination will give the diagnosis. 

Radiological imaging³ 

• Doppler ultrasound scan 

The finding is similar in both age groups. It will identify any vascular malformations present; the presence of dilated veins and their patency, blood clot and the competence of the valves. 

• Magnetic Resonance Imaging (MRI)

This will identify the presence of the vascular lesions and its relationship to the surrounding structures

• Abdominal MRI, chest MRI, Brain MRI 
• MRI angiography- 

Helps to delineate any vascular lesion present

• Computerised tomography (CT) scan 
• Genetic testing - testing the genes AGGF1
• Blood count - it will give information regarding the blood level, platelet count, presence of infection and need for blood transfusion
• D- dimer¹- gives information about ongoing coagulopathy

Differential diagnosis 

• Parkes weber syndrome
• PROS overgrowth syndromes such as Proteus syndrome, 
• Neurofibromatosis type 1

Treatment in children

Emergency treatment is administered when the child presents in emergency. 

Treatment is mostly non-operative and individualised, addressing complaints.

Non operative measures 

• Observation in asymptomatic children with frequent follow up and treatment when the need arises 
• Use of compression therapy using elastic garments or bandages in patients with limb hypertrophy, varicose veins, lymphatic disease. However, this is not very convenient in children who grow rapidly
• Intermittent pneumatic compression 
• Medications to relieve heaviness in venous congestion such as mTOR inhibitors eg sirolimus and alpelisib may slow down the progression of the vessel problem and reduce pain^10,15
• Blood thinners to reduce the risk of forming blood clot 
• Laser therapy- Pulsed dye laser for cosmesis in patients with capillary malformations 
• Antibiotics in the presence of infections
• Physical therapy helps the patient with abnormal limbs to ambulate 
• Skin care with emollients to reduce itching 

Surgical options:

• Sclerotherapy- using either ultrasound guided or unguided foam or steam sclerotherapy to occlude the lumen of the veins
• Surgical correction (rare in early years)- This is needed in patients with complications such as repeated ulceration, bleeding or the presence of limb length discrepancy
• Sung et al observed children with limb length discrepancy < 1.5cm. Orthotics insole was used for children with discrepancy between 1.5- 2 cm while for discrepancy > 2 cm in length, epiphysiodesis was done at the age of 10-14 years⁵
• Debulking procedures to reduce size- The patency of the deep veins is confirmed by imaging tests before this is done
•  Amputation or surgical removal of the limb¹⁰
• Surgical removal of dilated veins in intestines is safer in children than adults

 Patients with KTS have poor wound healing.¹⁶

Supportive care

• Local wound care
• Correction of anaemia
• Lifestyle modification
• Exercise

These children should be followed up for life, monitoring their growth and development and treating complications as they arise.

Treatment in adults

Non-operative management 

• Continuation of the treatment in children 
• Use of medications - Daflon helps to improve pain in venous stasis, mTOR inhibitors such as sirolimus 
• Compression therapy is more convenient for use in adults 

Surgical interventions

Indicated in the following:

• Varicosities- use of sclerotherapy, venous stripping. Sclerotherapy for gastrointestinal bleeding is safer in adults than surgical excision
• Debulking of large limbs
• Amputation
• Management of complications (e.g., bleeding, ulcers)
  

Summary 

Klippel Trenaunay Syndrome is a rare condition characterized by malformation of the capillaries, veins, lymphatics and the presence of limb hypertrophy. Although the syndrome starts manifesting in childhood and continues to adulthood, some differences exist in the presentation and treatment in both groups. 

Treatment options slightly differ in both age groups. The non-operative treatment in children includes observation, the use of compression, medications and wound care. Surgery is indicated in life threatening conditions. Although these suffice in adults, other options include the use of surgery by debulking, sclerotherapy and amputation. Early diagnosis and prompt treatment may help to alter the course of the illness. 

It is important to provide individualized care for patients, ensuring easy transition from pediatric to adult care.