Introduction

Klippel-Trenauny syndrome (KTS) is a constellation of symptoms and signs comprising capillary malformation, venous abnormality, lymphatic abnormalities, and limb overgrowth.¹ It occurs before the child is born. However, manifestation is variable, occurring at birth, childhood, or adulthood. It is also known as angio-osteohypertrophy syndrome.² 

It is rare and affects 2-5% of 100,000 population.¹ It is not restricted to any gender or race. 

Care of this condition involves multiple specialists, including vascular surgeons, dermatologists, plastic surgeons, and orthopaedic surgeons.¹ The care is for life.

This condition can resemble other conditions, confusing diagnosis. The purpose of reviewing the differential diagnosis in this article is to discuss other conditions that present similarly to KTS and distinguish it from KTS. 

Key features of klippel-trenaunay syndrome

KTS is characterised by a triad of 

• Capillary malformation (port wine stains) 
• Venous malformation or varicosities and 
• An abnormally enlarged limb ( with overgrowth of soft tissue and or bone).

The diagnosis is made when at least two of the above are present.¹ 

Usual onset and progression

It occurs before birth, during the formation of blood vessels and lymphatics. 

The capillary malformation is first seen at birth, where it appears as small patches; it grows as the child grows and becomes more pronounced with age, appearing coarse and raised.

The venous abnormality, which appears as abnormally dilated veins, is seen when the child starts walking. 

The lymphatic abnormality and limb overgrowth are also noted to progressively increase with age.  

Commonly affected areas

It affects the lower limbs commonly, usually unilateral, but is bilateral in 12.5% cases.³ The other parts affected include the upper limbs, the central nervous system, the abdomen, the vascular system, the gastrointestinal system, and the genitourinary system.²

Conditions similar to KTS and their distinguishing features

Parkes weber syndrome (PWS)

This is a condition that comprises malformation of multiple vessels: capillary, venous, lymphatic, arteriovenous (AV) malformation, and the presence of limb overgrowth in the limb with AV malformation.⁴

It occurs infrequently and is due to a mutation in the gene, RASA 1.⁵  It affects both genders equally. 

It commonly affects the lower limb; however, it can affect the upper limb, pelvis, etc.³

It may be asymptomatic, or present with clinical features suggestive of the disease, such as the presence of port wine stain, varicose veins, swelling of the limb which is warm with pulsatile varices, and or thrill.^4,5

Differences

Arteriovenous malformation is present in the Parkes-Weber syndrome and absent in KTS. Although both are distinct entities, it is sometimes wrongly referred to as Klippel-Trenaunay-Weber syndrome.

Diagnostic clues 

A Doppler ultrasound scan identifies the presence of arteriovenous shunts. Contrast CT scan or MRI also diagnoses and gives a full extent of the lesion. Contrast arteriography aids diagnosis and treatment.

Complications 

Congestive heart failure, limb pain, ulceration as a result of the arterial steal syndrome due to AV malformation, and cellulitis of the limb.

Treatment 

The use of compression garments early, embolectomy, surgical resection of the AVM, and the use of stent graft implantation. Amputation is offered to patients with intractable pain and non-healing ulcers arising from the disease.

Proteus syndrome

It is a congenital condition that occurs due to the excessive and uncontrolled irregular overgrowth of different  tissues such as the skin, soft tissues, bone, and other organs.⁷  

It is rare, occurring in 1:1,000,000 to 1 in 10,000,000 cases. 

It is characterised by the presence of epidermal nevi, connective tissue nevi appearing as the convolutions of the brain called cerebriform connective tissue nevi, malformation of the blood vessels (including capillary malformation, which is the commonest and, to a smaller extent, venous and lymphatic malformation), dysregulated growth of the fatty tissues, and limb overgrowth.^7,8

Although it occurs before birth, manifestations are commonly seen between 6 months to 18 months of age. 

It affects the brain, spinal cord, causing scoliosis; skin, kidneys, spleen, gastrointestinal tract; the bones and fatty tissues. The growth of the fatty tissues may be excessive or reduced. 

Affected individuals are prone to having cancers occurring before the age of 20 years, such as cancer of the parotid gland.

It occurs due to a mutation in the AKT1 gene. Thompson et al. described a set of criteria, major and minor criteria, to aid in its diagnosis.

Similarity to KTS  

Vascular malformation and limb overgrowth are present in both 

Difference 

The cerebriform nevus is a unique characteristic feature of this condition.⁹ Furthermore, the limb deformity is so severe, causing deformity with psychological embarrassment, epidermal nevi. 

Treatment 

This involves multiple specialists. It comprises non-operative methods, including the use of lasers for skin lesions, the use of splints to stop the progression of scoliosis, and medications such as anticoagulants for venous thrombosis. Surgery is used to remove deformity in exposed areas such as the face; correct scoliosis, control bony overgrowth, or amputate the limb.⁹ 

The life expectancy in these individuals is poor, ranging from 9 months to 29 years. It varies based on the severity of the anomaly and the affected site. The commonest cause of death is pulmonary embolism.⁸ 

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal anomalies)

CLOVES syndrome is an acronym for congenital lipomatous overgrowth, vascular malformation, Epidermal nevi, and skeletal anomalies, including deformity of the spinal cord (scoliosis) or limbs. It starts before birth but grows slowly with the child.¹⁰ It is rare, affecting 1:1,000,000 population, with only a few reported cases.¹¹ It is caused by a mutation in the PIK3A gene.

The fatty overgrowth occurs around the trunk, paraspinal muscles, and the limbs. It causes deformity in these regions; it may occur alone or in combination with a vascular malformation or nevi. Depending on its location, it may cause compression at sites where it occurs, resulting in complications, for example, respiratory difficulties if it occurs around the neck. 

The vascular malformation varies, and it may include capillary malformation, venous malformation, and lymphatic malformation, with most of these lesions found on the trunk. The epidermal nevi are seen on the trunk. The skeletal anomalies vary. It includes overgrowth of the digits or entire limb, or digits, most commonly the middle digit, scapula, gait, triangular feet with a wide forefoot. The limb can be severely affected, causing no appearance of toes.¹² 

Unlike the other overgrowth syndromes, it causes a ballooning of the affected part, causing asymmetrical, slow growth of the affected side.¹¹

Other organs affected include the renal system, spleen, and neurologic disorders manifestations such as tethered cord syndrome.¹³

Similarities

Vascular anomalies, limb overgrowth

Differences 

The presence of lipomatous masses, mainly affecting the trunk, and epidermal nevi, which are absent in KTS. Massive limb abnormality, Genetic marker: PIK3CA mutation

Generalised lymphatic anomaly (GLA)

This is a condition characterised by abnormal diffuse growth of lymphatic channels in multiple locations.^15,17 It may affect the soft tissue, viscera, bone, or skin. It affects the viscera, appearing as lymphatic fluid within the chest cavity (chylothorax) or peritoneum (chylous ascites).¹⁵ 

It is seen as a progressive enlargement of the limbs. It may occur at birth, childhood, or adulthood. When it affects the bone, it is seen as areas of bone loss within the bone. It differs from other lymphatic anomalies, such as the Gorham-Stout disease (GSD), which is similar to the GLA; however, in GSD, there is a progressive replacement of adjacent bone by lytic cells due to the presence of abnormal lymphatic tissue at the site. In GLA, contiguous bone may not be affected; the disease is not progressive.15,17 Clinical examination findings of a bag of fluid which can be displaced within the subcutaneous tissue of the limb are suggestive of the disease. The prognosis is good when it affects the limbs, but poorer with visceral involvement.¹⁵

Similarities

Limb enlargement and asymmetry, vascular nevi, chylous effusions

Difference 

Significant lymphatic channels affected, trunk involvement

Investigations

lymphoscintigraphy, histopathologic examination of specimens.

Treatment

Multidisciplinary 

Surgical resection of affected tissues 

Diffuse capillary malformation with overgrowth (DCMO)

Characterised by the presence of capillary malformation,  with associated proportional overgrowth of the soft tissues of the non-progressive limb. Although veins are present, they are not venous malformations, and other vessel malformations are typically absent. Other associated features present include the presence of limb anomaly such as syndactyly, macrodactyly, and widened 1st webspace of the foot, referred to as a sandal gap.¹⁴ 

The cause is unknown; however, it is thought to be due to a GNA 11 mutation. 

A high index of suspicion is needed to differentiate it from other vascular anomalies and limb overgrowth syndromes.

Maffucci syndrome maffucci syndrome

Characterised by the presence of vascular lesions and multiple tumours of the bone, referred to as enchondromas. The affected limb is enlarged compared to normal. It differs from KTS as there are no bone tumours in KTS.

Similarities

Vascular lesions

Differences

• The presence of multiple bone swellings or tumours called enchondromas, which have a high risk of being cancerous
• Imaging findings: cartilaginous tumours in bones
• Brain imaging: leptomeningeal angiomas

Table 1: Key distinguishing features of the differential diagnosis of KTS.

Diagnostic tools and workup

• Clinical history and physical examination
• Imaging includes Ultrasound scan, Doppler studies, CT scan, MRI - differentiate the vessels involved, distinguishing capillary, venous, lymphatic anomaly from an arterial malformation; determine the nature of the deformity, extent, and relation to surrounding viscera or structures
• Genetic testing
• Histopathologic examination of the resected specimen 

Summary 

Klippel-Trenauny syndrome is a rare abnormality with unique features. However, it presents similarly to other syndromes.

Early and accurate diagnosis will be obtained when the differential diagnosis and key distinguishing factors are known. 

In all, a high index of suspicion, evaluation by clinical, laboratory, and imaging techniques will help diagnose. Care is multidisciplinary and should be individualised.