HISTORYThis syndrome was first described in 1900 by the French physicians Maurice Klippel and Paul Trenaunay.1,2 Classically, Klippel-Trenaunay syndrome (KTS) is composed of a triad of clinical features: capillary malformations, congenital varicosities/venous malformations, and soft tissue and bony hypertrophy.3-5
INCIDENCE AND ETIOLOGY
The incidence is about 1 in 30,000 live births.6 There is no predilection for sex or race.3
The cause of this syndrome remains largely unknown. The occurrence is generally sporadic. Affected patients usually possess normal karyotypes.7 Rarely, reciprocal translocation of chromosomes 5 and 11, balanced translocation of chromosomes 8 and 14, and mosaic de novo supernumerary ring chromosome 18 have been reported.8,9 The E133K allele of gene VG5Q (an angiogenic growth factor) encoded on chromosome 5 is a potential etiological factor.10
Familial aggregation, with KTS or another vascular malformation in family members, has been reported.11,12 This has led to the following hypotheses on the syndrome's pattern of inheritance:
| ● | Autosomal inheritance.13 |
| ● | Paradominant, or a "two-hit," inheritance.14 |
| ● | Survival of dominant lethal genes via mosaicism—genetic mutations that occur late in embryogenesis, when enough nonmutated cells are present to survive.7,15 |
| ● | Polygenic inheritance of several simultaneous mutations in genes in a manner similar to paradominant inheritance.7 |
Pathologically, KTS results from malformation of capillary, venous, and lymphatic systems. Several hypotheses on the pathogenesis have been postulated3,7,16:
| ● | Congenital spinal anomalies, which result in reduced autonomic control of capillaries in the distribution of spinal nerves, lead to regional arteriovenous malformations and hypertrophy from localized increased blood flow. |
| ● | Disturbed embryonic vasculogenesis results in sporadic cutaneous findings and hypertrophy from abnormal capillary (afferent) blood flow (active hyperemia). |
| ● | Deep venous abnormalities decrease venous (efferent) blood flow and produce varicose veins and hypertrophy (passive hyperemia). |
| ● | Generalized mesodermal defects result in failure of the embryonic vascular system to regress. |
CLINICAL MANIFESTATIONS
The presence of 2 of the 3 cardinal features in at least one affected region of the body supports a diagnosis of KTS.7 These features can occur anywhere on the body but most commonly affect the trunk and limbs (95% of cases involve the lower extremities, whereas 5% involve the upper extremities).3,4,7 The face is involved in only 5% of cases.17 Multiple limbs (unilateral or bilateral) may be affected; KTS involving all 4 limbs is rare.7
Capillary malformations typically manifest as portwine stains of varying darkness distributed in a patchy configuration on the trunk and extremities. They rarely cross the midline and are ipsilateral to the hypertrophic limb in 85% of cases.3,4 The port-wine stains are present at birth and may fade with sporadic capillary thromboses, but they rarely completely disappear.4 Occasionally, capillary malformations affect subcutaneous tissues, muscles, and body cavities.18
Congenital varicosities usually affect the lower limbs and range from small, superficial vessels to extensive, large, erratic vessels that involve deep venous systems.3 In 68% to 80% of patients, an impressive superficial lateral vein, termed "vein of Servelle," extends from the dorsum of the foot proximally and laterally before it terminates at the internal iliac vein, profunda femoris vein, superficial femoral vein, or popliteal vein.4
Soft tissue and muscular hypertrophy primarily manifests as increased girth and length of a limb.3 The discrepancy is often evident, although sometimes subtly, at birth; it becomes more noticeable at the time of ambulation.3
COMPLICATIONS
Capillary malformations can lead to limb atrophy and hemorrhage.4,6,16,19 In addition, venous changes can be complicated by cellulitis, hemorrhage, paresthesia, stasis dermatitis, stasis ulcerations, thrombophlebitis, and lymphedema.4 Vascular complications can be potentially life-threatening and include venous thromboembolism, pulmonary embolism, variceal bleeding, and consumptive coagulopathies.16,19 Of note, patients who become pregnant and use prothrombotic medications have an increased risk of vascular complications.20
Mechanical effects of limb length abnormalities can lead to scoliosis, arthritis, and abnormal gait.16 Skeletal complications include congenital hip dislocation, arthritis, bone decalcification, macrodactyly, spina bifida, syndactyly, and carpal tunnel syndrome.3,4,16 Cutaneous complications include hyperhidrosis and hypertrichosis.16 Lymphedema, when present, can be devastating.3 The presence of "geographic" port-wine stains (large, darkpigmented stains with sharp borders) has been linked with increased risk of lymphatic complications.21 Debilitating chronic pain is also a significant complication resulting from the above-mentioned changes.22
DIFFERENTIAL DIAGNOSIS
Although phonetically similar, KTS should be distinguished from Klippel-Trenaunay-Weber syndrome, which is characterized by hemodynamically significant arteriovenous fistulas in the setting of a patient with KTS.5 Other differential diagnoses include Sturge-Weber syndrome, Proteus syndrome, Maffucci syndrome, isolated hemihypertrophy, and neurofibromatosis types 1 and 2.3,4,23 Each syndrome is clinically distinct and can be differentiated by a thorough history and the physical examination findings.3,4,23
DIAGNOSTIC STUDIES
Imaging complements clinical diagnosis and is used to evaluate disease severity and progression, determine clinically significant arteriovenous shunting, and guide therapy.4,5 MRI is particularly helpful for general assessment and has minimal adverse effects.5 Serial plain radiographs of long bones are also routinely used to monitor progression of limb length discrepancies; this is because imaging measurements are accurate to within 0.1 cm, whereas measurements obtained during the clinical examination are limited to 0.5 to 1.0 cm.5 Color duplex scanning may be used to examine the anatomy and patency of the superficial and deep venous systems.4,5 This test can be followed by high-quality 3-dimensional venography when chronic insufficiency is suspected.5
TREATMENT AND PROGNOSIS
Management is mainly symptomatic and conservative. External compression is first-line treatment of lymphedema, recurrent cellulitis, and chronic venous insufficiency.4,5 Other conservative management includes physiotherapy, massage therapy, local wound care, and orthotic supports.5 Also, psychological stressors of the illness should be routinely addressed with all patients.5
Absolute indications for treating vascular malformations include hemorrhage, infections, acute thromboembolism, and refractory ulcers. Relative indications include pain, cosmesis, and limb asymmetry.5 Noninvasive procedures include pulsed dye laser therapy to decrease the appearance of port-wine stains, sclerotherapy and embolotherapy to reduce low-flow capillary malformations, and foam sclerotherapy and endothermal ablation to reduce venous malformations.5
The prognosis is good; most patients have a full life span.3 Cognition is generally unaffected.2