Version May 2024
INTRODUCTION — Klippel-Trenaunay syndrome (KTS) is a complex congenital disorder defined as the triad of capillary malformation, venous malformation, and limb overgrowth, with or without lymphatic malformation [1,2]. In the past, a number of different conditions have been lumped together under the moniker of KTS, including Parkes Weber syndrome and diffuse capillary malformation with overgrowth (DCMO) [3], but clearer descriptions of phenotype and genotypic studies have helped in distinguishing these disorders.
KTS will be discussed in this topic. The diagnosis and management of other capillary malformations and related overgrowth syndromes are discussed separately. (See "Capillary malformations (port wine birthmarks) and associated syndromes" and "PTEN hamartoma tumor syndromes, including Cowden syndrome".)
EPIDEMIOLOGY — Klippel-Trenaunay syndrome (KTS) is rare. Its incidence and prevalence are not known. There is no apparent ethnic or sex predilection.
DEFINITION AND CLASSIFICATION — The 2018 classification of the International Society for the Study of Vascular Anomalies defines Klippel-Trenaunay syndrome (KTS) as a syndrome with capillary and venous malformations as well as limb overgrowth, with or without lymphatic malformation [2]:
●KTS as part of PROS − Because most of the more severe cases of KTS genomically analyzed have been found to be caused by mosaic activating variants in the PIK3CA gene, experts have proposed that KTS be labeled not as a distinct diagnostic entity but as part of the PIK3CA-related overgrowth spectrum (PROS) [2,4-6]. PROS groups lesions with heterogeneous, segmental, overgrowth phenotypes, with or without vascular anomalies, and, in addition to KTS, includes [2]:
•Fibroadipose hyperplasia or overgrowth
•Hemihyperplasia multiple lipomatosis
•CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies) syndrome
•Macrodactyly
•Fibroadipose infiltrating lipomatosis/facial infiltrative lipomatosis
•Macrocephaly-capillary malformation (M-CM, MCAP)
•Dysplastic megalencephaly
●Distinction between KTS and DCMO − We acknowledge that many milder cases previously diagnosed as KTS without lymphatic involvement fit better under the diagnosis of diffuse capillary malformation with overgrowth (DCMO) [3] (see 'Diffuse capillary malformation with overgrowth' below). Despite fulfilling the clinical criteria for KTS, these patients have more proportionate overgrowth rather than progressive overgrowth, lack lymphatic disease, and typically have more diffuse or reticulate stains, whereas patients with lymphatic disease typically have geographic stains.
The distinction between KTS and DCMO has become increasingly relevant with the advent of next-generation deoxyribonucleic acid (DNA) sequencing [7,8]. Although tissue genomic testing has identified activating somatic PIK3CA variants in many cases of KTS (particularly in the more severe ones), many cases of DCMO (previously considered "mild KTS") are commonly due to GNAQ or GNA11 variants [8]. However, some cases of DCMO have PIK3CA variants, so there is at least some genotypic overlap [9]. (See 'Pathogenesis' below and 'Diffuse capillary malformation with overgrowth' below.)
PATHOGENESIS — Klippel-Trenaunay syndrome (KTS) is, in the vast majority of cases, a sporadic condition, although rare familial cases have been reported [10]. While various genetic defects have been identified as possible causative factors for KTS, including overexpression of the angiogenic factor VG5Q and a de novo supernumerary ring chromosome 18 [11,12], it is now evident that most patients with KTS carry postzygotic somatic variants in the phosphatidylinositol-4, 5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) gene [4,5].
In particular, sharply demarcated, so-called "geographic stains" appear to be strongly associated with PIK3CA hot-spot variants [9,13,14]. Similar phenotypes with capillary and venous malformations in association with overgrowth have been described, due to somatic variants in PIK3R1, with remarkable overlap with the PIK3CA-related overgrowth spectrum (PROS), including mixed vascular malformations, sandal gap deformity (ie, widened space between great and second toes), macrodactyly, splaying of toes, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone [14].
Other cases with milder degrees of overgrowth and varicosities are often due to GNAQ or GNA11 activating variants and may better fit the diagnosis of diffuse capillary malformation with overgrowth (DCMO) [8]. (See 'Diffuse capillary malformation with overgrowth' below.)
Gain-of-function variants in PIK3CA lead to the activation of protein kinase B (AKT) and, ultimately, mammalian target of rapamycin (mTOR), with resultant cell proliferation and angiogenesis. Similar variants have been discovered in entities such as CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies) syndrome, fibro-adipose vascular anomaly (FAVA), and macrocephaly-capillary malformation (M-CM, MCAP) syndrome [5,15,16].
Although these syndromes have unique features, possibly related to tissue-specific distribution, they may also show considerable clinical overlap. Moreover, some cases do not fit neatly into a single category or diagnosis. The term "PIK3CA-related overgrowth spectrum" (PROS) has thus been used to encompass these distinct yet overlapping conditions [17]. (See 'Definition and classification' above and "Vascular lesions in the newborn", section on 'Vascular malformations associated with other anomalies'.)
CLINICAL MANIFESTATIONS — Cutaneous vascular stain, venous varicosities or malformation, and underlying soft tissue and/or bone hypertrophy of the involved extremity, with or without lymphatic anomalies, represent the key clinical features of Klippel-Trenaunay syndrome (KTS) (picture 1A-C). The severity of KTS likely reflects the timing of development in utero, which components of the vasculature and other anatomic structures (eg, bone, muscle, skin, subcutis) are predominantly affected, and the nature of specific gene variants causing the developmental anomalies.
Vascular stain — The cutaneous vascular stains (port wine birthmarks) of KTS are noted at birth and most commonly involve the lower extremity. Involvement of the ipsilateral or contralateral upper limb and extension to the adjacent truncal skin are not uncommon [18]. These flat, vascular birthmarks can often be classified as either geographic or blotchy/segmental. Geographic stains are usually dark red or purple in color and have a sharply demarcated, irregular shape resembling that of a country or continent (picture 1A-B). Blotchy/segmental stains, on the other hand, have less distinct margins and are often large and confluent with lighter pink-red coloration.
In a retrospective study of 40 patients with KTS, 21 of 22 with geographic stains had definite or probable lymphatic disease, while 16 of 17 with blotchy stains had no evidence or only possible lymphatic malformation. In addition to predicting lymphatic involvement in KTS, geographic stains may also identify patients with a propensity for disease complications [19]. (See "Capillary malformations (port wine birthmarks) and associated syndromes".)
Venous disease — In KTS, the persistence of embryonic avalvular venous structures, most notably the lateral vein of the thigh (lateral marginal vein of Servelle) and sciatic vein, can result in dilated, tortuous varicosities, with superficial ones being more often located over the anterolateral thigh and leg (picture 1B) [20]. If present in superficial soft tissues, these often present as soft, compressible, subcutaneous, blue masses, with increased prominence in dependent positions. Venous varicosities may be evident at birth or during infancy but typically become more apparent during childhood.
Structural abnormalities of the deep venous system can also occur. These include venous hypoplasia or aplasia, aneurysm formation or dilatation, valvular incompetence, and compression from fibrotic bands or anomalous vasculature, with the popliteal and superficial femoral veins most commonly affected [21]. Deeper venous anomalies may only be detected with imaging studies. (See 'Imaging studies' below.)
Lymphatic malformation — Lymphatic malformations in KTS may be microcystic, macrocystic, or mixed. Clinically, the disruption of the lymphatic system is frequently characterized by the presence of superficial vascular blebs or lymphangiectasias, resembling "frog spawn," often, but not exclusively, located in the area of geographic stains (picture 1B). These lesions are at risk for chronic leakage of lymph or blood and secondary infection.
Additional features of lymphatic malformations include pseudoverrucous hyperplasia and lymphedema [20]. When present, lymphatic anomalies can contribute to the enlargement of the affected limb. Furthermore, deep lymphatic malformations located in the pelvis and retroperitoneum may lead to compression of intrapelvic organs and disfigurement of the genitalia [22]. (See "Vascular lesions in the newborn", section on 'Lymphatic malformations'.)
Overgrowth — Limb hypertrophy is often noted at birth and is usually secondary to soft tissue and bony overgrowth, although the presence of venous malformations and lymphedema may be contributing factors (picture 1C). The affected limb can be both longer in length and larger in circumference compared with the unaffected limb. The natural course of overgrowth is unpredictable but can be progressive [18].
Other associated limb anomalies have been reported, including macrodactyly, syndactyly, polydactyly, clinodactyly, camptodactyly, ectrodactyly, and congenital hip dislocation [22,23]. One report suggests that the presence of hand and foot malformations may be a predictor of deep venous anomalies [23].
Complications
Clotting disorders and thromboembolism — Many patients with KTS have ongoing clotting, most often a localized intravascular coagulopathy in areas of venous malformation, and an increased risk of superficial thrombophlebitis and, less commonly, of deep venous thrombosis and pulmonary thromboembolism [24-27]. Persistent embryonic veins and other abnormal venous structures are often the source of thrombosis [28,29]. In a cohort of 48 patients with KTS, 23 had a history of superficial venous thrombosis, 8 had deep venous thrombosis and/or pulmonary embolism, and 2 had evidence of chronic pulmonary embolism [30]. Patients with dilated pelvic veins and large draining veins appear to be at the greatest risk for pulmonary embolism, and a small subset with recurrent or unresolved pulmonary embolism may go on to develop chronic pulmonary hypertension [28,31,32]. Laboratory studies may demonstrate elevated D dimer levels, low fibrinogen, and, occasionally, thrombocytopenia. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)
Bleeding — Bleeding severity in KTS varies, ranging from minor episodes secondary to vascular "blebs" (ectasias) within vascular stains to severe, disseminated, intravascular coagulation and major bleeding following invasive procedures. The risk of coagulopathy generally correlates with the extent of venous disease. Intrapelvic and intra-abdominal venous malformations and varicosities may result in occult or life-threatening gastrointestinal bleeding and hematuria, most commonly originating from the rectum and bladder, respectively [33]. It is important to note that the absence of significant venous disease of the extremity does not preclude the presence of pelvic anomalies nor of a coagulopathy [21].
Limb length discrepancy — KTS may be complicated by variable degrees of limb length discrepancy. In a large, retrospective study of 410 patients with KTS, 264 (44 percent) required orthopedic evaluation, and of these, 84 percent had documented limb length discrepancy [34]. In the lower extremities, length discrepancy may have long-term functional significance, with compensatory tilting and imbalance of the pelvis leading to secondary scoliosis, impaired gait, functional limitations, and pain [35]. These complications are of greatest concern when the length discrepancy is 2 cm or greater [36]. Generally, progressive limb overgrowth ceases at the end of adolescence but continues past that age in some cases.
Chronic lymphedema/venous insufficiency — Anomalies of the lymphatic and venous systems predispose patients with KTS to chronic lymphedema and chronic venous insufficiency. These may lead to stasis dermatitis and lipodermatosclerosis. Further complications include skin breakdown, recurrent infection, and chronic skin ulcers [37]. (See "Stasis dermatitis".)
Cellulitis — Patients with KTS are susceptible to recurrent bouts of cellulitis. In one study of 252 patients with KTS, 13 percent suffered from cellulitis [21]. It is uncertain whether cellulitis is in all cases due to bacterial infection. In a subset of patients, it may represent an inflammatory reaction to venous stasis, chronic lymphedema, or thrombosis. Nonetheless, it is prudent to have a high clinical suspicion for infection if new-onset erythema, pain, swelling, and warmth are present or if fever is associated with increased pain or heaviness of the affected area, even in the absence of overt signs of cellulitis. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
Pain — Pain can be a common and often debilitating aspect of KTS, with studies documenting a prevalence of 37 to 88 percent [21,38,39]. The etiology of pain is multifactorial and likely includes chronic venous insufficiency, cellulitis, superficial thrombophlebitis, deep vein thrombosis, "growing pains," intraosseous involvement, arthritis and contractures, in part attributable to intra-articular involvement and hemarthrosis, and neuropathic pain [37].
PATHOLOGY — The histopathologic features of Klippel-Trenaunay syndrome (KTS) include various types of vascular malformation; lipomatous overgrowth; and, in older lesions, secondary changes from clotting, infection, and other complications.
Capillary malformations demonstrate ectatic capillary vessels in the superficial dermis, which in later stages become more prominent with fibrous wall thickening and possible extension into the deep dermis [40]. Venous malformations are characterized by irregular vessels containing erythrocytes, with a single layer of endothelial cells, absent internal elastic membrane, and often scant smooth muscle in the vessel wall [40].
Thrombi or phleboliths may be evident. The histology of an excised persistent lateral marginal vein shows features similar to that of varicose veins in the general population [41].
Lymphatic malformations appear as numerous irregular, dilated spaces in the dermis and subcutaneous tissue lined by a single layer of endothelial cells and variable smooth muscle with surrounding loose or fibrotic stroma and lymphocytic aggregates. In contrast to venous malformations, those of lymphatic origin contain a pink, proteinaceous fluid with occasional erythrocytes, and their endothelial lining stains with the monoclonal antibody D2-40, a marker of lymphatic endothelium [40].
DIAGNOSIS — The diagnosis of Klippel-Trenaunay syndrome (KTS) is primarily based upon the presence of the key clinical features discussed above, which include vascular stain, venous varicosities, and limb overgrowth with or without lymphatic malformation (see 'Clinical manifestations' above). That said, radiologic evaluation and laboratory testing may be critical in securing the diagnosis.
Imaging studies — "Appropriateness criteria" for diagnosis and treatment of clinically suspected vascular anomalies of the extremities have been published by the American College of Radiology [42]. They provide guidance regarding advantages and disadvantages of various imaging studies in patients with KTS.
In general, ultrasonography and magnetic resonance imaging (MRI) without and with intravenous contrast are recommended as the initial imaging of a suspected vascular malformation presenting with pain or findings of physical deformity [42].
Ultrasonography — Doppler/duplex ultrasound is helpful in identifying anomalies of the superficial and deep venous systems. It provides confirmation of low flow, compressible vascular channels, valvular incompetence, and anatomical abnormalities such as atresia or aneurysms [22]. It is also the test of choice for the detection of acute venous thrombosis and phleboliths. On ultrasonography, venous malformations appear as phlebectatic or spongiform hypoechoic masses, while lymphatic malformations are mostly cystic [31]. Ultrasonography is relatively inexpensive and can be performed without sedation in infants and young children. Disadvantages include its high interoperator variability and poor soft tissue contrast [31]. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'Diagnostic ultrasonography suspected first DVT'.)
Magnetic resonance imaging — Magnetic resonance imaging (MRI), with and without gadolinium contrast, is the imaging study of choice to define the nature and extent of vascular anomalies in patients with KTS (image 1). MRI provides the highest diagnostic accuracy in the evaluation of the underlying venous and lymphatic abnormalities, as well as soft tissue and bony overgrowth [42]. Venous malformations show uniform enhancement, whereas lymphatic malformations demonstrate rim or septal enhancement of cyst walls [31]. Fluid-fluid levels and high T2 signal intensity are characteristic of lymphatic malformations [43]. The presence of phleboliths as signal voids is characteristic of venous malformations [43].
In patients with severe disease involving the lower extremity and perineum, magnetic resonance venography (MRV) should be considered. The finding of large pelvic veins indicates an increased risk of pulmonary embolism [31]. Though MRI is the imaging study of choice, testing can be costly and may require sedation for younger patients. (See "Anesthesia for magnetic resonance imaging and computed tomography procedures".)
Conventional venography — Contrast venography is useful to assess the anatomy and patency of the superficial and deep venous systems before and after endovascular or intralesional treatment of varicosities and venous malformations [18,44]. (See 'Surgical therapies' below.)
Plain radiograph — Scanogram, orthoroentgenogram, and teleroentgenogram are standard radiographic techniques used in conjunction with leg length measurements for the evaluation of leg length discrepancy, bony hypertrophy, and additional osseous anomalies, which may include syndactyly, polydactyly, and congenital hip dislocation [44-46]. Serial plain films may also be obtained to monitor patients with secondary scoliosis.
Laboratory studies — Baseline complete blood count, D-dimer, fibrinogen, prothrombin time, and partial thromboplastin time should be performed in all patients with suspected KTS. Elevated D-dimer with or without low fibrinogen suggests chronic, localized, intravascular coagulopathy. (See 'Clotting disorders and thromboembolism' above.)
Repeat coagulation studies should be performed periodically and especially prior to any invasive procedures or during pregnancy, as patients with KTS have an increased risk of deep vein thrombosis and pulmonary thromboembolism in these settings [31,47]. Testing may also be prompted by the finding of phleboliths on clinical examination or imaging.
Biopsy — A biopsy for routine histopathologic confirmation is typically not necessary to confirm the diagnosis of KTS (see 'Pathology' above). However, biopsy of the involved tissue via punch or incisional biopsy, while not done routinely, can be useful for the purposes of molecular and genetic testing.
Genomic testing — Next-generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes have helped capture somatic variants in lesional tissue samples from individuals affected with vascular anomalies with overgrowth [5,13]. A more inclusive approach using a panel including several genes causing overgrowth has been successful in identifying somatic variants [13]. This analysis can be performed on paraffin-embedded tissue. Several commercial laboratories have cancer or overgrowth panels that include PIK3CA, GNAQ, GNA11, and other relevant genes, and depending upon the threshold settings of the laboratories used for testing, they may be sufficiently sensitive to detect the often low percentages of lesional tissue (eg, 1 to 3 percent) that harbor the pathogenic variant [13].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Klippel-Trenaunay syndrome (KTS) from other capillary malformation-overgrowth syndromes is summarized in the table (table 1) and discussed below. It includes isolated capillary malformation, diffuse capillary malformation with overgrowth (DCMO), Parkes Weber syndrome, and other overgrowth syndromes.
Capillary malformation — Isolated capillary malformations (port wine birthmarks) of the limb, in the absence of varicosities, venous or lymphatic malformations, and overgrowth, carry a much better prognosis than KTS with few complications (table 1) [20]. In uncertain cases or in cases in which lesions are symptomatic (eg, painful, warm to the touch), ultrasonography or MRI should be performed to exclude KTS or Parkes Weber syndrome.
In patients with diffuse capillary malformation, monitoring of head circumference and neurologic development and, if appropriate, serial neuroimaging may be indicated to exclude macrocephaly-capillary malformation (M-CM) [3]. (See "Capillary malformations (port wine birthmarks) and associated syndromes" and 'Macrocephaly-capillary malformation' below.)
Diffuse capillary malformation with overgrowth — Many patients previously diagnosed with KTS have findings compatible with diffuse capillary malformation with overgrowth (DCMO) [3]. Many cases of DCMO have been associated with somatic variants in the GNA11 gene or in GNAQ, which is genetically homologous to GNA11 [7]. However, there can be phenotypic overlap between GNAQ-associated and PIK3CA-associated vascular stains, including soft tissue and musculoskeletal overgrowth. Early in life, it may be hard to distinguish between these two conditions, emphasizing the need for long-term follow-up and consideration of tissue genotyping [8,9].
Individuals affected with DCMO typically have extensive vascular stains, often with a reticulated pattern in some areas, in the setting of proportionate, nonprogressive overgrowth (picture 2). The vascular stains are often more widespread but fainter in color than those seen in KTS and lack the characteristic, geographic, sharply demarcated borders (table 1).
Approximately one-third of patients with DCMO have prominent varicosities, thus fulfilling the classic KTS triad of capillary stain, overgrowth, and venous malformations. However, the venous malformations in DCMO do not include the persistent embryonic veins and deep venous anomalies typically seen in KTS. Most notably, DCMO lacks any evidence of lymphatic malformations. These differences have a prognostic significance, since patients with DCMO are at low risk for cellulitis, coagulopathy, pulmonary embolism, and progressive overgrowth [3,48]. It is important to monitor patients with a provisional diagnosis of DCMO, particularly infants and young children, to ensure that this, rather than KTS, is the correct diagnosis.
Parkes Weber syndrome — Parkes Weber syndrome is defined by the combination of capillary malformation, fast-flow arteriovenous fistulae, and limb overgrowth, preferentially involving the lower extremity [1]. Parkes Weber syndrome has been associated with variants in the RASA1 gene, particularly when smaller capillary stains are present on other parts of the body [49]. Unlike KTS, structural venous anomalies and lymphatic malformations are frequently absent, though enlarged veins due to venous hypertension may be present (table 1).
Parkes Weber syndrome and KTS can be difficult to distinguish in younger patients. Clues to the diagnosis of Parkes Weber syndrome include brighter pink stains with rapid capillary refill, unusual skin warmth, lack of lymphatic disease, and excessive pain out of proportion for physical findings. Doppler ultrasound studies may demonstrate high flow within the vascular stains or adjacent soft tissue.
Servelle-Martorell syndrome — Servelle-Martorell syndrome is a rare congenital angiodysplastic disease presenting with capillary and venous malformations but with decreased, rather than increased, limb girth due to bone undergrowth [50]. It can be confused with KTS, but the progressive limb hypotrophy rather than overgrowth helps in differentiating the two conditions.
Macrocephaly-capillary malformation — This condition, also known as megalencephaly-capillary malformation, is considered to fall under the umbrella of the PIK3CA-related overgrowth spectrum (PROS) [15]. The vascular stains in this condition are often widespread, asymmetric, and blotchy or reticulate. Lymphatic anomalies are very uncommon. Asymmetric overgrowth and digital anomalies (syndactyly/polydactyly) are common and overlapping features in both macrocephaly-capillary malformation (M-CM) and KTS, which is not surprising since both can be due to PIK3CA somatic variants (table 1). The presence of midline facial vascular stains, skin/joint laxity, increased head circumference, and severe neurologic disease favor the diagnosis of M-CM. Additional neurologic findings in M-CM include developmental delay, seizures, hypotonia, frontal bossing, hydrocephalus, ventriculomegaly, polymicrogyria, cerebral and/or cerebellar asymmetry, and cerebellar tonsillar herniation [51].
CLOVES syndrome — Patients with CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies) syndrome are sometimes initially diagnosed as having KTS, since the early clinical findings are virtually identical (table 1), while the lipomatous overgrowth and epidermal nevi tend to appear later. The substantial clinical overlap between KTS and CLOVES syndrome is likely explained by the identification of similar somatic PIK3CA variants in both conditions [17].
Clues to the diagnosis of CLOVES syndrome include facial asymmetry and macrodactyly with "sandal gap" toe deformity [52]. High-flow spinal and paraspinal arteriovenous malformations have also been reported in CLOVES syndrome [53]. (See "Vascular lesions in the newborn", section on 'CLOVES syndrome'.)
Proteus syndrome/PTEN hamartoma tumor syndrome — Proteus syndrome is caused by activating variants in the AKT1 gene [54], resulting in asymmetric, disproportionate, and progressive overgrowth of soft tissue and bone and extensive, cutaneous and visceral, mixed vascular malformations. Aggressive, progressive overgrowth favors the diagnosis of Proteus syndrome over KTS and should prompt consideration of tissue genotyping. Distinct clinical characteristics of Proteus syndrome that set it apart from KTS include cerebriform connective tissue nevi of the plantar feet (picture 3), epidermal nevi, lipomas, café-au-lait macules, macrocephaly, learning difficulties, pulmonary cysts, and ovarian cystadenomas [55]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)
PTEN hamartoma tumor syndrome also encompasses the Bannayan-Riley-Ruvalcaba syndrome (BRRS), which shares overlapping features with Proteus syndrome, including macrocephaly, developmental delay, lipomas, and vascular malformations. Unique to BRRS are genital lentigines, gastrointestinal polyposis, and pseudopapilledema [56]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Bannayan-Riley-Ruvalcaba syndrome'.)
MANAGEMENT
General principles — The management of patients with Klippel-Trenaunay syndrome (KTS) requires a multidisciplinary approach, ideally in a multidisciplinary vascular anomalies center. Consultations with pediatric dermatology, interventional radiology, plastic surgery, orthopedic surgery, vascular surgery, hematology, urology, gastroenterology, physical and occupational therapy, and pain management may be warranted. The approach should be individualized, based upon the extent of disease and complications. For many patients, treatment is mainly supportive, centering on the prevention and management of complications. Medical, interventional radiologic, or surgical interventions may be necessary if there are significant symptoms or functional impairment. Alpelisib has been approved by the US Food and Drug Administration for the treatment of PIK3CA-related overgrowth spectrum (PROS) and is the first on-label targeted treatment for KTS [57]. (See 'PIK3CA inhibitors (alpelisib)' below.)
Supportive treatment and surveillance — Patients with KTS are at risk for severe and chronic edema of the affected limb due to venous and lymphatic insufficiency. Conservative management includes compression garments, lymphatic massage, physical therapy, and physical activity [58] (see "Clinical staging and conservative management of peripheral lymphedema"):
●Compression garments – Compression garments should extend from above the affected area to cover the distal digits. Reducing edema may decrease the risk of recurrent cellulitis and chronic wounds as well as improve mobility and comfort. There is no evidence, however, that compression reduces soft tissue hypertrophy. Young children tend not to tolerate compression garments and quickly outgrow them, a reality which should be considered in deciding at what age to recommend compression.
●Surveillance for embryonal tumors – Although the embryonal tumor risk in PIK3CA-related segmental overgrowth syndromes (eg, macrocephaly-capillary malformation [M-CM], CLOVES [congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies] syndrome) is still undetermined, some experts suggest that these patients should also be screened for Wilms tumor [59]. However, for patients with KTS without the additional features of CLOVES syndrome, screening for Wilms tumor is not generally recommended since data do not suggest an increased risk [60,61]. Similarly, limited data suggest that patients with diffuse capillary malformation with overgrowth (DCMO) are not at increased risk for Wilms tumor, unless there is associated hemihypertrophy [62].
In contrast, patients with isolated hemihypertrophy or overgrowth syndromes (eg, Beckwith-Wiedemann syndrome, Sotos syndrome, Perlman syndrome) have an increased risk of embryonal tumors such as Wilms tumor and hepatoblastoma [63]. In such cases, tumor surveillance (eg, with serial renal ultrasounds and serum alpha-fetoprotein measurements using standard protocols for frequency of monitoring) is recommended [64]. (See "Beckwith-Wiedemann syndrome", section on 'Surveillance'.)
Management of leg length discrepancy — All patients with KTS should be followed closely for leg length discrepancy using regular measurements of distance between the anterior superior iliac spine and medial malleolus, especially during periods of rapid somatic growth [45]. Early involvement of orthopedics is recommended to help determine the need and optimal timing for surgical intervention [34]. Generally, a less than 2 cm difference is considered inconsequential and can be managed nonsurgically with shoe lifts. When discrepancies are greater than 2 cm, an epiphysiodesis (obliteration of the growth plate) may be performed to halt the growth of the longer leg and reduce such a discrepancy [35]. The timing of this procedure is crucial.
Medical treatment — The medical management for KTS involves the treatment of coagulation disorders, treatment and prevention of infection, pain management, and, if possible, pathogenesis-directed therapy.
Chronic coagulopathy — Chronic coagulopathy, as evidenced by elevated D-dimer, low fibrinogen, and presence of phleboliths or signs of superficial thrombophlebitis on clinical examination and imaging studies, is common in patients with KTS and extensive venous malformations. Low-dose aspirin appears to be beneficial in patients with venous malformations, with improvement of pain and swelling [65]. Although there are no specific data on its use in KTS, low-dose aspirin is a reasonable first-line treatment for patients with laboratory or clinical evidence of chronic coagulopathy.
According to the Special Interest Group in Vascular Anomalies within the American Society of Pediatric Hematology/Oncology, patients with KTS are considered high risk for periprocedural and postprocedural venous thromboembolic disease, in particular those with low fibrinogen levels, persistent embryonic veins, D-dimer levels five times normal, thrombocytopenia, and a personal or family history of thrombosis. They recommend that these patients receive two weeks of low molecular weight heparin prior to any invasive procedures and at least two weeks postprocedure [28].
Patients with established thromboses or thromboembolism require long-term treatment with oral or parenteral anticoagulants. Coordination of care with hematologists is strongly recommended. If there is clinical concern, high-resolution computed tomography of the chest and pulmonary angiography should be considered to evaluate for chronic thromboembolic pulmonary hypertension and to determine the need for surgical intervention [32]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects" and "Venous thromboembolism: Anticoagulation after initial management".)
Infection — Patients with KTS, especially those who have associated lymphatic anomalies, are predisposed to recurrent cellulitis and lymphangitis. In severe cases, skin infections can progress to bacteremia and sepsis [66]. If possible, cultures should be obtained to help in directing therapy, although they can often be negative despite signs and symptoms of infection. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
Patients with suspected cellulitis should receive early empiric treatment with antibiotics effective against beta-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus, such as penicillin, amoxicillin, or first-generation cephalosporins, as well as meticulous wound care. Additional empiric coverage for methicillin-resistant Staphylococcus aureus (MRSA) is warranted in patients who do not respond to initial therapy. (See "Acute cellulitis and erysipelas in adults: Treatment".)
Although there are no data to support the use of chronic or prophylactic antibiotic therapy in patients with KTS, suppressive antibiotic therapy may be indicated in those with recurrent skin infections.
Pain control — Pain is a significant source of morbidity in patients with KTS. As previously noted, the etiology of pain in KTS is often multifactorial, and treatment can be extremely challenging. Addressing the underlying cause of pain is critical and involves targeted treatment of infection, superficial or deep vein thrombosis, contractures, and neuropathic pain [37]. Targeted therapy with either sirolimus of alpelisib is an important treatment option if pain is severe or chronic. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates are frequently prescribed but may only provide temporary relief. Ultimately, reducing the burden of vascular malformation, including intraosseous/articular disease, through surgical and endovascular interventions may be required as a means of pain management.
Targeted medical therapies — The mammalian target of rapamycin (mTOR) inhibitor sirolimus and the PIK3CA inhibitor alpelisib are targeted treatments for patients with symptomatic KTS or functional impairment due to KTS [59,67-69].
mTOR inhibitors (sirolimus) — The mTOR inhibitor sirolimus has been used as a key therapeutic option for complex venous-lymphatic malformations, including in the setting of KTS [70-75]. Its primary mechanism of action is the inhibition of mTOR, which acts downstream of the PI3K/AKT pathway to promote cell proliferation and angiogenesis:
●In the first 2011 report, one patient with kaposiform hemangioendothelioma, one with capillary-lymphatic-venous malformation, and four with microcystic lymphatic malformations were treated with sirolimus, with dramatic improvement in clinical status and reduction in size of the vascular anomalies [70]. Initial dosing was 0.8 mg/m2 per dose given twice daily, with a goal trough of 10 to 15 ng/mL. Adverse effects of sirolimus include mucositis, headache, hyperlipidemia, transaminitis, myelosuppression, and infection [70,72].
●One study presented the first mouse model for human venous malformations and demonstrated effective growth suppression with rapamycin (sirolimus) [76]. The authors also conducted a pilot clinical study in five patients with venous malformations and one with KTS. Treatment with sirolimus resulted in improvement in pain, quality of life, functional impairment, bleeding, coagulation parameters, and lesion size.
●The first prospective trial on the safety and efficacy of sirolimus for complex vascular anomalies was published in February 2016 [77]. Sixty-one patients, including 13 with mixed capillary-venous-lymphatic malformations, were treated with 12 consecutive 28-day courses of sirolimus. Forty-five of 53 patients (85 percent) who completed 12 courses of treatment had a partial response to sirolimus, as assessed by imaging studies, and reported improvement in quality of life and function. The most common adverse effect was bone marrow toxicity in 27 percent of patients.
●An open-label study across three centers evaluated the safety and efficacy of low-dose sirolimus in reducing tissue growth at overgrown sites in patients with PROS [78]. Among 30 patients who completed the study, sirolimus resulted in a change in mean percentage total tissue volume of -7.2 percent at 26 weeks. While low-dose sirolimus led to a modest reduction in overgrowth, a high proportion of patients (72 percent) experienced at least one adverse event, with infection being the most common.
●An observational phase, randomized trial (PERFORMUS trial) found sirolimus to be effective in decreasing pure lymphatic malformations [79]. In combined malformations (eg, KTS, CLOVES syndrome), sirolimus also significantly reduced pain, oozing, and bleeding.
Consultation with hematology is recommended for initiation of sirolimus. The optimal duration of treatment is not yet known. Further studies are necessary to evaluate the efficacy and safety of oral sirolimus for the treatment of KTS and to establish treatment guidelines and protocols.
For patients with KTS who are not ideal candidates for systemic sirolimus, compounded topical sirolimus 0.1 to 1% may be helpful in alleviating symptoms from superficial, lymphatic malformations [80,81].
PIK3CA inhibitors (alpelisib) — Alpelisib, an orally available, direct inhibitor of PIK3CA, was approved by the US Food and Drug Administration in April 2022 for the treatment of adult and pediatric patients two years of age and older with severe manifestations of PROS who require systemic therapy [82].
In an uncontrolled study of 19 patients with PROS (primarily CLOVES syndrome and M-CM), alpelisib improved vascular malformation size and hemihypertrophy [83]. Additional case reports and small case series have also confirmed clinical improvement [84-86]. Alpelisib is generally well tolerated, with hyperglycemia (often dose dependent) and oral ulceration uncommonly reported. However, further studies are needed to assess long-term adverse effects of alpelisib on growth and development in pediatric patients.
Further evidence for its efficacy comes from EPIK-P1, a retrospective, noninterventional medical chart review of patients (age ≥2 years) with PROS, which included data from 57 patients [87]. At week 24, alpelisib improved pain (20 of 22 patients [91 percent]), fatigue (32 of 42 patients [76 percent]), vascular malformation (30 of 38 patients [70 percent]), limb asymmetry (20 of 29 patients [69 percent]), and disseminated intravascular coagulation (16 of 29 patients [55 percent]). The most common treatment-related adverse effects were hyperglycemia (n = 7, 12 percent), aphthous ulcer (n = 6, 11 percent), and stomatitis (n = 3, 5 percent). No deaths were reported. This evidence formed the basis of provisional approval by the US Food and Drug Administration, pending further data from a randomized, controlled trial that is underway (NCT04589650).
Surgical therapies — Superficial vascular stains and lymphatic blebs if recurrently bleeding, leaking, or crusting may be treated with laser therapy. The pulsed dye laser is effective in lightening vascular stains, whereas ablative carbon dioxide (CO2) lasers are often more useful in controlling leakage and bleeding from lymphatic vesicles. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Capillary malformations (port wine birthmarks)'.)
When conservative measures, such as the use of compression garments, are inadequate, endovascular ablation with laser, radiofrequency, or sclerotherapy have been used for the treatment of venous and lymphatic disease with good results [58,88]. Early ablation of embryonal veins in young children has been proposed to not only reduce the risk of fatal thromboembolic disease but to also take advantage of minimally invasive techniques that have limitations as veins enlarge over time [22,28]. Ablation of anomalous veins, however, does not prevent limb overgrowth [89]. Macrocystic components of lymphatic malformations respond particularly well to sclerotherapy [90]. Multiple treatments over years are often needed.
Symptomatic varicosities have also been successfully treated with vein stripping, high ligation, or ambulatory phlebectomy [91]. Prior to the performance of these procedures, it is important to assess the patency of the deep venous system with MRI and/or venography. (See "Techniques for endovenous laser ablation for the treatment of lower extremity chronic venous disease" and "Injection sclerotherapy techniques for the treatment of telangiectasias, reticular veins, and small varicose veins" and "Approach to treating symptomatic superficial venous insufficiency", section on 'Intervention for axial vein reflux'.)
Surgical resection is most desirable to treat localized or superficial components, as a means of improving function and mobility, reducing the risk of infection, and managing chronic bleeding, lymph leakage, and ulceration. Complete surgical removal of extensive vascular malformations is typically not feasible, especially when they extend deep into muscle and bone. Persistent and life-threatening gastrointestinal or genitourinary bleeds or obstruction may prompt radical resection of pelvic malformations [92,93].
Debulking of overgrown soft tissue and amputation may be considered in selected patients with severe, progressive overgrowth and inability to ambulate. Ray resection and foot amputation can aid in improving gait. In cases of severe flexion contracture, amputation at the knee may be indicated [22]. Before pursuing these procedures, patients must be informed of the risks and potential complications, including but not limited to bleeding, worsening edema, seroma, chronic lymphatic leakage, pain, infection, poor wound healing, and excessive scarring [94]. If surgical debulking is planned, it may be prudent to start more distally to avoid further worsening of the distal lymphatic or venous drainage.
PROGNOSIS — The prognosis of Klippel-Trenaunay syndrome (KTS) is variable and depends upon the extent of disease and presence of complications. Life-threatening massive pulmonary embolism has been reported, although the exact incidence is not known. In one series of 75 patients with KTS, 39 percent experienced thromboembolic complications, including superficial thrombosis, and 8 percent had either a deep vein thrombosis or pulmonary thromboembolism [26]. Some patients may develop chronic thromboembolic pulmonary hypertension [30].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic venous disorders" and "Society guideline links: Vascular anomalies".)
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder defined as a syndrome with capillary and venous malformations as well as limb overgrowth, with or without lymphatic malformation. KTS is, in most cases, associated with gain-of-function, postzygotic somatic variants in the PIK3CA gene and is thus considered to be part of the PIK3CA-related overgrowth spectrum (PROS). (See 'Pathogenesis' above.)
●Clinical presentation – KTS is characterized by the presence of capillary malformation, venous malformation or varicosities, and limb overgrowth with or without lymphatic anomalies (picture 1A, 1C):
•Vascular stain – The cutaneous vascular stains (port wine birthmarks) of KTS are noted at birth and most commonly involve the lower extremity. They are classified as geographic or blotchy/segmental. Geographic stains are usually dark red or purple in color and have a sharply demarcated, irregular shape resembling that of a country or continent (picture 1A-B). (See 'Vascular stain' above.)
•Venous malformations – The persistence of avalvular embryonal veins (lateral vein of the thigh and sciatic vein) is a venous malformation characteristic of KTS. It results in dilated, tortuous varicosities, most often located over the anterolateral thigh and leg (picture 1B). Structural abnormalities of the deep venous system can also occur. (See 'Venous disease' above.)
•Limb hypertrophy – Limb hypertrophy is often noted at birth and is usually secondary to soft tissue and bony overgrowth, although the presence of venous malformations and lymphedema may be contributing factors (picture 1C). (See 'Overgrowth' above.)
●Complications – Complications of KTS include clotting disorder and chronic thromboembolism, bleeding, limb length discrepancy, lymphedema, soft tissue infection, and pain. (See 'Complications' above.)
●Diagnosis – The diagnosis of KTS is made clinically in most cases. MRI, with and without contrast, is the best way to confirm and assess the extent of underlying venous and lymphatic disease as well as soft tissue and bony overgrowth (image 1). (See 'Diagnosis' above.)
●Management – The management of patients with KTS requires a multidisciplinary approach, ideally in a multidisciplinary vascular anomalies center. Treatment should be individualized and may include supportive care; medical management of coagulopathy, infection, and pain; orthopedic interventions for limb length discrepancy; and surgical interventions to reduce tissue overgrowth and improve function.
The mammalian target of rapamycin (mTOR) inhibitor sirolimus and alpelisib, a PIK3CA inhibitor, are important targeted treatments for the complex venous-lymphatic malformations in KTS. (See 'Management' above and 'mTOR inhibitors (sirolimus)' above and 'PIK3CA inhibitors (alpelisib)' above.)
●Prognosis – The prognosis of KTS is variable and depends upon the extent of disease and presence of complications. Some patients may develop pulmonary embolism and chronic thromboembolic pulmonary hypertension. (See 'Prognosis' above.)
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