Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder characterized by abnormal development of blood vessels, soft tissues, and bones, typically manifesting as a port-wine stain birthmark, vein malformations such as varicose veins, and overgrowth (hypertrophy) of one limb, most commonly a leg.[1] The condition is present at birth and primarily affects the vascular and lymphatic systems, leading to a triad of capillary malformations, venous anomalies, and tissue/bony hypertrophy.[2] KTS is estimated to occur in at least 1 in 100,000 people worldwide, with no significant gender predominance.[3]The underlying cause of KTS involves a somatic (post-zygotic) mutation, most frequently in the PIK3CA gene, which regulates cell growth and occurs randomly during early embryonic development rather than being inherited from parents.[1] This mutation leads to overactivation of signaling pathways that promote excessive tissuegrowth and vascular irregularities.[3] While the exact prevalence of the mutation varies, it is a key feature in the majority of cases, classifying KTS as part of the PIK3CA-related overgrowth spectrum (PROS) disorders.[3]Diagnosis of KTS is typically made clinically at birth based on the characteristic triad of symptoms, often confirmed through imaging studies like ultrasound, MRI, or venography to assess vascular involvement.[1] There is no cure for the syndrome; management focuses on symptomatic relief and complication prevention, including laser therapy for port-wine stains, compression garments or sclerotherapy for varicose veins, orthopedic interventions for limb discrepancies, and medications to address pain or clotting risks.[2] Potential complications include chronic pain, deep vein thrombosis, infections, and psychosocial challenges due to visible malformations.[4] Multidisciplinary care involving vascular specialists, dermatologists, and orthopedists is essential for optimizing quality of life.[1]
Signs and symptoms
Capillary malformations
Capillary malformations in Klippel–Trénaunay syndrome (KTS) are primarily manifested as port-wine stains, which are flat, congenital vascular birthmarks ranging in color from pink to reddish-purple. These lesions result from ectatic capillaries in the superficial dermis and are typically present at birth, serving as the most common initial visible sign of the syndrome. In approximately 98% of cases, port-wine stains are observed, often unilaterally affecting a single limb or portion of the trunk.[5][1][3][4]Histologically, these capillary malformations consist of dilated, ectatic postcapillary venules and capillaries within the papillary and upper reticular dermis, without evidence of endothelial cell proliferation or abnormal vessel growth. This distinguishes them from proliferative vascular lesions such as hemangiomas. The lesions generally follow a segmental distribution along the affected limb, covering a significant portion—often part of one limb—without crossing midline boundaries in typical presentations.[6][7][3][1]Over time, port-wine stains in KTS may evolve, with the affected skin potentially darkening in color or developing hypertrophic changes that result in a nodular or cobblestoned texture due to progressive vessel ectasia. These alterations can become more pronounced during childhood and adolescence, contributing to cosmetic and functional concerns in the involved area. Although primarily superficial, these capillary malformations are often associated with underlying venous anomalies that may exacerbate local vascular dysfunction.[3][6][8][2]
Venous and lymphatic malformations
Venous malformations are a hallmark feature of Klippel–Trénaunay syndrome (KTS), occurring in approximately 70-100% of affected individuals and manifesting as congenital anomalies of the venous system.[9] These include tortuous superficial varicosities, persistent embryonic veins, and valvular incompetence, which often lead to venous stasis and chronic venous hypertension.[9] Hypoplasia or agenesis of deep veins is also common, further impairing venous return and increasing the risk of recurrent superficial thrombophlebitis and deep vein thrombosis (DVT), with venous thromboembolism reported as a significant complication.[10] In one study of 61 patients, predominantly venous defects were identified in 74% of cases, underscoring their high prevalence.[11]These venous anomalies contribute to functional impairments such as chronic pain, affecting up to 88% of patients due to venous insufficiency and associated inflammation.[10]Bleeding episodes, often from fragile superficial veins or associated visceral involvement, occur in 1-12.5% of cases and can range from minor oozing to more severe hemorrhage.[10] The malformations are typically present at birth and predominantly affect the lower limbs in a unilateral distribution, though pelvic and visceral extensions are possible in up to 20% of patients, potentially leading to additional stasis-related issues.[9]Lymphatic malformations accompany venous anomalies in a substantial proportion of KTS cases, with involvement noted in 15-50% overall and up to 97% in extremity-affected limbs according to imaging studies.[9][12] These congenital lymphatic anomalies often present as hyperplasia, hypoplasia, or aplasia of lymphatic vessels, resulting in impaired lymph drainage and secondary lymphedema, which affects approximately 84% of patients and causes persistent swelling, particularly in the lower extremities.[10]Lymphedema exacerbates tissue fibrosis and increases susceptibility to recurrent soft tissue infections, such as cellulitis, due to stagnant lymphatic flow and skin barrier compromise.[10]The venous and lymphatic malformations in KTS form part of the broader vascular triad that includes capillary stains, collectively driving the syndrome's morbidity through interconnected hemodynamic disruptions.[9]
Soft tissue and bony hypertrophy
Soft tissue hypertrophy in Klippel–Trénaunay syndrome (KTS) manifests as enlargement of the skin, subcutaneous tissues, and muscles, occurring in approximately 67% of cases and contributing to increased limb girth.[13] This overgrowth typically affects a single limb in about 80% of patients, most commonly the lower extremity, leading to visible asymmetry that becomes more pronounced over time. The hypertrophy is often progressive during childhood, with accelerated growth spurts frequently observed during puberty, resulting in functional limitations such as altered gait and reduced mobility.[4][14]Bony hypertrophy accompanies soft tissue changes, involving elongation and thickening of the affected limb's bones, which can produce leg length discrepancies typically ranging from 1 to 10 cm.[15] Specific bony alterations include cortical hypertrophy, where the outer bone layer thickens excessively, as well as joint deformities such as angular deviations and contractures.[16][15] If the spine is involved, scoliosis may develop secondary to pelvic tilt from unilateral limb overgrowth, affecting up to 9% of patients and necessitating orthopedic evaluation.[15] These structural changes require regular monitoring to assess progression and mitigate complications like uneven weight distribution.The resulting asymmetry from soft tissue and bony hypertrophy can exacerbate pain associated with underlying vascular malformations, though such symptoms are addressed separately.[17] Orthopedic interventions, including serial measurements via scanograms, are essential for tracking discrepancies and planning supportive measures to preserve joint function and prevent secondary deformities.[13]
Associated complications
Individuals with Klippel–Trénaunay syndrome (KTS) face increased thrombotic risks primarily due to venous malformations and stasis, which predispose to deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of DVT in KTS patients is reported to range from 8% to 22%, while PE occurs in approximately 4% of cases, often at a young age.[18][19] These events arise from intravascular coagulopathy and localized consumptive coagulopathy within malformed vessels, potentially leading to life-threatening thromboembolism if untreated.[19]Lymphatic malformations in KTS can cause obstruction and fluid pooling, resulting in recurrent cellulitis and secondary infections. This occurs as slowed lymphatic drainage promotes bacterial entry through compromised skin barriers, exacerbating lymphedema and risking sepsis.[4][20]Pain represents the most prevalent complaint among KTS patients, affecting 37% to 88% depending on age and involvement severity, often stemming from venous insufficiency, thrombophlebitis, or tissue overgrowth.[21][22]Visceral involvement, though less common, heightens the risk of gastrointestinal bleeding, particularly rectal hemorrhage from vascular ectasias or hemangiomas in the colon. Neurological deficits may arise from spinal arteriovenous or venous malformations, which have a prevalence of approximately 16% in KTS cohorts and can cause compression, leading to paresis or sensory loss.[23]Rarely, arteriovenous shunting within malformations imposes cardiac strain, potentially resulting in high-output heart failure due to increased circulatory demands. Over the long term, chronic venous hypertension and lymphatic dysfunction elevate the risk of skin ulcers, recurrent infections, and tissue breakdown, particularly in hypertrophied limbs where asymmetry amplifies mechanical stress.[24][4]
Pathophysiology
Genetic mutations
Klippel–Trénaunay syndrome (KTS) arises primarily from somatic mosaic mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3K).[25] These postzygotic activating mutations, first identified in affected tissues of KTS patients in 2015, place the syndrome within the PIK3CA-related overgrowth spectrum (PROS) of disorders.[26] By enhancing PI3K activity, the mutations drive localized cellular proliferation and vascular anomalies through activation of the PI3K/AKT/mTOR signaling pathway.[25]Such PIK3CA mutations are detected in up to 85-90% of KTS cases in recent studies using targeted next-generation sequencing, with earlier cohorts reporting 20% to 50% due to less sensitive methods; common hotspots include c.3140A>G (p.His1047Arg) and c.1624G>A (p.Glu542Lys).[27][28][29] For instance, one study found the p.His1047Arg variant in 3 of 15 patients via targeted sequencing of lesional tissue.[28] Another reported pathogenic variants in 6 of 13 clinically diagnosed cases, supporting PIK3CA's role in a substantial subset of sporadic KTS.[29]Prior hypotheses linking KTS to germline mutations in the AGGF1 gene (also known as VG5Q), proposed in 2004 based on variants in 5 of 130 patients, were later refuted as these changes represent benign polymorphisms without causal effect.[30][31] Similarly, early cytogenetic reports of de novo translocations like t(8;14)(q22.3;q13) in isolated cases suggested disruption of a vascular growth regulator, but these abnormalities have not been consistently associated with KTS pathogenesis.[30][32]KTS exhibits no familial inheritance pattern, occurring sporadically due to these non-heritable somatic events with no evidence of germline transmission or recurrence in siblings.[25] The condition shows equal prevalence among males and females and across all racial and ethnic backgrounds, consistent with its random postzygotic origin.[3]
Molecular mechanisms
The molecular mechanisms underlying Klippel–Trénaunay syndrome (KTS) primarily involve dysregulation of the PI3K/AKT/mTOR signaling pathway, driven by somatic gain-of-function mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K).[33] These mutations result in constitutive activation of the pathway, leading to excessive phosphorylation of downstream targets such as AKT and mTOR, which in turn promote uncontrolled endothelial cell proliferation, migration, and survival.[33] In affected tissues, this overactivation enhances angiogenesis and lymphangiogenesis by upregulating vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3, contributing to the formation of malformed, dilated capillaries, veins, and lymphatic vessels characteristic of the syndrome.[33] Additionally, hyperactive mTOR stimulates protein synthesis and cellular metabolism, amplifying tissue hypertrophy through sustained cell growth in mesenchymal and vascular compartments.[33]A key aspect of this dysregulation is the impairment of apoptosis, mediated by persistent AKT signaling, which inhibits pro-apoptotic proteins like FOXO and BAD while activating anti-apoptotic factors such as Bcl-2.[33] This reduction in programmed cell death allows for the accumulation of excess cells in soft tissues and bone, resulting in asymmetric overgrowth confined to specific somatic segments.[33] The pathway's effects are particularly pronounced in endothelial and lymphatic cells, where PI3K/AKT/mTOR hyperactivation disrupts normal vascular remodeling during embryogenesis, leading to persistent structural anomalies.[33]These mutations arise post-zygotically during early embryonic development, typically after the formation of the zygote, which explains the mosaic distribution of affected cells and the localized, segmental nature of KTS manifestations.[33] Allele frequencies in lesional tissues range from 0.8% to 59.6%, reflecting the timing and extent of mutational events, with higher mosaicism correlating to more severe localized overgrowth.[33] This post-zygotic origin ensures that only a subset of cells in the affected limb or region carry the mutation, sparing systemic involvement and contributing to the syndrome's variability.[33]Recent research highlights an emerging role for epigenetic modifiers in the variable expressivity of KTS within the broader PIK3CA-related overgrowth spectrum (PROS), where DNA methylation and histone modifications may modulate the penetrance of PI3K/AKT/mTOR dysregulation beyond genetic mosaicism alone.[34] These epigenetic changes, observed in overgrowth disorders, influence gene expression patterns in affected tissues, potentially explaining phenotypic heterogeneity such as differing degrees of hypertrophy despite similar PIK3CA variants.[35] Studies from 2023 onward suggest that such modifiers interact with the core pathway to fine-tune cellular responses, offering insights into why some individuals exhibit milder or more asymmetric features.[34]
Diagnosis
Clinical criteria
Klippel–Trénaunay syndrome (KTS) is clinically diagnosed based on the presence of a classical triad of vascular malformations and soft tissue or bony hypertrophy, typically affecting a limb. The triad consists of capillary malformations, often appearing as port-wine stains on the skin; venous malformations, manifesting as varicosities or dilated veins; and hypertrophy of soft tissues and bones, leading to limb enlargement or length discrepancy.[9][36][37]A definitive diagnosis requires at least two of these three features, with the malformations usually confined to a single limb, most commonly the lower extremity, though upper limbs or the trunk may be involved. The condition presents congenitally, with capillary malformations evident at birth and other features becoming apparent during infancy or early childhood as the affected limb grows disproportionately.[9][37][1]Under the International Society for the Study of Vascular Anomalies (ISSVA) classification, KTS is categorized as a combined vascular malformation involving capillary (CM), venous (VM), and optionally lymphatic (LM) components, associated with limb overgrowth, often within the PIK3CA-related overgrowth spectrum.[38][9]The presence of arteriovenous fistulas or significant arteriovenous shunting excludes pure KTS and indicates a variant such as Parkes Weber syndrome. Supporting imaging, such as ultrasound or MRI, may confirm the vascular anomalies but is not required for initial clinical diagnosis.[9][37]
Diagnostic imaging
Diagnostic imaging plays a crucial role in confirming the presence of vascular malformations and assessing the extent of soft tissue and bony involvement in Klippel-Trenaunay syndrome (KTS).[9]Ultrasound with Doppler is typically the first-line modality, providing a noninvasive means to evaluate superficial venous structures, detect varicosities, and assess blood flow dynamics, including reflux and thrombosis.[39] This approach is particularly valuable for initial screening due to its accessibility, lack of radiation, and ability to guide subsequent interventions.[40]Magnetic resonance imaging (MRI), often combined with magnetic resonance angiography (MRA) or venography (MRV), serves as the gold standard for comprehensive evaluation in KTS.[9] It excels in delineating the full extent of soft tissue hypertrophy, lymphatic malformations, and deep venous anomalies, offering multiplanar views that reveal the three-dimensional architecture of affected tissues.[41] MRI is preferred over computed tomography (CT) in pediatric patients, as it avoids ionizing radiation exposure, which is a significant concern for children with this lifelong condition.[41][42]Lymphoscintigraphy is employed specifically to assess lymphatic function and identify abnormalities such as lymphatic leakage or hypoplasia, which are common in KTS and contribute to complications like lymphedema.[43] This nuclear medicine technique involves injecting a radiotracer into the lymphatic system and imaging its drainage patterns, providing functional insights that complement the structural details from MRI.Recent advances in imaging, including 3D vascular modeling derived from MRI datasets, have enhanced preoperative planning for surgical interventions in KTS by enabling precise visualization of complex malformation networks and simulation of procedural outcomes.[44] These techniques, increasingly integrated into multidisciplinary care, improve accuracy in mapping hypertrophic regions and vascular anomalies for targeted therapies.[9]
Differential diagnosis
Klippel-Trenaunay syndrome (KTS) must be differentiated from other vascular malformation and overgrowth disorders that share features such as limb hypertrophy, cutaneous vascular lesions, or soft tissue anomalies. Accurate distinction relies on clinical evaluation of the malformation type, distribution, and associated features, often supplemented by genetic testing.[9]A primary differential is Parkes Weber syndrome, which involves soft tissue and bony hypertrophy alongside a cutaneous capillary stain but is distinguished by the presence of high-flow arteriovenous fistulas, absent in the low-flow venous and capillary malformations characteristic of KTS.[9][45] The lack of arteriovenous shunting in KTS helps confirm this separation clinically.[46]Proteus syndrome represents another key differential, featuring progressive postnatal overgrowth of skeletal and connective tissues, epidermal nevi, and occasional vascular malformations, in contrast to the congenital, segmental presentation of KTS without epidermal involvement.[9][45]Sturge-Weber syndrome, involving a facial port-wine stain with central nervous system angiomatosis leading to seizures, intellectual disability, and glaucoma, differs from KTS by its predominant cranial and ocular involvement rather than limb-focused vascular anomalies and hypertrophy.[47]Genetic testing for somatic PIK3CA mutations, common in KTS as part of the PIK3CA-related overgrowth spectrum, aids in ruling out PIK3CA-negative conditions such as Beckwith-Wiedemann syndrome, which presents with generalized macrosomia, visceromegaly, and hemihypertrophy but lacks vascular malformations.[9][46] A negative PIK3CA result does not exclude KTS but supports consideration of alternative etiologies.[46]Less common mimics include isolated lymphatic malformations, which manifest as cystic or vesicular lesions without the capillary stain or overgrowth seen in KTS, and hemangiomas, which are benign proliferative tumors that typically involute spontaneously unlike the persistent structural anomalies in KTS.[46]
Management and treatment
Supportive therapies
Supportive therapies for Klippel-Trenaunay syndrome (KTS) emphasize conservative, non-invasive measures to alleviate symptoms, enhance quality of life, and mitigate risks associated with vascular malformations and tissue hypertrophy. These approaches focus on symptom control and functional support, often integrated into a patient's daily routine to address issues like swelling, pain, and mobility limitations.[9]Compression garments, such as graduated stockings or custom-fitted elastic wraps, play a central role in managing lymphedema and varicosities by improving venous return and reducing tissue swelling. These devices, typically prescribed at 30-40 mm Hg pressure for lower limbs, also help lower the risk of superficial thrombophlebitis and deep vein thrombosis by promoting better circulation and preventing stasis. Limb elevation and intermittent pneumatic compression devices complement garments to further minimize edema and venous insufficiency. In cases of limb overgrowth, custom-made compression therapy has demonstrated safety and efficacy in controlling hypertrophy progression.[46][9][36][48]Physical therapy is essential for preserving joint mobility, preventing contractures, and addressing functional challenges from limb hypertrophy or discrepancy. Tailored exercises and manual therapies help maintain muscle strength, improve range of motion, and support overall limb function, particularly in affected lower extremities. For leg length differences, orthotics such as shoe inserts or lifts provide compensatory support to promote balanced gait and reduce strain on joints and the spine.[9][36][46]Pain, a common complication in KTS often stemming from vascular issues or tissue changes, is typically managed with nonsteroidal anti-inflammatory drugs (NSAIDs) alongside supportive measures like elevation and compression to target inflammation and discomfort without relying on opioids. A multidisciplinary team, involving dermatologists for skin care, orthopedists for structural support, and psychologists for addressing psychosocial burdens such as anxiety or body image concerns, ensures holistic care tailored to individual needs. This collaborative framework coordinates ongoing monitoring and adjustments to therapies, optimizing long-term symptom control.[46][9][46]
Interventional procedures
Interventional procedures for Klippel-Trenaunay syndrome (KTS) encompass surgical and minimally invasive techniques aimed at addressing structural abnormalities, such as vascular malformations and limb overgrowth, when conservative measures are insufficient.[49] These interventions are typically reserved for cases with significant functional impairment or cosmetic concerns, with decisions guided by multidisciplinary teams including vascular surgeons, interventional radiologists, and orthopedic specialists.[50] Procedures target soft tissue and bony hypertrophy, which can lead to limb length discrepancies and mobility issues, but they carry risks that necessitate careful patient selection.[51]Debulking surgery involves the excision of excess soft tissue and abnormal vascular structures to reduce limb girth and improve function in patients with severe hypertrophy.[50] This procedure is often performed in stages to minimize complications and is considered a last resort due to its invasive nature and high recurrence rates, which can exceed 90% in associated varicosities.[49] It is particularly indicated for large complex lymphatic malformations with fatty overgrowth, though it may damage underlying venous and lymphatic structures, potentially worsening edema.[46] Risks include infection, scarring, and lymphorrhea, with outcomes optimized when performed after growth completion.[51]Epiphysiodesis is an orthopedic intervention used to equalize limb lengths in growing children with significant discrepancies, typically greater than 1.5 cm, by surgically arresting growth at the affected epiphysis, such as the knee.[49] This procedure slows bone overgrowth on the involved side, allowing the contralateral limb to catch up, and is often combined with monitoring via serial imaging.[50] It is preferably timed in early adolescence, post-puberty if possible, to account for final growth patterns and reduce the need for more extensive corrections later.[46] Potential complications mirror those of debulking, including infection and scarring, alongside risks of over- or under-correction if growth predictions are inaccurate.[51]Sclerotherapy offers a minimally invasive option for managing venous malformations in KTS by injecting sclerosing agents to obliterate dilated venous channels and reduce pain or swelling.[49] It is effective for superficial varicosities and macrocystic lymphatic components but is contraindicated in cases with deep venous anomalies unless targeting isolated superficial systems.[46] Agents like bleomycin may be used for cutaneous vesicles, with sessions repeated as needed for optimal results.[51] Risks include skin ulceration, scarring, and hyperpigmentation, though it generally has a lower complication profile than open surgery.[50]Embolization is employed for problematic bleeding vessels or anomalous veins in KTS, using endovascular coils or agents to occlude flow and prevent hemorrhage, particularly in pelvic or lower extremity involvement.[46] This technique minimizes thromboembolism risk prior to other interventions and is suitable for intrafascial veins like the sciatic.[49] It serves as an adjunct for visceral malformations, such as in the bladder, to control recurrent bleeding.[51] Associated risks encompass infection at access sites, vessel perforation, and post-procedural clotting, with procedures ideally timed early to avert complications.[50]
Pharmacological approaches
Pharmacological management of Klippel-Trenaunay syndrome (KTS) primarily targets the dysregulated vascular proliferation and overgrowth associated with the condition, often involving the PI3K/AKT/mTOR signaling pathway, which can be briefly referenced as a key mediator of tissuehypertrophy in affected limbs.Anti-angiogenic agents such as propranolol have shown efficacy in treating early vascular lesions in KTS, particularly lymphatic and capillary malformations, by reducing edema and lesion size through vasoconstriction and inhibition of angiogenesis. In clinical cases, oral propranolol at doses of 1-3 mg/kg/day has led to partial resolution of segmental hemangiomas and lymphatic anomalies, with improvements observed within months of initiation.[52] Similarly, low-dose aspirin is commonly employed for thrombosis prophylaxis due to the high risk of coagulopathy and deep veinthrombosis in KTS patients, serving as an anticoagulant to prevent clot formation in malformed veins without significant bleeding risks at 81-100 mg daily doses.[4]mTOR inhibitors, notably sirolimus, represent an emerging class of therapies for KTS, particularly for managing overgrowth and complex low-flow vascular malformations unresponsive to conventional treatments. Post-2020 clinical trials and case series have demonstrated that low-dose oral sirolimus (target levels 5-15 ng/mL) reduces lesion volume by up to 20-30% and alleviates symptoms like pain and swelling in pediatric and adult patients, with a favorable safety profile including manageable side effects such as mucositis.[53][54][55]Targeted therapies against PIK3CA mutations, which underlie many KTS cases as part of the PIK3CA-related overgrowth spectrum (PROS), include alpelisib, a selective PI3Kα inhibitor approved by the FDA in 2022 for the treatment of severe manifestations of PROS in adult and pediatric patients two years of age and older. Phase 1/2 studies that supported the approval have reported that alpelisib at low doses (250-300 mg daily for adults, adjusted for pediatrics) slows lesion progression, reduces overgrowth by 10-25% in measurable tissues, and improves quality of life in patients with confirmed PIK3CA mosaicism, though hyperglycemia remains a notable adverse effect requiring monitoring. Ongoing phase 3 trials, such as EPIK-P2 as of 2024, continue to evaluate long-term efficacy and safety.[56][57][58] For superficial vascular components like port-wine stains, pulsed-dye laser therapy serves as a specific adjunctive approach, achieving 50-75% lightening after multiple sessions by targeting ectatic vessels, often integrated with pharmacological regimens to enhance cosmetic outcomes.[36][59]Recent developments post-2023 have explored gene therapy strategies to address the somatic mosaicism in KTS, focusing on correcting PIK3CA or related variants in affected tissues, though these remain in preclinical and early-phase investigations with no approved applications yet, emphasizing the potential for personalized interventions in mosaic disorders.[60][61]
With appropriate multidisciplinary management, the prognosis for individuals with Klippel-Trenaunay syndrome (KTS) is generally favorable, allowing for a normal lifespan in the absence of major complications such as pulmonary embolism or severe bleeding.[4][2] Ongoing monitoring is essential, as the condition is not static and may involve progression of vascular malformations, limb hypertrophy, or venous insufficiency over time, necessitating periodic clinical assessments and imaging.[9]Many patients achieve significant functional independence through interventions like physical therapy, compression garments, orthopedic supports, and selective surgeries to address limb discrepancies, enabling improved mobility and daily activities despite potential chronic impairments.[4]Quality of life can be substantially affected by visible disfigurement, leading to psychological impacts such as diminished emotional well-being and social challenges, including difficulties in employment for those with severe cases; studies indicate lower mental health and physical function scores compared to the general population.[62][63]A 2023 multicenter study highlights improved long-term outcomes with early initiation of sirolimus therapy, an mTOR inhibitor, which has demonstrated efficacy in reducing the size of vascular malformations and alleviating symptoms in KTS and related capillary-lymphatic-venous malformations, with 86% of patients showing symptom improvement and 93% reporting enhanced quality of life.[64] This treatment approach contributes to better disease control and functional status by limiting hypertrophy progression, though long-term follow-up remains crucial to manage potential side effects and sustained benefits.[65]
Common complications
Patients with Klippel-Trenaunay syndrome (KTS) are at elevated risk for thrombotic events due to underlying venous malformations and stasis, with deep vein thrombosis (DVT) occurring in approximately 17% of cases in institutional series.[66]Pulmonary embolism (PE), a potentially life-threatening complication, has been reported in 14-22% of affected individuals, often stemming from dislodged thrombi.[66] Anticoagulation monitoring is essential, particularly perioperatively, to mitigate these risks through prophylactic measures such as low-molecular-weight heparin.[46]Infections represent another frequent complication, particularly recurrent cellulitis associated with lymphedema and lymphatic malformations, affecting up to 22% of patients with cutaneous involvement.[67] These episodes can lead to significant morbidity, including skin breakdown and sepsis, exacerbated by impaired lymphatic drainage that hinders immune responses.[20] In cases involving pelvic vascular malformations, gastrointestinal hemorrhage, most commonly rectal bleeding, emerges as a notable issue, requiring vigilant endoscopic evaluation.[68]Joint stress from limb hypertrophy and overgrowth in KTS contributes to osteoarthritis, particularly in weight-bearing joints like the knee, often necessitating orthopedic interventions such as total knee arthroplasty.[69] Although vascular malformations carry a theoretical risk of malignancy, such as squamous cell carcinoma in chronic ulcers, the overall incidence remains rare and does not exceed general population rates for most cancers.[70]Prevention of these complications involves multidisciplinary annual screening protocols, including vascular imaging and coagulation assessments, to enable early detection and intervention, such as compression therapy for lymphedema or vein closure procedures to reduce thrombotic potential.[46]
Epidemiology
Incidence and prevalence
Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder with an estimated incidence of 1 to 5 cases per 100,000 live births.[9]Prevalence is approximately 5 per 100,000 individuals, reflecting its lifelong nature.[71]The condition is often underreported, particularly mild cases that may go undiagnosed or be misattributed to other vascular anomalies.[72] There is no evidence of seasonal or geographic variation in occurrence, consistent with its sporadic presentation.[73]Recent advancements in genetic screening, particularly for PIK3CA variants associated with overgrowth syndromes, have improved diagnostic yield from around 2% to over 80%, leading to increased detection of KTS cases.[74] However, exact incidence and prevalence remain uncertain, with some sources estimating them as unknown due to diagnostic challenges.[73] Registry data from the International Society for the Study of Vascular Anomalies (ISSVA) support these estimates, emphasizing the rarity and uniform distribution across demographics.[38] KTS shows no significant differences in incidence by sex or ethnicity.[75]
Demographic patterns
Klippel-Trenaunay syndrome (KTS) is a congenital condition present at birth, often diagnosed during infancy as vascular malformations and limb overgrowth become apparent.[51][17] The affected limb typically exhibits progressive hypertrophy through childhood and adolescence, after which enlargement generally stabilizes.[1]KTS affects males and females equally, with no documented predilection for specific races or ethnicities, occurring sporadically worldwide without familial clustering.[51][17] The condition demonstrates a strong predominance for the lower limbs, involving approximately 90-95% of cases, while upper limb, trunk, or facial involvement is less common.[76][1] Bilateral cases are rare, accounting for about 15% of presentations, compared to the more typical unilateral pattern.[77]Socioeconomic factors influence KTS management, particularly in developing regions where limited access to specialized multidisciplinary care can delay diagnosis and worsen long-term outcomes, such as through inadequate monitoring of limb discrepancies or complication prevention.[78] In resource-constrained settings, insurance status and urban-rural divides further exacerbate disparities in treatment availability.[78]
History
Initial descriptions
In 1900, French neurologist Maurice Klippel and physician Paul Trénaunay published the first detailed medical report on a condition characterized by vascular malformations and limb overgrowth, now recognized as Klippel-Trenaunay syndrome (KTS). Their seminal paper, titled "Du naevus variqueux ostéohypertrophique," appeared in the Archives générales de médecine and described two patients with unilateral hypertrophy of the soft tissues and bones in the lower limb, accompanied by extensive vascular stains resembling port-wine stains and prominent venous varicosities.[9][17] The authors emphasized the varicose nature of the vascular lesions, interpreting the condition as a form of angiomatosis involving dilated veins and hypertrophic changes without any identified underlying cause.[9]Both cases involved the leg on one side of the body, with the affected limbs showing significant enlargement, cutaneous vascular markings, and painful varicosities that contributed to discomfort and functional impairment. At the time, there was no understanding of genetic or developmental mechanisms, and the syndrome was viewed primarily as a rare angiomatous disorder limited to vascular and tissue abnormalities. Subsequent refinements in nomenclature and classification built upon these foundational observations.[17]
Nomenclature and classification
The syndrome was initially described in 1900 by French physicians Maurice Klippel and Paul Trénaunay, who termed it "naevus vasculosus osteohypertrophicus" based on cases featuring capillary stains, varicose veins, and limb hypertrophy.[79] In 1907, British dermatologist Frederick Parkes Weber reported additional similar cases involving vascular anomalies and soft tissue/bony overgrowth, but these were distinguished by the presence of arteriovenous fistulas, a high-flow feature absent in the original Klippel-Trénaunay descriptions.[17] The eponym Klippel-Trenaunay syndrome was established in the early 20th century, coinciding with proposals like "angiosteohypertrophy" to describe the condition's vascular and hypertrophic elements, though early nomenclature often conflated Weber's contributions, leading to the outdated term Klippel-Trenaunay-Weber syndrome.[51]Classification evolved significantly in the 1990s, as clinical and histopathological studies reframed KTS within a spectrum of congenital overgrowth disorders, emphasizing its mosaic nature and association with localized tissue hyperplasia rather than isolated vascular defects.[79] The International Society for the Study of Vascular Anomalies (ISSVA) classification, updated in 2025, formalizes KTS as a slow-flow combined vascular malformation, defined by capillary malformation (CM) plus venous malformation (VM), with or without lymphatic malformation (LM), and accompanied by limb overgrowth; it highlights somatic PIK3CA variants as a key genetic driver in many cases.[80]Post-2023 research has integrated KTS into the PIK3CA-related overgrowth spectrum (PROS), underscoring how activating mutations in the PIK3CA gene—encoding a subunit of the PI3K enzyme—underlie the syndrome's vascular dysplasias and asymmetric growth through dysregulated signaling pathways.[81] Ongoing debates center on diagnostic overlap with Parkes Weber syndrome, where ambiguous arteriovenous shunting can blur distinctions, but recent ISSVA-aligned guidelines promote unified terminology: slow-flow malformations without fistulas for KTS versus fast-flow lesions for Parkes Weber, facilitating targeted therapies like PI3K inhibitors.[51]