RARE DISEASE
Klippel-Trénaunay syndrome
Klippel-Trénaunay syndrome
Klippel-Trénaunay syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Klippel-Trénaunay syndrome (KTS) is a rare congenital disorder characterized by the triad of capillary malformations (port-wine stains), venous/lymphatic anomalies, and asymmetric limb hypertrophy. It arises from somatic PIK3CA gene mutations, causing dysregulated vascular and tissue growth. Complications include thromboembolism, chronic pain, and organ compression. Management focuses on symptom control through compression therapy, anticoagulation, and interventional procedures, supported by multidisciplinary care to mitigate morbidity [1][4][7][14].
Burden
Morbidity: Chronic pain (88% of patients), recurrent cellulitis, and thromboembolism (DVT/PE) [1][8][18].
Functional impact: Limb-length discrepancies, mobility limitations, and psychosocial challenges [14][18].
Lifelong monitoring required for complications, with 30-40% requiring surgery [1][9][10].
Therapies
Compression therapy and prophylactic anticoagulation to reduce thrombosis risk [3][8][12].
Interventional procedures: Sclerotherapy, thermal ablation, and debulking surgeries for symptomatic malformations [1][8][16].
Multidisciplinary care: Vascular anomalies specialists, physiotherapy, and pain management to optimize function [2][5][7].
Categories: rare bone diseases, rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare skin diseases
Research Papers
232 drug discovery papers about Klippel-Trénaunay syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
232 drug discovery papers about Klippel-Trénaunay syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-08 | Klippel-Trenaunay syndrome presenting with bilateral chronic central serous chorioretinopathy: a case report.
Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder characterized by capillary malformations, venous and/or lymphatic malformations, and asymmetric limb overgrowth. It results from somatic activating mutations in the PIK3CA gene, leading to dysregulated vascular development. While primarily affecting the skin and musculoskeletal system, ocular manifestations are uncommon. Central serous chorioretinopathy (CSC), a condition involving choroidal vascular hyperpermeability and retinal pigment epithelium dysfunction, has not been previously associated with KTS. A 52-year-old Iranian male presented with a 6-month history of bilateral vision loss. Ophthalmologic examination revealed best-corrected visual acuity of 20/30 in the right eye and 20/25 in the left eye. Optical coherence tomography (OCT) and fluorescein angiography (FA) confirmed bilateral chronic CSC. The patient exhibited an extensive capillary malformation on the right upper limb and trunk with mild limb hypertrophy. Magnetic resonance angiography (MRA) revealed venous malformations, supporting a diagnosis of previously unrecognized KTS. Laboratory tests excluded secondary causes of CSC. Bilateral photodynamic therapy (PDT) was performed. This novel case suggests a potential association between KTS-related venous malformations and CSC, possibly mediated by venous overload choroidopathy. Although follow-up was limited, routine ophthalmic screening in KTS patients may be warranted.
2026-03-15 | Klippel-Trénaunay syndrome: the etiology, clinical presentation, and treatment options
Cie: Klippelov-Trnaunayov syndrm (KTS) je zriedkav kombinovan cievna malformcia spojen s nadmernm rastom konatiny. Cieom tejto prehadovej prce je zhrn sasn poznatky o predpokladanej etiolgii, najastejch anomlich spojench s KTS, diagnostickom prstupe a lieebnch stratgich. Metdy: V obdob od janura do mja 2025 bola vykonan analza literatry s vyuitm databz PubMed a Google Scholar so zameranm na kov pojmy Klippelov-Trnaunayov syndrm a PIK3CA-related overgrowth spectrum (PROS). Zver: KTS sa prejavuje ako sbor vrodench malformci postihujcich konatinu a typicky postihuje jednostranne doln konatinu. Je dsledkom postzygotnej aktivanej mutcie v gne PIK3CA, ktor vedie k nadmernej aktivcii signlnej drhy PI3K-AKT-mTOR. Klinick obraz je variabiln, od miernych foriem a po zvan ochorenie s postihnutm viscerlnych orgnov a trombohemoragickmi komplikciami. Preferovanou zobrazovacou metdou na posdenie rozsahu cievnych malformci a postihnutia tkanv je MR angiografia. Lieba KTS si asto vyaduje multidisciplinrny prstup. V roku 2022 FDA schvlila alpelisib ako systmov lieebn monos pre pacientov s akmi formami KTS. © 2025, KS.
2026-01-23 | Unusual association: Sturge-Weber syndrome with Klippel-Trenaunay syndrome.
Sturge-Weber syndrome (SWS) and Klippel-Trenaunay syndrome (KTS) are rare vascular malformation disorders characterised by distinct clinical features but overlapping pathogenic mechanisms, involving somatic mosaic mutations and dysregulation of the mTOR pathway. SWS typically presents with facial port-wine stains, leptomeningeal angiomas and glaucoma, while KTS is characterised by limb hypertrophy, varicosities and venous malformations without central nervous system involvement. We report an unusual case of a middle childhood boy with features of both syndromes, including extensive facial and truncal port-wine stains, seizures, glaucoma, limb hypertrophy and venous anomalies. Imaging and clinical findings confirmed the coexistence of SWS and KTS phenotypes, highlighting the diagnostic complexity of overlap syndromes. Exome sequencing did not reveal any pathogenic variants. Multidisciplinary management, including seizure control, glaucoma care, vascular interventions and psychosocial support, remains crucial. Recognition of such overlap syndromes broadens understanding of their pathogenesis and opens avenues for targeted therapies such as mTOR inhibitors.
2025-09-30 | Management of nipple-areolar necrosis in a patient with Klippel-Trenaunay Syndrome.
We present a case of a 49-year-old female with Klippel-Trenaunay Syndrome who developed partial thickness nipple-areolar complex (NAC) necrosis following explantation of breast implants with concurrent mastopexy. Notably, she had received pulse dye laser therapy to her left breast 2 years prior for treatment of a congenital capillary vascular malformations. Initial management included the use of nitropaste topically to ischemic left breast nipple areola complex, however, due to intolerance patient was switched to topical dimethyl sulfoxide, yielding improvement. This case highlights potential microvascular compromise in patient with capillary malformations of the breast undergoing breast surgery and suggests a successful application of dimethyl sulfoxide in treating NAC ischemic complications. The patient declined consent for clinical photography; therefore, we provide detailed narrative descriptions and anatomical measurements. At 12-week follow-up, the NAC had re-epithelialized completely with preserved projection and excellent symmetry. To our knowledge, this is the first reported case of this kind.
2025-03-28 | Efficacy of ultrasound-guided microwave ablation for vascular malformations in children.
The aim of this study was to report our center's experience in treating pediatric vascular malformations using ultrasound-guided microwave ablation. Twenty-two symptomatic children with vascular malformations underwent ultrasound-guided microwave ablation. All patients received ultrasound follow-up after microwave ablation, whereas magnetic resonance imaging follow-up was conducted depending on the disease's condition. The Visual Analog Scale and the PedsQL4.0 Chinese Version was utilized to assess the changes in pain severity, limb motion evaluation, and quality of life before and after treatment. The study included 22 cases, comprising four arteriovenous malformations, nine venous malformations, two diffuse microcystic lymphatic malformations, two cases of Klippel-Trenaunay syndrome, and five cases of fibro adipose vascular anomaly. All children presented with pain at the affected site (22 cases; 100%). The malformations were located in the limbs in 17 cases (77%), subcutaneous and intramuscular tissues of the buttocks in one case (4.5%), subcutaneous tissue of the abdominal wall in one case (4.5%), and retroperitoneal in three cases (14%). All 22 patients (100%) experienced pain. Additionally, 20 cases (91%) exhibited swelling at the affected site or developed swelling after physical activity. Limb hypertrophy was observed in five cases (23%), whereas another five cases (23%) showed signs of limb atrophy. Joint mobility restrictions were present in four cases (18%). Among these 22 patients, 17 cases (77.3%) experienced complete resolution of pain and local lesion appearance changes, whereas four cases (18.2%) reported pain relief. However, in one case (4.5%) of Klippel-Trenaunay syndrome, postoperative improvement was observed at the treatment site, but a new centripetal malformation developed within the treated region. This patient subsequently underwent surgical intervention, resulting in an improvement in clinical symptoms. The pre-treatment malformation volume was 209.85 ± 343.17 cm3, which reduced to 32.95 ± 66.04 cm3 1 year after ablation. The volume reduction was statistically significant (t = 2.374; P = .026; P < .05), with an average volume reduction rate of 85.51%. No major complications were found, such as nerve damage or skin burns. Ultrasound-guided microwave ablation is a relatively safe and effective technique for treating pediatric vascular malformations. Further multicenter studies are recommended to validate these findings.
antibodies
2022-03-28 | A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies
Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF-β) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel-Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype-genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case-based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.
2004-03-08 | Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome.
Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.
proteins
2025-03-04 | Angiogenic factor AGGF1 is a general splicing factor regulating angiogenesis and vascular development by alternative splicing of SRSF6.
AGGF1 encodes an angiogenic factor that causes vascular disease Klippel-Trenaunay syndrome when mutated. AGGF1 also acts at the top of the genetic regulatory hierarchy for mesodermal differentiation of hemangioblasts, multipotent stem cells for differentiation of blood cells and vascular cells. Alternative splicing (AS) is a post-transcriptional process that generates multiple mature mRNAs from a single primary transcript (pre-mRNA), producing protein diversity. Deregulation of AS leads to many human diseases. The physiological role and mechanism of AGGF1 in AS are not clear. Full-length transcriptome sequencing of human pulmonary artery endothelial cells (HPAECs) with AGGF1 silencing revealed 63 121 genes, including 1144 new unannotated genes, and showed that AGGF1 is a general splicing factor regulating AS of 436 genes, including SRSF6 regulating AS of many target genes. AGGF1 promoted the skipping of exon 3 that produces the full-length SRSF6 protein, an evolutionarily conserved AS event. Overexpression of full-length SRSF6 reversed the reduced cell proliferation, migration, and capillary tube formation of HPAECs with AGGF1 silencing. Knockdown of SRSF6 and overexpression of the shorter, alternatively spliced isoform of SRSF6 both inhibited HPAEC proliferation, migration, and capillary tube formation, whereas opposite results were obtained for overexpression of full-length SRSF6. Knockdown of srsf6 impaired development of ISVs in zebrafish, whereas overexpression of srsf6 enhanced vascular development and partially rescued impaired ISV development in zebrafish embryos with aggf1 knockdown. Overall, our findings reveal that AGGF1 is a general splicing factor, and that AGGF1-mediated exon 3 skipping of SRSF6 pre-mRNA is important for endothelial cell functions, angiogenesis, and vascular development.
2021-11-22 | Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis.
Angiogenic factor AGGF1 (angiogenic factor with G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Using functional blocking studies with neutralizing antibodies, we identified [alpha]5[beta]1 as the receptor for AGGF1 on ECs. AGGF1 interacts with [alpha]5[beta]1 and activates FAK (focal adhesion kinase), Src (proto-oncogene tyrosine-protein kinase), and AKT (protein kinase B). Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from -RDD- to -RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. We have identified integrin [alpha]5[beta]1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of [alpha]5[beta]1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with [alpha]5[beta]1 and signaling.
2017-07-24 | Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin.
Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumour angiogenesis in vivo. Two lines of Aggf1 knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4. Aggf1+/- KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3β and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by PIK3CA), our data establish a potential mechanistic link between AGGF1 and PIK3CA, the two genes identified for KTS.
2013-07-22 | Functional characterization of Klippel-Trenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis.
Specification of arteries and veins is a key process for establishing functional vasculature during embryogenesis and involves distinctly different signaling mechanisms. Vascular endothelial growth factor-A (VEGFA) is required for differentiation of arteries; however, the upstream angiogenic factor for vein specification is unknown. Klippel-Trenaunay syndrome (KTS) is a congenital vascular disease associated with capillary and venous malformations (VMs), but not with arterial defects. We have previously reported that upregulation of angiogenic factor AGGF1 is associated with KTS, but the molecular mechanism is not clear. Here, we show that AGGF1 is involved in establishing venous identity in zebrafish embryos. Overexpression of AGGF1 led to increased angiogenesis and increased lumen diameter of veins, whereas knockdown of AGGF1 expression resulted in defective vasculogenesis and angiogenesis. Overexpression of AGGF1 increased expression of venous markers (e.g. flt4), but had little effect on arterial markers (e.g. notch5). Knockdown of AGGF1 expression resulted in a loss of venous identity (loss of expression of flt4, ephb4 and dab2), but had no effect on the expression of arterial development. We further show that AGGF1 activates AKT, and that decreased AGGF1 expression inhibits AKT activation. Overexpression of constitutively active AKT rescues the loss of venous identity caused by AGGF1 downregulation. Our study establishes AGGF1 as an angiogenic factor with an important role in the specification of vein identity and suggests that AGGF1-mediated AKT signaling is responsible for establishing venous cell fate. We propose that increased AGGF1 expression leads to increased vein differentiation by inducing activation of AKT signaling, resulting in VMs s in KTS patients.
2007-03-01 | Recombinant granulocyte-macrophage colony-stimulating factor in the treatment of indolent ulcers with Klippel-Trénaunay-Weber syndrome: a case report
Klippel-Trénaunay-Weber syndrome (KTWS) is a rare congenital disease characterized by cutaneous hemangiomata, venous varicosities and osseous soft tissue hypertrophy of the affected limb. We report a case of a patient with KTWS who had developed severe chronic, non-healing cutaneous ulcers resulting from several angiography procedures with embolization by various agents. The ulcers were treated with perilesional granulocyte-macrophage colony-stimulating-factor (GM-CSF) with gratifying results. This case report suggests that GM-CSF may enhance the healing of chronic wounds not responding to other treatment modalities in patients with congenital angiodystrophy syndromes, thus salvaging a limb from amputation.
gene therapies
2026-07-27 | Rare Upper Extremity Manifestation of Klippel–Trénaunay Syndrome in a Neonate
Introduction Klippel-Trénaunay syndrome (KTS) is a rare congenital vascular disorder involving a triad of capillary malformations (port-wine stains), venous anomalies, and soft tissue and/or bony hypertrophy. The condition typically presents in the lower extremities and often unilaterally. Involvement of other body parts such as the upper extremity, trunk, or viscera is highly uncommon and poorly documented. KTS is now classified within the PIK3CA-related overgrowth spectrum (PROS), a group of disorders associated with somatic activating mutations in the PIK3CA gene. We report a unique case of KTS presenting with superficial and deep venous abnormalities confined to the right upper extremity and chest wall, emphasizing the radiologic evaluation and embryologic interpretation of this unusual distribution. Publication History Received: 10 March 2026 Accepted after revision: 28 June 2026 Article published online: 27 July 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-09-03 | Multidisciplinary approach to Klippel-Trenaunay syndrome: a case report.
Klippel-Trenaunay syndrome (KTS) is a rare inherited disorder presenting as a triad of capillary malformations (cutaneous hemangiomas), soft tissue hypertrophy, and varicosities. Two out of three signs are enough to make a diagnosis. It is associated with gastrointestinal, hematological, neuro-ophthalmic, dermatological, pulmonary, oro-dental, renal cardiac, and vascular complications. There is no curative treatment for the disease. Complications are currently managed symptomatically and thorough documentation of all signs and symptoms is essential for timely identification and management of potential complications, thereby improving patient outcomes. KTS was diagnosed in a 16-year-old female, with dyspnea and fever associated with hemoptysis and abdominal pain. On physical examination, cutaneous findings and signs of respiratory compromise as well as evidence of vascular disease were observed. After appropriate medical care, the patient was soon discharged from the hospital. Following initial treatment, the patient's symptoms arbitrarily recurred requiring continued medical management and blood product administration to manage complications resulting from KTS. KTS is a chronic disorder with no cure. Patients with KTS are managed symptomatically and require frequent hospitalizations for the same.
2025-04-09 | Recurrent preeclampsia in a pregnant woman with Klippel-Trenaunay syndrome: two cesarean deliveries and multiple extremity involvement - a case report and literature review.
In this study, a total of 17 patients with Klippel-Trenaunay Syndrome (KTS) and pregnancy were evaluated. The patients were divided into two groups: those with organ involvement (10 patients) and those without organ involvement (7 patients). The clinical findings, complications, and treatment approaches between the two groups were compared, and the effects of KTS on the pregnancy process and potential risks were examined in detail. Significant clinical differences were observed between pregnant women with involvement of abdominal organs such as the liver, spleen, rectum, sigmoid, kidney, bladder, and uterus, as well as central organs like the brain, and those without such involvement. Organ involvement was defined as organ enlargement or venous anomalies detected by techniques such as ultrasound, magnetic resonance imaging (MRI), or computed tomography. Our literature review found that the risk of postpartum hemorrhage (PPH) was significantly higher in the group with organ involvement (p < 0.05). The presence of varicose malformations in organs such as the spleen, liver, and uterus was identified as an important factor increasing the risk of PPH. Therefore, close monitoring of coagulopathic disorders and taking precautions against thromboembolism in pregnant women with KTS is crucial. The case report discusses the complications and treatment processes experienced by a 26-year-old woman diagnosed with KTS and who developed preeclampsia during her two pregnancies. Complications such as preeclampsia and varices were observed in the first pregnancy, and intrauterine growth restriction (IUGR) and preeclampsia in the second pregnancy. Successful outcomes were achieved in both cases with a multidisciplinary approach and appropriate treatment methods. This study provides important information to understand the effects of KTS on pregnancy and the potential complications associated with this rare condition. Future studies will provide more information on the management of preeclampsia and other complications in pregnant women with KTS.
2025-01-16 | Klippel-Trenaunay Syndrome: A Case Study of Severe Anemia in a Rare Vascular Disorder.
Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder involving varicosities, cutaneous vascular malformations, and hypertrophy of soft tissues and bones. It is often linked to PIK3CA gene mutations. It affects the lymphatic, capillary, and venous systems. The diagnosis is usually based on clinical presentation, supplemented by magnetic resonance imaging (MRI) and computed tomography (CT) imaging. This case involves a 43-year-old male diagnosed with KTS after presenting with severe anemia (hemoglobin 2.5 g/dL) and left lower limb swelling with varicosities. Investigations revealed hepatosplenomegaly, hemangiomas, rectosigmoid malformations, an enlarged inferior vena cava (IVC), and vascular congestion. MRI confirmed an extensive veno-lymphatic malformation in the left lower limb. The case highlights KTS's complex presentation, emphasizing the importance of timely diagnosis, multidisciplinary care, and ongoing monitoring to manage its complications. Further research is needed to enhance treatment strategies for this rare condition.
2024-09-10 | Genetic basis and imaging findings of neurofibromatosis 1 and other somatic overgrowth disorders.
Somatic overgrowth disorders comprise a wide range of rare conditions that present with focal enlargement of one or more tissue types. The PI3K-AKT-mTOR pathway is a signalling pathway that induces angiogenesis and cell proliferation, and is one of the most commonly overactivated signalling pathways in cancer. The PI3K-AKT-mTOR pathway can be up-regulated by genetic variants that code for proteins in this pathway, or down-regulated by proteins that inhibit the pathway. Mosaic genetic variations can result in cells that proliferate excessively in specific anatomical locations. The PIK3CA-related overgrowth spectrum (PROS) disorders include CLOVES syndrome, macrodystrophia lipomatosa, and Klippel-Trenaunay syndrome among many. The neurofibromatosis type 1 (NF1) gene encodes neurofibromin which down-regulates the PI3K-AKT-mTOR pathway. Thousands of pathological variants in the NF1 gene have been described which can result in lower-than-normal levels of neurofibromin and therefore up-regulation of the PI3K-AKT-mTOR pathway promoting cellular overgrowth. Somatic overgrowth is a rare presentation in NF1 with a wide range of clinical and radiological presentations. Hypertrophy of all ectodermal and mesodermal elements has been described in NF1 including bone, muscle, fat, nerve, lymphatics, arteries and veins, and skin. The shared signalling pathway for cellular overgrowth means that these radiological appearances can overlap with other conditions in the PIK3CA-related overgrowth spectrum. The aim of this review is to describe the genetic basis for the radiological features of NF1 and in particular compare the appearances of the somatic overgrowth disorders in NF1 with other conditions in the PIK3CA-related overgrowth spectrum.
small molecules
2026-07-08 | Klippel-Trenaunay syndrome presenting with bilateral chronic central serous chorioretinopathy: a case report.
Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder characterized by capillary malformations, venous and/or lymphatic malformations, and asymmetric limb overgrowth. It results from somatic activating mutations in the PIK3CA gene, leading to dysregulated vascular development. While primarily affecting the skin and musculoskeletal system, ocular manifestations are uncommon. Central serous chorioretinopathy (CSC), a condition involving choroidal vascular hyperpermeability and retinal pigment epithelium dysfunction, has not been previously associated with KTS. A 52-year-old Iranian male presented with a 6-month history of bilateral vision loss. Ophthalmologic examination revealed best-corrected visual acuity of 20/30 in the right eye and 20/25 in the left eye. Optical coherence tomography (OCT) and fluorescein angiography (FA) confirmed bilateral chronic CSC. The patient exhibited an extensive capillary malformation on the right upper limb and trunk with mild limb hypertrophy. Magnetic resonance angiography (MRA) revealed venous malformations, supporting a diagnosis of previously unrecognized KTS. Laboratory tests excluded secondary causes of CSC. Bilateral photodynamic therapy (PDT) was performed. This novel case suggests a potential association between KTS-related venous malformations and CSC, possibly mediated by venous overload choroidopathy. Although follow-up was limited, routine ophthalmic screening in KTS patients may be warranted.
2026-03-15 | Klippel-Trénaunay syndrome: the etiology, clinical presentation, and treatment options
Cie: Klippelov-Trnaunayov syndrm (KTS) je zriedkav kombinovan cievna malformcia spojen s nadmernm rastom konatiny. Cieom tejto prehadovej prce je zhrn sasn poznatky o predpokladanej etiolgii, najastejch anomlich spojench s KTS, diagnostickom prstupe a lieebnch stratgich. Metdy: V obdob od janura do mja 2025 bola vykonan analza literatry s vyuitm databz PubMed a Google Scholar so zameranm na kov pojmy Klippelov-Trnaunayov syndrm a PIK3CA-related overgrowth spectrum (PROS). Zver: KTS sa prejavuje ako sbor vrodench malformci postihujcich konatinu a typicky postihuje jednostranne doln konatinu. Je dsledkom postzygotnej aktivanej mutcie v gne PIK3CA, ktor vedie k nadmernej aktivcii signlnej drhy PI3K-AKT-mTOR. Klinick obraz je variabiln, od miernych foriem a po zvan ochorenie s postihnutm viscerlnych orgnov a trombohemoragickmi komplikciami. Preferovanou zobrazovacou metdou na posdenie rozsahu cievnych malformci a postihnutia tkanv je MR angiografia. Lieba KTS si asto vyaduje multidisciplinrny prstup. V roku 2022 FDA schvlila alpelisib ako systmov lieebn monos pre pacientov s akmi formami KTS. © 2025, KS.
2026-01-23 | Unusual association: Sturge-Weber syndrome with Klippel-Trenaunay syndrome.
Sturge-Weber syndrome (SWS) and Klippel-Trenaunay syndrome (KTS) are rare vascular malformation disorders characterised by distinct clinical features but overlapping pathogenic mechanisms, involving somatic mosaic mutations and dysregulation of the mTOR pathway. SWS typically presents with facial port-wine stains, leptomeningeal angiomas and glaucoma, while KTS is characterised by limb hypertrophy, varicosities and venous malformations without central nervous system involvement. We report an unusual case of a middle childhood boy with features of both syndromes, including extensive facial and truncal port-wine stains, seizures, glaucoma, limb hypertrophy and venous anomalies. Imaging and clinical findings confirmed the coexistence of SWS and KTS phenotypes, highlighting the diagnostic complexity of overlap syndromes. Exome sequencing did not reveal any pathogenic variants. Multidisciplinary management, including seizure control, glaucoma care, vascular interventions and psychosocial support, remains crucial. Recognition of such overlap syndromes broadens understanding of their pathogenesis and opens avenues for targeted therapies such as mTOR inhibitors.
2025-09-30 | Management of nipple-areolar necrosis in a patient with Klippel-Trenaunay Syndrome.
We present a case of a 49-year-old female with Klippel-Trenaunay Syndrome who developed partial thickness nipple-areolar complex (NAC) necrosis following explantation of breast implants with concurrent mastopexy. Notably, she had received pulse dye laser therapy to her left breast 2 years prior for treatment of a congenital capillary vascular malformations. Initial management included the use of nitropaste topically to ischemic left breast nipple areola complex, however, due to intolerance patient was switched to topical dimethyl sulfoxide, yielding improvement. This case highlights potential microvascular compromise in patient with capillary malformations of the breast undergoing breast surgery and suggests a successful application of dimethyl sulfoxide in treating NAC ischemic complications. The patient declined consent for clinical photography; therefore, we provide detailed narrative descriptions and anatomical measurements. At 12-week follow-up, the NAC had re-epithelialized completely with preserved projection and excellent symmetry. To our knowledge, this is the first reported case of this kind.
2025-03-28 | Efficacy of ultrasound-guided microwave ablation for vascular malformations in children.
The aim of this study was to report our center's experience in treating pediatric vascular malformations using ultrasound-guided microwave ablation. Twenty-two symptomatic children with vascular malformations underwent ultrasound-guided microwave ablation. All patients received ultrasound follow-up after microwave ablation, whereas magnetic resonance imaging follow-up was conducted depending on the disease's condition. The Visual Analog Scale and the PedsQL4.0 Chinese Version was utilized to assess the changes in pain severity, limb motion evaluation, and quality of life before and after treatment. The study included 22 cases, comprising four arteriovenous malformations, nine venous malformations, two diffuse microcystic lymphatic malformations, two cases of Klippel-Trenaunay syndrome, and five cases of fibro adipose vascular anomaly. All children presented with pain at the affected site (22 cases; 100%). The malformations were located in the limbs in 17 cases (77%), subcutaneous and intramuscular tissues of the buttocks in one case (4.5%), subcutaneous tissue of the abdominal wall in one case (4.5%), and retroperitoneal in three cases (14%). All 22 patients (100%) experienced pain. Additionally, 20 cases (91%) exhibited swelling at the affected site or developed swelling after physical activity. Limb hypertrophy was observed in five cases (23%), whereas another five cases (23%) showed signs of limb atrophy. Joint mobility restrictions were present in four cases (18%). Among these 22 patients, 17 cases (77.3%) experienced complete resolution of pain and local lesion appearance changes, whereas four cases (18.2%) reported pain relief. However, in one case (4.5%) of Klippel-Trenaunay syndrome, postoperative improvement was observed at the treatment site, but a new centripetal malformation developed within the treated region. This patient subsequently underwent surgical intervention, resulting in an improvement in clinical symptoms. The pre-treatment malformation volume was 209.85 ± 343.17 cm3, which reduced to 32.95 ± 66.04 cm3 1 year after ablation. The volume reduction was statistically significant (t = 2.374; P = .026; P < .05), with an average volume reduction rate of 85.51%. No major complications were found, such as nerve damage or skin burns. Ultrasound-guided microwave ablation is a relatively safe and effective technique for treating pediatric vascular malformations. Further multicenter studies are recommended to validate these findings.
antibodies
2022-03-28 | A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies
Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF-β) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel-Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype-genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case-based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.
2004-03-08 | Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome.
Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.
proteins
2025-03-04 | Angiogenic factor AGGF1 is a general splicing factor regulating angiogenesis and vascular development by alternative splicing of SRSF6.
AGGF1 encodes an angiogenic factor that causes vascular disease Klippel-Trenaunay syndrome when mutated. AGGF1 also acts at the top of the genetic regulatory hierarchy for mesodermal differentiation of hemangioblasts, multipotent stem cells for differentiation of blood cells and vascular cells. Alternative splicing (AS) is a post-transcriptional process that generates multiple mature mRNAs from a single primary transcript (pre-mRNA), producing protein diversity. Deregulation of AS leads to many human diseases. The physiological role and mechanism of AGGF1 in AS are not clear. Full-length transcriptome sequencing of human pulmonary artery endothelial cells (HPAECs) with AGGF1 silencing revealed 63 121 genes, including 1144 new unannotated genes, and showed that AGGF1 is a general splicing factor regulating AS of 436 genes, including SRSF6 regulating AS of many target genes. AGGF1 promoted the skipping of exon 3 that produces the full-length SRSF6 protein, an evolutionarily conserved AS event. Overexpression of full-length SRSF6 reversed the reduced cell proliferation, migration, and capillary tube formation of HPAECs with AGGF1 silencing. Knockdown of SRSF6 and overexpression of the shorter, alternatively spliced isoform of SRSF6 both inhibited HPAEC proliferation, migration, and capillary tube formation, whereas opposite results were obtained for overexpression of full-length SRSF6. Knockdown of srsf6 impaired development of ISVs in zebrafish, whereas overexpression of srsf6 enhanced vascular development and partially rescued impaired ISV development in zebrafish embryos with aggf1 knockdown. Overall, our findings reveal that AGGF1 is a general splicing factor, and that AGGF1-mediated exon 3 skipping of SRSF6 pre-mRNA is important for endothelial cell functions, angiogenesis, and vascular development.
2021-11-22 | Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis.
Angiogenic factor AGGF1 (angiogenic factor with G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Using functional blocking studies with neutralizing antibodies, we identified [alpha]5[beta]1 as the receptor for AGGF1 on ECs. AGGF1 interacts with [alpha]5[beta]1 and activates FAK (focal adhesion kinase), Src (proto-oncogene tyrosine-protein kinase), and AKT (protein kinase B). Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from -RDD- to -RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. We have identified integrin [alpha]5[beta]1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of [alpha]5[beta]1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with [alpha]5[beta]1 and signaling.
2017-07-24 | Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin.
Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumour angiogenesis in vivo. Two lines of Aggf1 knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4. Aggf1+/- KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3β and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by PIK3CA), our data establish a potential mechanistic link between AGGF1 and PIK3CA, the two genes identified for KTS.
2013-07-22 | Functional characterization of Klippel-Trenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis.
Specification of arteries and veins is a key process for establishing functional vasculature during embryogenesis and involves distinctly different signaling mechanisms. Vascular endothelial growth factor-A (VEGFA) is required for differentiation of arteries; however, the upstream angiogenic factor for vein specification is unknown. Klippel-Trenaunay syndrome (KTS) is a congenital vascular disease associated with capillary and venous malformations (VMs), but not with arterial defects. We have previously reported that upregulation of angiogenic factor AGGF1 is associated with KTS, but the molecular mechanism is not clear. Here, we show that AGGF1 is involved in establishing venous identity in zebrafish embryos. Overexpression of AGGF1 led to increased angiogenesis and increased lumen diameter of veins, whereas knockdown of AGGF1 expression resulted in defective vasculogenesis and angiogenesis. Overexpression of AGGF1 increased expression of venous markers (e.g. flt4), but had little effect on arterial markers (e.g. notch5). Knockdown of AGGF1 expression resulted in a loss of venous identity (loss of expression of flt4, ephb4 and dab2), but had no effect on the expression of arterial development. We further show that AGGF1 activates AKT, and that decreased AGGF1 expression inhibits AKT activation. Overexpression of constitutively active AKT rescues the loss of venous identity caused by AGGF1 downregulation. Our study establishes AGGF1 as an angiogenic factor with an important role in the specification of vein identity and suggests that AGGF1-mediated AKT signaling is responsible for establishing venous cell fate. We propose that increased AGGF1 expression leads to increased vein differentiation by inducing activation of AKT signaling, resulting in VMs s in KTS patients.
2007-03-01 | Recombinant granulocyte-macrophage colony-stimulating factor in the treatment of indolent ulcers with Klippel-Trénaunay-Weber syndrome: a case report
Klippel-Trénaunay-Weber syndrome (KTWS) is a rare congenital disease characterized by cutaneous hemangiomata, venous varicosities and osseous soft tissue hypertrophy of the affected limb. We report a case of a patient with KTWS who had developed severe chronic, non-healing cutaneous ulcers resulting from several angiography procedures with embolization by various agents. The ulcers were treated with perilesional granulocyte-macrophage colony-stimulating-factor (GM-CSF) with gratifying results. This case report suggests that GM-CSF may enhance the healing of chronic wounds not responding to other treatment modalities in patients with congenital angiodystrophy syndromes, thus salvaging a limb from amputation.
gene therapies
2026-07-27 | Rare Upper Extremity Manifestation of Klippel–Trénaunay Syndrome in a Neonate
Introduction Klippel-Trénaunay syndrome (KTS) is a rare congenital vascular disorder involving a triad of capillary malformations (port-wine stains), venous anomalies, and soft tissue and/or bony hypertrophy. The condition typically presents in the lower extremities and often unilaterally. Involvement of other body parts such as the upper extremity, trunk, or viscera is highly uncommon and poorly documented. KTS is now classified within the PIK3CA-related overgrowth spectrum (PROS), a group of disorders associated with somatic activating mutations in the PIK3CA gene. We report a unique case of KTS presenting with superficial and deep venous abnormalities confined to the right upper extremity and chest wall, emphasizing the radiologic evaluation and embryologic interpretation of this unusual distribution. Publication History Received: 10 March 2026 Accepted after revision: 28 June 2026 Article published online: 27 July 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-09-03 | Multidisciplinary approach to Klippel-Trenaunay syndrome: a case report.
Klippel-Trenaunay syndrome (KTS) is a rare inherited disorder presenting as a triad of capillary malformations (cutaneous hemangiomas), soft tissue hypertrophy, and varicosities. Two out of three signs are enough to make a diagnosis. It is associated with gastrointestinal, hematological, neuro-ophthalmic, dermatological, pulmonary, oro-dental, renal cardiac, and vascular complications. There is no curative treatment for the disease. Complications are currently managed symptomatically and thorough documentation of all signs and symptoms is essential for timely identification and management of potential complications, thereby improving patient outcomes. KTS was diagnosed in a 16-year-old female, with dyspnea and fever associated with hemoptysis and abdominal pain. On physical examination, cutaneous findings and signs of respiratory compromise as well as evidence of vascular disease were observed. After appropriate medical care, the patient was soon discharged from the hospital. Following initial treatment, the patient's symptoms arbitrarily recurred requiring continued medical management and blood product administration to manage complications resulting from KTS. KTS is a chronic disorder with no cure. Patients with KTS are managed symptomatically and require frequent hospitalizations for the same.
2025-04-09 | Recurrent preeclampsia in a pregnant woman with Klippel-Trenaunay syndrome: two cesarean deliveries and multiple extremity involvement - a case report and literature review.
In this study, a total of 17 patients with Klippel-Trenaunay Syndrome (KTS) and pregnancy were evaluated. The patients were divided into two groups: those with organ involvement (10 patients) and those without organ involvement (7 patients). The clinical findings, complications, and treatment approaches between the two groups were compared, and the effects of KTS on the pregnancy process and potential risks were examined in detail. Significant clinical differences were observed between pregnant women with involvement of abdominal organs such as the liver, spleen, rectum, sigmoid, kidney, bladder, and uterus, as well as central organs like the brain, and those without such involvement. Organ involvement was defined as organ enlargement or venous anomalies detected by techniques such as ultrasound, magnetic resonance imaging (MRI), or computed tomography. Our literature review found that the risk of postpartum hemorrhage (PPH) was significantly higher in the group with organ involvement (p < 0.05). The presence of varicose malformations in organs such as the spleen, liver, and uterus was identified as an important factor increasing the risk of PPH. Therefore, close monitoring of coagulopathic disorders and taking precautions against thromboembolism in pregnant women with KTS is crucial. The case report discusses the complications and treatment processes experienced by a 26-year-old woman diagnosed with KTS and who developed preeclampsia during her two pregnancies. Complications such as preeclampsia and varices were observed in the first pregnancy, and intrauterine growth restriction (IUGR) and preeclampsia in the second pregnancy. Successful outcomes were achieved in both cases with a multidisciplinary approach and appropriate treatment methods. This study provides important information to understand the effects of KTS on pregnancy and the potential complications associated with this rare condition. Future studies will provide more information on the management of preeclampsia and other complications in pregnant women with KTS.
2025-01-16 | Klippel-Trenaunay Syndrome: A Case Study of Severe Anemia in a Rare Vascular Disorder.
Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder involving varicosities, cutaneous vascular malformations, and hypertrophy of soft tissues and bones. It is often linked to PIK3CA gene mutations. It affects the lymphatic, capillary, and venous systems. The diagnosis is usually based on clinical presentation, supplemented by magnetic resonance imaging (MRI) and computed tomography (CT) imaging. This case involves a 43-year-old male diagnosed with KTS after presenting with severe anemia (hemoglobin 2.5 g/dL) and left lower limb swelling with varicosities. Investigations revealed hepatosplenomegaly, hemangiomas, rectosigmoid malformations, an enlarged inferior vena cava (IVC), and vascular congestion. MRI confirmed an extensive veno-lymphatic malformation in the left lower limb. The case highlights KTS's complex presentation, emphasizing the importance of timely diagnosis, multidisciplinary care, and ongoing monitoring to manage its complications. Further research is needed to enhance treatment strategies for this rare condition.
2024-09-10 | Genetic basis and imaging findings of neurofibromatosis 1 and other somatic overgrowth disorders.
Somatic overgrowth disorders comprise a wide range of rare conditions that present with focal enlargement of one or more tissue types. The PI3K-AKT-mTOR pathway is a signalling pathway that induces angiogenesis and cell proliferation, and is one of the most commonly overactivated signalling pathways in cancer. The PI3K-AKT-mTOR pathway can be up-regulated by genetic variants that code for proteins in this pathway, or down-regulated by proteins that inhibit the pathway. Mosaic genetic variations can result in cells that proliferate excessively in specific anatomical locations. The PIK3CA-related overgrowth spectrum (PROS) disorders include CLOVES syndrome, macrodystrophia lipomatosa, and Klippel-Trenaunay syndrome among many. The neurofibromatosis type 1 (NF1) gene encodes neurofibromin which down-regulates the PI3K-AKT-mTOR pathway. Thousands of pathological variants in the NF1 gene have been described which can result in lower-than-normal levels of neurofibromin and therefore up-regulation of the PI3K-AKT-mTOR pathway promoting cellular overgrowth. Somatic overgrowth is a rare presentation in NF1 with a wide range of clinical and radiological presentations. Hypertrophy of all ectodermal and mesodermal elements has been described in NF1 including bone, muscle, fat, nerve, lymphatics, arteries and veins, and skin. The shared signalling pathway for cellular overgrowth means that these radiological appearances can overlap with other conditions in the PIK3CA-related overgrowth spectrum. The aim of this review is to describe the genetic basis for the radiological features of NF1 and in particular compare the appearances of the somatic overgrowth disorders in NF1 with other conditions in the PIK3CA-related overgrowth spectrum.
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