Klippel-Trenaunay Syndrome Research Articles

Klippel–Trenaunay syndrome in a child presented with bladder hemangioma: a rare manifestation of a rare syndrome

Introduction: Klippel–Trenaunay syndrome (KTS) is a rare congenital anomaly. Involvement of visceral organs is rarely described, especially in the gastrointestinal system, liver, spleen, mediastinum, and genitourinary system, which typically leads to internal hemorrhage and may present as hematuria or hematochezia. Rectal and bladder bleeding in patients with KTS I are rare conditions. Case presentation: We present a rare instance of a 13-year-old female who experienced an unprompted visible hematuria for several days without any additional urinary symptoms. An investigative cystotomy was performed, which unveiled a hemangioma surrounding the opening of the left ureter and a large intramuscular hemangioma on the posterior wall. Discussion: A review of the cases showed that most patients with bladder hemangioma associated with KTS were men with an average age of 16 years (range: 3–37 years). The symptom that we have detected in nearly all cases, including ours, was gross hematuria, except in one case with microscopic hematuria. Conclusion: Pediatricians should suspect this syndrome in any child with one of its symptoms, especially since the skin manifestation is distinctive and indicative of this syndrome.

Rectal bleeding due to cavernous hemangioma in Klippel–Trenuany syndrome: a rare presentation and review of management

Introduction and importance: Klippel–Trenaunay syndrome (KTS) is a rare congenital disorder with an incidence of about 2–5:100 000. It is characterized by the triad of cutaneous hemangiomas, soft tissue or bone hypertrophy, and venous malformations. Gastrointestinal (GI) involvement in KTS, although uncommon, can lead to severe complications such as profuse GI bleeding. Our case highlights the challenges and management strategies of a patient with KTS. Case presentation: A 5-year-old child presented with rectal bleeding since birth, accompanied by swelling and bluish discoloration on left flank, and multiple varicose veins on left leg. Examination revealed small hemangiomatous lesions scattered along the torso and trunk. Barium enema showed diffuse mucosal irregularity with polypoidal filling defects in the rectum and sigmoid colon. Doppler ultrasound revealed slow-flow vascular lesions in the left flank and leg without arteriovenous communication. Computed tomography (CT) scan showed diffuse cavernous hemangiomas in the descending colon, sigmoid colon, and rectum. Histopathology demonstrated numerous dilated, irregular vascular channels with calcification and hemosiderin-laden macrophages. Clinical discussion: GI tract cavernous hemangiomas can cause chronic bleeding and anemia, necessitating careful evaluation. Imaging modalities like CT and Doppler ultrasound are crucial for assessing vascular lesions. Surgical interventions, including partial proctocolectomy and colorectal anastomosis, effectively control bleeding and improve outcomes. A multidisciplinary approach is essential for managing such cases. Conclusion: This case underscores the importance of multidisciplinary management in KTS with GI bleeding. Effective diagnostic imaging and surgical treatment are key to managing severe complications and achieving successful outcomes. Long-term follow-up is crucial to monitor for recurrence and residual lesions.

In-Human Clinical Experience with Direct Stick Embolization of Low-Flow Vascular Malformations Using an mTOR Inhibitor

BackgroundWhile direct stick embolization (DSE) of low-flow vascular malformations (LFVMs) with off-label embolotherapeutic compounds is the current mainstay of therapy, systemic oral mTOR inhibition has evolved into an important adjunctive therapy that is associated with frequent blood draws, systemic toxicity, and rebound signs/symptoms upon cessation. We, herein, report our experience with in-human DSE of LFVMs with an mTOR inhibitor for direct, intralesional targeting of the culprit mutated pathway without repeated systemic exposure. MethodsSince 2020, 33 procedures involving DSE were performed in 25 patients with LFVMs using a patented formulation and technique involving the intravenously compatible mTOR inhibitor Yale-OCR7737, used as a liquid compound in a collagen matrix emulsion for added viscosity and intralesional residence. Data was prospectively maintained and retrospectively reviewed for technical success (successful catheterization of the lesion and intralesional delivery of compound); clinical success (improvement in signs/symptoms with radiologically documented reduction in flow and/or volume of treated lesion); complications; side effects; and re-interventions. ResultsFrom 2020 to 2023, 33 procedures involving DSE were performed using Yale-OCR7737 in 25 patients (10[40%] men; 15[60%] women; mean age: 28 years [range 1 -70 years]) with LFMVs involving the head/neck (48%) and limbs (40%); 88% were non-syndromic while 12% had Klippel-Trenaunay Syndrome; 68% exhibited venous malformations, while 32% had lymphatic malformations. Technical and clinical success were 100%. Mean DSE sessions per patient was 1.4 (range 1 to 5). Localized intravascular coagulopathy was present after 16 (49%) DSE procedures; D-dimer improved post-DSE in 7 cases. No perioperative or delayed complications occurred. Side-effects were 7 (21%) cases of self-limited, transient oral aphthous ulcers. ConclusionsOur findings suggest that DSE of LFVMs with mTOR inhibitors (Yale-OCR7737) may be safe and effective. This may represent the new embolotherapeutic frontier in the endovascular treatment of LFMVs.

Open reduction and plate fixation of fractures of both bones in the forearm in Klippel-Trenaunay-Weber syndrome: a case report

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare disease characterized by vascular malformations, port-wine staining, and soft tissue and bone hypertrophy. Lesions occur in the lower extremities in 95% of cases, whereas only 5% occur in the upper extremities. Several case reports have described the treatment of fractures in the lower extremities in patients with KTWS. However, the risk of massive bleeding, bone deformity, and poor bone quality can lead to suboptimal surgical outcomes. No reports describing the treatment of forearm shaft fractures in KTWS could be found in the English-language literature. Intramedullary nailing is difficult due to the deformed bone and the risk of nonunion. Open reduction and internal fixation (ORIF) should be considered with caution in KTWS patients due to the risks of intraoperative bleeding and wound problems. The authors report that satisfactory results were obtained with ORIF after preoperative vascular embolization in a 60-year-old KTWS patient with fractures in both bones of the forearm.

A rare case of a 5-year-old girl with Klippel-Trénaunay syndrome and a bleeding focal vulvar hemangioma in Uganda.

Klippel-Trénaunay syndrome can present with atypical manifestations such as a bleeding vulvar hemangioma. This case report, the first documented in Uganda, highlights the need for awareness of such presentations and underscores the importance of continuous follow-up in female patients to manage potential complications throughout adolescence and pregnancy. Klippel-Trénaunay syndrome (KTS) is a rare congenital disorder marked by bone and soft tissue hypertrophy, port-wine stains, and varicosities. Cases involving genital hemangiomas are rare. This report highlights a 5-year-old girl in Uganda with typical KTS features, including hypertrophy and port-wine stains, along with a bleeding vulvar hemangioma, emphasizing its uncommon presentation and potential complications. Treatment involved compression bandaging and timolol 0.2% solution. This case underscores the importance of awareness of atypical manifestations of hemangiomas with KTS and continuous follow-up for female patients, especially through adolescence and pregnancy, due to potential complications such as prepubertal per vaginal bleeding, menorrhagia, and post-partum bleeding.

Splenectomy for Klippel-Trenaunay syndrome: systematic review and case series

Splenectomy for Klippel-Trenaunay syndrome: systematic review and case series

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.

Obstetric management for pregnant women with Klippel-Trenaunay syndrome: A UK case report and review of the literature.

Klippel-Trenaunay Syndrome (KTS) is a rare congenital vascular disorder characterized by extensive capillary and venous malformations that pose unique challenges during pregnancy. This case report discusses the successful management of a 34-year-old pregnant woman with KTS who had two caesarean sections, resulting in the birth of two healthy babies. Despite the lack of evidence-based guidelines for obstetrical management in KTS, a multidisciplinary team collaborated to devise a high-risk thrombosis management plan, involving the use of compression stocking and low molecular weight heparin prophylaxis. The patient's elevated risk of thrombosis, exacerbated during pregnancy, informed the decision of caesarean sections, aligning with finding that in most KTS pregnancies, this method of delivery based on obstetric indications and arteriovenous malformations is chosen. This case highlights the importance of systematic and patient-centered care, advocating for comprehensive obstetric management guidelines to address the unique challenges posed by KTS during pregnancy. Further research is warranted to enhance our understanding and refine guidelines for individuals with vascular abnormalities linked to KTS.

Identifying Genetic Mutations in Vascular Anomalies Using a Sequencing Panel for Childhood Cancers: A Pilot Study

Introduction: Genetic mutations have been identified in the pathogenesis of vascular anomalies. Due to overlaps in genetic variants causing vascular anomalies and cancer, we used a next-generation sequencing panel for genomic profiling of childhood cancers to detect somatic mutations in children with vascular anomalies. We aim to review the utility of an oncology panel for the molecular diagnosis of vascular anomalies. Methods: Nine patients with histologically confirmed vascular anomalies were included. DNA was extracted from formalin-fixed paraffin-embedded tissue specimens obtained from affected tissue following diagnostic punch biopsies of the skin and core biopsies of the vascular malformation or tumor during sclerotherapy or surgical excision. Molecular analysis of the tissue samples was performed using AmpliSeq for Childhood Cancer DNA Assay Panel. Results: Two patients had antenatally detected vascular anomalies. The median age at diagnosis for the remaining patients was 7.0 years (IQR, 0.6–10.0 years). Seven were diagnosed with vascular malformations, while 2 had vascular tumors. Pathological somatic mutations were identified in 4 patients, leading to a diagnostic yield of 44.4%. Two different PIK3CA mutations were identified in 3 cases: 1 in a case of macrocystic lymphatic malformation, the other in a case of Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevus, Spinal/Skeletal anomalies syndrome and Klippel–Trenaunay syndrome. BRAF mutation was identified in a patient with a veno-lymphatic malformation. Conclusion: An oncology next-generation sequencing panel can be used for genetic profiling of vascular anomalies. However, a more customized and sensitive panel may be of better diagnostic yield, as detection of somatic mutations in vascular anomalies is challenging due to tissue mosaicism, low-abundant genetic variants, and specimen limitations.

Klippel–Trenaunay syndrome presenting as pulmonary embolism in an elderly person

Abstract An elderly woman was admitted with acute-onset breathlessness and right-sided chest pain suggestive of pleurisy. The initial impression of the chest X-ray was ‘right upper lobe consolidation’. Her hypertrophied leg along with the presence of large visible arteriovenous malformation was suggestive of Klippel–Trenaunay syndrome (KTS). A conscientious relook at the X-ray revealed other radiological features suggesting a possible pulmonary embolism. Subsequent D-dimer and echocardiography supported the diagnosis, and a computerised tomography pulmonary angiogram confirmed the same. Prompt systemic anticoagulation along with supportive therapy led to a smooth recovery of the patient over the next few days.

526 Clinical Efficacy and Safety of Oral Sirolimus Therapy in Patients with Klippel-Trenaunay Syndrome in a Single Specialist Centre

526 Clinical Efficacy and Safety of Oral Sirolimus Therapy in Patients with Klippel-Trenaunay Syndrome in a Single Specialist Centre

A Cautionary Tale of Vascular Abnormalities in Klippel-Trenaunay Syndrome: A Case Report

Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder characterized by a port-wine stain birthmark, venous anomalies, and soft-tissue hypertrophy. Diagnosis of KTS is made based on two of the three characteristic diagnostic features. Klippel-Trenaunay syndrome is unilateral and more commonly affects the lower extremities. This case report describes a unique patient who lacked a patent deep system in the affected limb, making the traditional treatment of varicosities a dangerous outcome for this patient.

Dermato-Radiological Evaluation of Congenital Limb Overgrowth Vascular Syndromes

Abstract International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes with other abnormalities that present with unilateral limb overgrowth. It includes Klippel–Trenaunay Syndrome, Parkes–Weber Syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis) Syndrome, Proteus Syndrome, PTEN Hamartomatous Syndrome, and Fibroadipose Vascular Anomaly. Due to their rare and complex nature, a multidisciplinary approach to diagnosis and treatment is required. A thorough clinical and radiological workup can go miles in reflecting on the patient’s outcome. Here we report five cases of CLOS with their detailed dermato-radiological profiles.

Megalencephaly: Classification, Genetic Causes, and Related Syndromes

AbstractMegalencephaly is a developmental disorder due to an abnormal neuronal proliferation and migration during intrauterine or postnatal brain development that leads to cerebral overgrowth and neurological dysfunction. This cerebral overgrowth may affect the whole encephalon or only a region; when it involves one hemisphere it is referred to as hemimegalencephaly. Megalencephaly presents with a head circumference measurement of 2 standard deviations above the average measure for age. This group of disorders is clinically characterized by early onset and refractory to therapy epilepsy, neurodevelopmental disorders, behavioral problems, and autism spectrum disorder. Syndromic forms of megalencephaly should be considered when associated with other congenital abnormalities. Megalencephaly in fact could be associated with segmental overgrowth and cutaneous/vascular abnormalities (i.e., Proteus syndrome, CLOVES [congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis, and/ or skeletal abnormalities] syndrome, Klippel-Trenaunay syndrome, megalencephaly-capillary malformation-polymicrogyria syndrome , megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus syndrome, etc.) or generalized overgrowth (i.e., Weaver or Beckwith-Wiedemann syndrome) as well as with nanism in achondroplasia where megalencephaly is associated with disproportionate short stature, primary skeletal dysplasia, characteristic facies (prominent forehead, flat nasal bridge), narrow chest, and normal intelligence. It is possible to identify three main groups of disorders associated with megalencephaly: idiopathic or benign, metabolic, and anatomic. The idiopathic (benign) form indicates an abnormal increased head circumference in absence of neurological impairment, such as in benign familial megalencephaly. In metabolic megalencephaly (such as in organic acid disorders, metabolic leukoencephalopathies, or lysosomal diseases) there is an increase of different constituents that increase the size of the brain, whereas in the anatomical form there are underlying genetic causes. Neuroimaging is crucial for diagnosis, as it can reveal a generalized brain growth or a segmental one and possible specific frameworks associated. In all these conditions it is necessary to identify possible microdeletion-microduplication by chromosomal arrays.

Recurrent hematuria involving urinary system with Klippel-Trenaunay syndrome: A case report.

Klippel-Trenaunay syndrome (KTS) is a rare congenital venous malformation, it had been found to be caused by mutations of the phosphatidylinositol 4, 5-diphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Currently KTS is defined as a triad of skin wine pigmented spots, varicose veins and malformations of the lower extremities, and hypertrophy of bone and soft tissue, involving urinary system up to 6% to 30%. When the urinary system is involved, KTS is often presented as painless massive gross hematuria. This article describes a woman who was hospitalized with painless massive gross hematuria. Physical examination revealed significant hypertrophy of the right lower limb with varicose veins, port-wine stains in the skin, and right perineal hemangiomatous changes with swelling. The patient was admitted to hospital 4 times for repeated hematuria and infection. By physical examination, CT urography, ureteroscopy and cystoscopy, the patient was diagnosed to have Klippel-Trenaunay syndrome, involving the urinary system. The patient hematuria improved after multiple indwelling D-J tubes and anti-inflammatory treatment. The final symptoms of hematuria improved significantly, follow-up so far has not recurred. This case presents the possibility of painless gross hematuria with KTS. Most of patients can be improved by conservative treatment. Cystoscopic laser therapy is the preferred treatment for poor bleeding control. Cystectomy and nephrectomy should be considered when life-threatening.

A multidisciplinary approach to managing lymphorroea in primary lymphoedema: a case study.

This case study describes the successful management of a patient with primary lymphoedema, who was experiencing lymphorrhoea and epidermolysis, using a multidisciplinary approach. The patient had Klippel-Trenaunay syndrome. The multidisciplinary team, in an outpatient clinic in Japan, included a certified lymphoedema therapist, plastic surgeons, and a wound, ostomy and continence nurse. The team performed complex physical therapy and lymphaticovenular anastomosis, which promoted the resolution of the lymphorrhoea. This resulted in improvements in skin condition, the prevention of recurrent cellulitis, and no increase in limb circumferences during the 1-year follow-up period. This report highlights the importance of a multidisciplinary approach to lymphoedema management, including lymphorrhoea control that fitted in with the patient's daily life. It is hoped that this article will contribute to the improvement of the quality of life of patients with lymphoedema.

Klippel-trenaunay syndrome and pregnancy – the case report

Klippel-trenaunay syndrome and pregnancy – the case report

O06 Clinical phenotype of the Klippel-Trenaunay syndrome with mosaic PIK3R1 mutations

Abstract Segmental overgrowth syndromes with cutaneous vascular malformations (Klippel-Trenaunay syndrome (KTS), CLOVES syndrome) are mainly due to mosaic PIK3CA mutations, but the GNAQ, GNA11, HRAS, KRAS, MAP2K1, AKT1, AKT3, and PIK3R1 genes may also be involved. We sought to determine the frequency and phenotype of patients with PIK3R1-related segmental overgrowth. Patients were ascertained nationwide in the French MUSTARD cohort of skin mosaic phenotypes. We searched for PIK3R1 mutations by next-generation sequencing on affected tissue in 297 patients with a clinical presentation suggestive of PIK3CA related overgrowth (PROS), but without PIK3CA variants. We retrospectively studied the clinical phenotype of PIK3R1-positive patients. We identified three missense variants and six in-phase indels of PIK3R1 in 15 patients (5.0%), exclusively in affected tissue. Variant allele fraction was 2.0% to 12.0%. We found extensive pale or dark capillary malformations in 14 patients, segmental overgrowth in 11, venous truncal anomalies (varicose veins or persistent lateral marginal vein) in 10, lymphatic malformation in six and a café-­au-lait macule or naevus spilus in three, thus defining phacomatosis pigmento-vascularis (PPV). One patient had limb hypoplasia. None had MCAP (Megalencephaly-Capillary malformation). PIKR1 mutations account for a minority of patients with KTS/CLOVES (5%). They are about 20 times less common than PIK3CA mutations. Truncal venous malformations, limb hypoplasia and PPV (spilorosea or melanorosea type) may be more common in PIK3R1-related KTS. No patient had severe or life-threatening involvement. Whether Sirolimus or Alpelisib are treatment options remains to be determined.

A rare presentation of pupillary block glaucoma and persistent tunica vasculosa lentis in Klippel–Trenaunay syndrome

Phacomatoses are a group of neurocutaneous disorders characterized by vascular and pigmentary birthmarks, often involving multiple organ systems. Klippel–Trenaunay syndrome (KTS), a rare phacomatosis, is characterized by the classical triad of cutaneous capillary hemangiomas, venous malformations, and soft tissue overgrowth. Glaucoma secondary to angle dysgenesis, raised episcleral venous pressure, or excess angle pigmentation is observed. We report a case of KTS that presented with cutaneous capillary hemangiomas and limb hypertrophy along with unilateral buphthalmos. This eye was noted to have persistent tunica vasculosa lentis and persistent pupillary membrane with pupillary block glaucoma that was treated with pupilloplasty. To the best of our knowledge, this mechanism of glaucoma in KTS has not been reported before. The purpose of this article is to document this rare presentation as well as highlight the importance of detecting the underlying mechanism for appropriate management.

Anaesthetic Management of Paediatric Patient with Klippel-Trenaunay Syndrome undergoing Excision of Scalp Cyst: A Case Report

Klippel-Trenaunay Syndrome (KTS) is a sporadic condition characterised by the clinical triad of capillary malformation, atypical varicosity, and soft-tissue and bony hypertrophy. This triad was observed in the current case. Despite being initially described over a century ago, the exact incidence of this syndrome remains unestimated. The clinical presentation of KTS is highly diverse, ranging from asymptomatic cases to severe instances involving life-threatening bleeding and embolism. The authors present a case report of a 10-year-old girl with complaints of a cystic swelling in her left temporal region. She exhibited distinct features such as facial asymmetry, a high-arched palate, a prominent mandible, a port-wine stain on her cheeks, nasal bridge depression, and right-sided body hypertrophy. The child showed delayed developmental milestones, including holding her neck at 1.5 months, a bidextrous approach at seven months, and social smiling at six months, indicating global developmental delay. The patient was scheduled for excision of the swelling. Following the successful excision of the cyst, the child was extubated. The extubation was uneventful. In the postoperative period, the patient remained haemodynamically stable. Managing such a patient for a surgical procedure requires a meticulous approach involving accurate anaesthetic preparation and the prevention of complications.