Hip Dysplasia in a Context of Blue Rubber Bleb Nevus Syndrome, 5-years Follow-up after Hip Arthroplasty.

Introduction: Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital vascular disorder that affects the venous system. Lesions are multiple and involved not only the skin and subcutaneous tissue but also muscles, joints and organs such as the gastrointestinal tract. At present, little is known regarding its potential orthopedic complications. Case Report: We present a unique case of a patient with BRBNS displaying both intra-articular and extra-articular severe venous malformation (VM) of the hip. This extensive VM caused severe deformities in bone growth, mainly affecting the proximal femur, and impacted the muscular development of the gluteus medius and gluteus maximus. Its intra-articular extension, along with repeated secondary hemarthrosis, led to cartilaginous destruction. Consequently, the patient presented with significant coxa valga and developed acetabular dysplasia and subluxation of femoral head, during growth. In order to restore hip function and alleviate pain, the patient underwent a total hip arthroplasty (THA) at the age of 18. Discussion: The dysplastic changes in the hip joint observed in this case are attributed to the deleterious effects of VMs and coxa valga on joint anatomy and biomechanics. VMs induce recurrent hemarthrosis, leading to cartilage destruction and hip instability. Additionally, coxa valga alters hip biomechanics, exacerbating joint instability and accelerating wear. Surgical intervention with THA aimed to restore joint stability and function, although challenges arose due to anatomical complexities and limited prosthetic options. Conclusion: This is the first reported case of hip dysplasia associated with BRBNS. This case shows the involvement of vascular malformation in the development of hip dysplasia leading to total hip arthroplasty. The surgical planning and technique must take the specificity of this pathology into account to get the best result possible for the patient. This case illustrates the importance of a multidisciplinary approach to treat patients with this specific syndrome and adds valuable information to the limited literature on orthopedic complications in BRBNS.

Targeted Treatments for Vascular Malformations: Current State of the Art.

Vascular malformations, which arise from anomalies in angiogenesis, encompass capillary, lymphatic, venous, arteriovenous and mixed malformations, each affecting specific vessel types. Historically, therapeutic options such as sclerotherapy and surgery have shown limited efficacy in complicated malformations. Most vascular malformations stem from hereditary or somatic mutations akin to oncogenic alterations, activating the PI3K-AKT-mTOR, RAS-MAPK-ERK, and G-protein coupled receptor pathways. Recognizing the parallels with oncogenic mutations, we emphasize the potential of targeted molecular inhibitors in the treatment of vascular malformations by repurposing anticancer drugs. This review delves into the recent development and future use of such agents for the management of slow- and fast-flow vascular malformations, including in more specific situations, such as prenatal treatment and the management of associated coagulopathies.

Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus.

Repurposing anticancer drugs to vascular malformations has significantly improved patient outcomes. Complex Lymphatic Anomalies (CLA) are part of the spectrum of lymphatic malformations (LMs) that share similar oncogenic mutations to cancer. We report the case of a young patient with highly symptomatic CLA who was initially treated with sirolimus, due to the frequent involvement of the PI3K-AKT-mTOR pathway in CLA pathogenesis. Despite an initial reduction in symptoms, sirolimus progressively lost its effectiveness. After an unsuccessful attempt with trametinib alone, sirolimus was added to trametinib and resulted in a significant, rapid and sustained improvement in symptoms. This suggests that, contrary to current dogmas, combination therapy using sub-therapeutic doses targeting both the PI3K and RAS pathways retains efficacy without generating the toxicity known for combination therapies, and is beneficial in the management of CLAs and potentially other vascular anomalies.

Direct oral anticoagulants and venous malformations: literature review and retrospective study of 29 patients.

Background: Venous malformations (VMs) are commonly associated with localized intravascular coagulopathy leading to elevated D-dimer and risks of hemorrhagic and thromboembolic events, particularly in extensive lesions. While low-molecular-weight heparin (LMWH) has been effective in managing coagulopathy and pain, direct oral anticoagulants (DOACs) emerge as a promising alternative. Objectives: This study aims to evaluate the efficacy and safety of DOACs in treating VMs associated with localized intravascular coagulopathy, offering a comparative perspective to LMWH. Methods: A retrospective study was conducted on 29 patients with VMs and secondary localized intravascular coagulopathy treated with DOACs between 2013 and 2023 in a single tertiary center specialized in vascular anomalies. Data were collected from February 24, 2023, to September 1, 2023. Results: Patients' median age was 40 years (range, 22-76 years), with a female predominance of 66%. Descriptive statistical analysis showed that 85% of patients experienced pain improvement, and 86% showed a reduction in D-dimer by at least 25%, with a mean reduction of 57% (SD, ±32%; IQR, [38-81%]). Additionally, 37% of patients reported a bleeding event, mostly minor. Conclusion: The study findings suggests that DOACs may serve as an alternative to LMWH for patients with VMs associated with pain management and reduced D-dimer, alongside a low observed risk of major bleeding. Tailored dosing considering the location of the malformation, bleeding and thrombotic tendencies, and laboratory abnormalities is recommended. Future studies with larger cohorts and extended follow-up are necessary for more conclusive evidence on DOACs' role in this patient population.

Has Propranolol Eradicated the Need for Surgery in the Management of Infantile Hemangioma?

BACKGROUND: To assess the impact of propranolol as the first-line treatment of infantile hemangioma (IH) on the need for surgery in the management of IH. METHODS: Retrospective study of 420 patients, with IH, referred to our multidisciplinary center between January 2005 and August 2014. Clinical data including sex, age at first consultation and at treatment initiation, location, size, number, aspect, and complication of IH, as well as the type of treatment were collected. Statistical analyses were conducted considering each patient and each tumor independently. RESULTS: A total of 625 IH(420 patients (P))were reviewed, 113 patients had more than one IH (26.91%). Median age at first consultation was 7 months old. Overall, 243 patients were treated (57.86%) using either surgery (n=128 P/141 IH), propranolol (n=79 P/89 IH), corticosteroids (n=51 P/56 IH), and/or laser (n=34 P /36 IH). Propranolol was effective in all but 2 infants with IH. Seven patients (n=7/79 P; 8.86%) initially treated with propranolol, still required surgery, in contrast to 18 patients (n=18/51 P; 35.29%) initially treated with corticosteroids, and 103 patients (n=103/290 P; 35.51%) with no medical treatment. Since the availability of propranolol, patients were less likely to undergo surgery (48 P versus 80 P; P-Value < 0.001). This demonstrated that the use of propranolol reduced the need for surgery (P-Value < 0.001 with an OR of 0.177: CI 95% 0.079-0.396). CONCLUSION: Propranolol has dramatically reduced the need for surgery, regarding indications and number of patients. Surgical correction remains important for sequelae management, non-responders or strawberry-like IH.

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.

Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function.

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Somatic Loss-of-Function PIK3R1 and Activating Non-hotspot PIK3CA Mutations Associated with Capillary Malformation with Dilated Veins (CMDV).

Common capillary malformations are red vascular skin lesions, most commonly associated with somatic activating GNAQ or GNA11 mutations. We focused on capillary malformations lacking such a mutation to identify previously unreported genetic causes. We used targeted next-generation sequencing on 82 lesions. Bioinformatic analysis allowed the identification of 9 somatic pathogenic variants in PIK3R1 and PIK3CA, encoding for the regulatory and catalytic subunits of phosphoinositide 3-kinase, respectively. Recharacterization of these lesions unraveled a common phenotype: a pale capillary malformation associated with visible dilated veins. Primary endothelial cells from 2 PIK3R1-mutated lesions were isolated, and PI3k-Akt-mTOR and RAS-RAF-MAPK signaling were assessed by western blot. This unveiled an abnormal increase in Akt phosphorylation, effectively reduced by PI3K pathway inhibitors, such as mTOR, Akt, and PIK3CA inhibitors. The effects of mutant PIK3R1 were further studied using zebrafish embryos. Endothelium-specific expression of PIK3R1 mutants resulted in abnormal development of the posterior capillary-venous plexus. In summary, capillary malformation associated with visible dilated veins emerges as a clinical entity associated with somatic pathogenic variants in PIK3R1 or PIK3CA (nonhotspot). Our findings suggest that the activated Akt signaling can be effectively reversed by PI3K pathway inhibitors. In addition, the proposed zebrafish model holds promise as a valuable tool for future drug screening aimed at developing patient-tailored treatments.

Epilepsy with faint capillary malformation or reticulated telangiectasia associated with mosaic AKT3 pathogenic variants.

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies. Instead, we identified two somatic pathogenic variants in the AKT3 gene. Subsequent analysis of the DNA obtained from surgically resected brain tissue of one of the two patients confirmed the presence of the AKT3 variant. Focal cortical dysplasia was also detected in this patient. Genetic analysis thus facilitated workup to reach a precise diagnosis for these patients, associating the vascular anomaly with the neurological symptoms. This study underscores the importance of searching for additional signs and symptoms to guide the diagnostic workup, especially in cases with atypical vascular malformations. In addition, it strongly emphasizes the significance of genotype-phenotype correlation studies in guiding clinicians' informed decision-making regarding patient care.