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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.
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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.
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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.
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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.
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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.
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Mutación con Pérdida de Función , Linfedema , Receptor TIE-1 , Linfedema/genética , Linfedema/patología , Linfedema/metabolismo , Humanos , Animales , Ratones , Receptor TIE-1/genética , Receptor TIE-1/metabolismo , Femenino , Masculino , Mutación Missense , Edad de Inicio , Persona de Mediana Edad , Adulto , Receptor TIE-2RESUMEN
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.
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Anomalías Linfáticas , Piridonas , Pirimidinonas , Sirolimus , Humanos , Anomalías Linfáticas/tratamiento farmacológico , Anomalías Linfáticas/patología , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Sirolimus/uso terapéuticoRESUMEN
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.
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Factor de Crecimiento de Hepatocito , Linfedema , Humanos , Factor de Crecimiento de Hepatocito/genética , Factor de Crecimiento de Hepatocito/metabolismo , Masculino , Femenino , Niño , Adulto , Linfedema/genética , Linfedema/patología , Adolescente , Persona de Mediana Edad , Animales , Mutación Missense/genética , Mutación con Pérdida de Función , Edad de Inicio , Preescolar , Células COS , Chlorocebus aethiops , Células Endoteliales/metabolismo , Células Endoteliales/patología , Adulto JovenRESUMEN
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.
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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.
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Capilares , Epilepsia , Proteínas Proto-Oncogénicas c-akt , Telangiectasia , Malformaciones Vasculares , Femenino , Humanos , Recién Nacido , Masculino , Capilares/anomalías , Capilares/patología , Epilepsia/genética , Epilepsia/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mosaicismo , Mutación/genética , Fenotipo , Proteínas Proto-Oncogénicas c-akt/genética , Telangiectasia/genética , Telangiectasia/patología , Telangiectasia/diagnóstico , Malformaciones Vasculares/genética , Malformaciones Vasculares/patología , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/complicaciones , AdolescenteRESUMEN
BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.
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Sirolimus , Malformaciones Vasculares , Adulto , Niño , Humanos , Europa (Continente) , Fosfatidilinositol 3-Quinasas , Estudios Prospectivos , Sirolimus/efectos adversos , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/genéticaRESUMEN
To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. Results: The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. Conclusion: The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/).
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BACKGROUND: Primary lymphoedema (PL) is a chronic, debilitating disease caused by developmental and functional defects of the lymphatic system. It is marked by an accumulation of interstitial fluid, fat and tissue fibrosis. There is no cure. More than 50 genes and genetic loci have been linked to PL. We sought to study systematically cell polarity signalling protein Cadherin Epidermal Growth Factor Laminin G Seven-pass G-type Receptor 1 (CELSR1) variants linked to PL. METHODS: We investigated 742 index patients from our PL cohort using exome sequencing. RESULTS: We identified nine variants predicted to cause CELSR1 loss of function. Four of them were tested for nonsense-mediated mRNA decay, but none was observed. Most of the truncated CELSR1 proteins would lack the transmembrane domain, if produced. The affected individuals had puberty/late-onset PL on lower extremities. The variants had a statistically significant difference in penetrance between female patients (87%) and male patients (20%). Eight variant carriers had a kidney anomaly, mostly in the form of ureteropelvic junction obstruction, which has not been associated with CELSR1 before. CELSR1 is located in the 22q13.3 deletion locus of the Phelan-McDermid syndrome. As variable renal defects are often seen in patients with the Phelan-McDermid syndrome, CELSR1 may be the long-sought gene for the renal defects. CONCLUSION: PL associated with a renal anomaly suggests a CELSR1-related cause.
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Trastornos de los Cromosomas , Linfedema , Femenino , Humanos , Masculino , Cadherinas/genética , Cadherinas/metabolismo , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Linfedema/genéticaRESUMEN
OBJECTIVE: In recent years, genotypic characterization of congenital vascular malformations (CVMs) has gained attention; however, the spectrum of clinical phenotype remains difficult to attribute to a genetic cause and is rarely described in the adult population. The aim of this study is to describe a consecutive series of adolescent and adult patients in a tertiary center, where a multimodal phenotypic approach was used for diagnosis. METHODS: We analyzed clinical findings, imaging, and laboratory results at initial presentation, and set a diagnosis according to the International Society for the Study of Vascular Anomalies (ISSVA) classification for all consecutively registered patients older than 14 years of age who were referred to the Center for Vascular Malformations at the University Hospital of Bern between 2008 and 2021. RESULTS: A total of 457 patients were included for analysis (mean age, 35 years; females, 56%). Simple CVMs were the most common (n = 361; 79%), followed by CVMs associated with other anomalies (n = 70; 15%), and combined CVMs (n = 26; 6%). Venous malformations (n = 238) were the most common CVMs overall (52%), and the most common simple CVMs (66%). Pain was the most frequently reported symptom in all patients (simple, combined, and vascular malformation with other anomalies). Pain intensity was more pronounced in simple venous and arteriovenous malformations. Clinical problems were related to the type of CVM diagnosed, with bleeding and skin ulceration in arteriovenous malformations, localized intravascular coagulopathy in venous malformations, and infectious complications in lymphatic malformations. Limb length difference occurred more often in patients with CVMs associated with other anomalies as compared with simple or combined CVM (22.9 vs 2.3%; P < .001). Soft tissue overgrowth was seen in one-quarter of all patients independent of the ISSVA group. CONCLUSIONS: In our adult and adolescent population with peripheral vascular malformations, simple venous malformations predominated, with pain as the most common clinical symptom. In one-quarter of cases, patients with vascular malformations presented with associated anomalies on tissue growth. The differentiation of clinical presentation with or without accompanying growth abnormalities need to be added to the ISSVA classification. Phenotypic characterization considering vascular and non-vascular features remains the cornerstone of diagnosis in adult as well as pediatric patients.
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Malformaciones Arteriovenosas , Malformaciones Vasculares , Femenino , Humanos , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Arteriovenosas/diagnóstico por imagen , Malformaciones Arteriovenosas/genética , Malformaciones Arteriovenosas/terapia , Venas/anomalías , Dolor , FenotipoRESUMEN
Somatic activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations have been reported in patients with arteriovenous malformations. By producing LSL-Kras (G12D); Cdh5 (PAC)-CreERT2 [iEC-Kras (G12D*)] mice, we hoped to activate KRAS within vascular endothelial cells (ECs) to generate an arteriovenous malformation mouse model. Neonatal mice were treated daily with tamoxifen from postnatal (PN) days 1-3. Mortality and phenotypes varied amongst iEC-Kras (G12D*) pups, with only 31.5% surviving at PN14. Phenotypes (focal lesions, vessel dilations) developed in a consistent manner, although with unpredictable severity within multiple soft tissues (such as the brain, liver, heart and brain). Overall, iEC-Kras (G12D*) pups developed significantly larger vascular lumen areas compared with control littermates, beginning at PN8. We subsequently tested whether the MEK inhibitor trametinib could effectively alleviate lesion progression. At PN16, iEC-Kras (G12D*) pup survival improved to 76.9%, and average vessel sizes were closer to controls than in untreated and vehicle-treated mutants. In addition, trametinib treatment helped normalize iEC-Kras (G12D*) vessel morphology in PN14 brains. Thus, trametinib could act as an effective therapy for KRAS-induced vascular malformations in patients.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Ratones , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pancreáticas/genética , Células Endoteliales/patología , Modelos Animales de Enfermedad , MutaciónRESUMEN
BACKGROUND: Hydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis. METHODS AND RESULTS: Whole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted. CONCLUSION: Pathogenic heterozygous ANGPT2 missense variants were recently shown to cause autosomal dominant primary lymphoedema. ANGPT2 is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive ANGPT2-related disorder in humans.
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Angiopoyetina 2 , Hidropesía Fetal , Animales , Femenino , Humanos , Ratones , Embarazo , Angiopoyetina 2/genética , Codón sin Sentido/genética , Heterocigoto , Hidropesía Fetal/genética , Hidropesía Fetal/metabolismo , Mutación Missense , Recién NacidoRESUMEN
Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.
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Anomalías Linfáticas , Escleroterapia , Humanos , Escleroterapia/efectos adversos , Escleroterapia/métodos , Resultado del Tratamiento , Anomalías Linfáticas/diagnóstico , Anomalías Linfáticas/terapia , Anomalías Linfáticas/etiología , Cuello , Cabeza , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS. METHODS: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. RESULTS: We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. CONCLUSIONS: We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.
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Subunidades alfa de la Proteína de Unión al GTP , Síndrome de Sturge-Weber , Anticonvulsivantes , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Subunidades alfa de la Proteína de Unión al GTP/genética , Humanos , Imagen por Resonancia Magnética , Estudios Retrospectivos , Síndrome de Sturge-Weber/complicaciones , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologíaRESUMEN
Vascular anomalies are a heterogenous group of vascular lesions that can be divided, according to the International Society for the Study of Vascular Anomalies Classification, into two main groups: vascular tumors and vascular malformations. Vascular malformations can be further subdivided into slow-flow and fast-flow malformations. This clinical and radiological classification allows for a better understanding of vascular anomalies and aims to offer a more precise final diagnosis. Correct diagnosis is essential to propose the best treatment, which traditionally consists of surgery, embolization, or sclerotherapy. Since a few years, medical treatment has become an important part of multidisciplinary treatment. Genetic and molecular knowledge of vascular anomalies are increasing rapidly and opens the door for a molecular classification of vascular anomalies according to the underlying pathways involved. The main pathways seem to be PI3K/AKT/mTOR and RAS/RAF/MEK/ERK. Knowing the underlying molecular cascades allows us to use targeted medical therapies. The first part of this article aims to review the vascular anomalies seen in the head and neck region and their underlying molecular causes and involved pathways. The second part will propose an overview of the available targeted therapies based on the affected molecular cascade. This article summarizes theragnostic treatments available in vascular anomalies.
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Fosfatidilinositol 3-Quinasas , Malformaciones Vasculares , Humanos , Malformaciones Vasculares/terapia , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/patología , Cuello/patología , Escleroterapia , RadiografíaRESUMEN
The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.
Asunto(s)
Hemangioma , Neoplasias Cutáneas , Enfermedades Vasculares , Europa (Continente) , Hemangioma/complicaciones , Hemangioma/diagnóstico , Hemangioma/terapia , Humanos , Lactante , Neoplasias Cutáneas/complicaciones , Síndrome , Enfermedades Vasculares/complicacionesRESUMEN
Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in MDFIC, encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous Mdfic mutant mice was profoundly mispatterned and exhibited major defects in lymphatic vessel valve development. Mechanistically, we determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin ß1 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies MDFIC variants underlying human lymphatic disease and reveals a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature. Ultimately, understanding the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex disease.