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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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Anormalidades Linfáticas , Piridonas , Pirimidinonas , Sirolimo , Humanos , Anormalidades Linfáticas/tratamento farmacológico , Anormalidades Linfáticas/patologia , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Sirolimo/uso terapêuticoRESUMO
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-Oncogênicas c-akt , Telangiectasia , Malformações Vasculares , Feminino , Humanos , Recém-Nascido , Masculino , Capilares/anormalidades , Capilares/patologia , Epilepsia/genética , Epilepsia/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Mosaicismo , Mutação/genética , Fenótipo , Proteínas Proto-Oncogênicas c-akt/genética , Telangiectasia/genética , Telangiectasia/patologia , Telangiectasia/diagnóstico , Malformações Vasculares/genética , Malformações Vasculares/patologia , Malformações Vasculares/diagnóstico , Malformações Vasculares/complicações , AdolescenteRESUMO
Introduction: Esophageal replacement surgery in children is sometimes necessary for long-gap esophageal atresia. Ileocolic esophagoplasty in the retrosternal space can serve as a good alternative technique in case of hostile posterior mediastinum. We present two cases of successful ileocolic transposition performed at 6 months of age. Methods: Esophageal replacement was performed through a midline laparotomy incision associated with a left cervical approach. The ileocolic transplant was pediculized on the right superior colic artery after ligating the right colic and ileocolic vessels. A retrosternal tunnel was created, and the ileocolic transplant pulled through it to reach the cervical region. Proximally, esophageal-ileal anastomosis and, distally, colonic-gastric anastomosis were performed. Ileocolic continuity was repaired. Results: There were no early postoperative complications. In both cases, the patients presented oral feeding difficulties during the first 6 postoperative months. Thereafter, full oral feeding was achieved, and both patients were clinically asymptomatic during the following 18 and 20 years, respectively, with satisfactory oral radiological assessments, showing no redundancy or inappropriate growth of the graft and no anastomotic stricture. Currently, these patients do not complain of dysphagia, pathological reflux, or respiratory symptoms. Conclusion: When native esophagus preservation in long-gap esophageal atresia is estimated unfeasible, ileocolic transposition in the retrosternal space might be considered a good and safe option, particularly in those difficult cases after multiple previous surgical attempts and mediastinitis. This technique is putatively associated with a beneficial anti-reflux effect, thanks to the presence of the ileocecal valve, in preventing cervical peptic esophagitis. Long-term follow-up confirms that the transposed colon in the retrosternal space did not suffer any abnormal modification in size and growth.
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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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Sirolimo , Malformações Vasculares , Adulto , Criança , Humanos , Europa (Continente) , Fosfatidilinositol 3-Quinases , Estudos Prospectivos , Sirolimo/efeitos adversos , Malformações Vasculares/tratamento farmacológico , Malformações Vasculares/genéticaRESUMO
Poretti-Boltshauser syndrome (PTBHS) is an autosomal recessive disorder characterized by cerebellar dysplasia with cysts and an abnormal shape of the fourth ventricle on neuroimaging, due to pathogenic variants in the LAMA1 gene. The clinical spectrum mainly consists of neurological and ophthalmological manifestations, including non-progressive cerebellar ataxia, oculomotor apraxia, language impairment, intellectual disability, high myopia, abnormal eye movements and retinal dystrophy. We report a patient presenting with ventriculomegaly on antenatal neuroimaging and a neonatal diagnosis of Type III esophageal atresia. She subsequently developed severe myopia and strabismus with retinal dystrophy, mild developmental delay, and cerebellar dysplasia. Genetic investigations confirmed PTBHS. This report confirms previous reports of antenatal ventriculomegaly in PTBHS patients and documents a so far unreported occurrence of esophageal atresia in PTBHS. We additionally gathered phenotype and genotype descriptions of published cases in an effort to better define the spectrum of PTBHS.
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Anormalidades Múltiplas , Apraxias , Ataxia Cerebelar , Atresia Esofágica , Hidrocefalia , Deficiência Intelectual , Miopia , Distrofias Retinianas , Gravidez , Humanos , Feminino , Ataxia Cerebelar/genética , Deficiência Intelectual/genética , Atresia Esofágica/diagnóstico por imagem , Atresia Esofágica/genética , Anormalidades Múltiplas/genética , Fenótipo , Distrofias Retinianas/genética , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/genética , Apraxias/genética , Miopia/genéticaAssuntos
Hemangioma , Doenças do Recém-Nascido , Neoplasias Hepáticas , Doenças Placentárias , Edema , Feminino , Hemangioma/complicações , Hemangioma/diagnóstico por imagem , Humanos , Hidropisia Fetal/diagnóstico por imagem , Hidropisia Fetal/etiologia , Recém-Nascido , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Placenta/diagnóstico por imagem , Doenças Placentárias/diagnóstico por imagem , GravidezRESUMO
Involution of a rapidly involuting congenital hemangioma is an unknown cause of neonatal ascites. As involution phase is completed by 14 months after birth, conservative management with diuretics and drainage is possible and may avoid surgical resection.
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The occurrence of a pathological fracture in children requires a rigorous diagnostic approach in order to establish the etiology and to develop a precise therapeutic strategy. Several causes are associated with these fractures, the most frequent being benign tumors in children in developed countries and chronic osteomyelitis in developing countries. More rarely, malignant tumors must however always be considered. The differential diagnosis on imaging may be difficult to establish between bone tumors and chronic infection. Surgical biopsy is therefore often performed to establish the precise origin of the fracture. We report the case of an adamantinoma (osteofibrous dysplasia-like) of the fibula in a 7-year-old child, discovered during the management of a pathologic fracture. The presumed diagnosis before biopsy was chronic osteomyelitis. A 14-cm-resection of the affected fibula was performed with good functional result. Differential diagnosis between adamantinoma, osteofibrous dysplasia and osteofibrous dysplasia-like adamantinoma remains very challenging.
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Ultrasound (US) is widely used in pediatric musculoskeletal pathology at all ages. Although the focus is often on soft tissues, joints and cartilage, the examiner might be confronted with changes in the underlying bone surface that are important to understand and integrate in the diagnosis. This article illustrates the normal US aspects of the cortical bone surface and periosteum, as well as the most common US anomalies seen in infections, trauma and bone tumors in children.
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Sistema Musculoesquelético , Periósteo , Criança , Osso Cortical/diagnóstico por imagem , Humanos , Periósteo/diagnóstico por imagem , UltrassonografiaRESUMO
Current imaging guidelines in Belgium advise a systematic X-ray screening of the hips after an episode of transient synovitis of the hip, in order to detect Perthes disease. The aim of this study was to analyze whether systematic radiological screening is necessary for all children or whether the X-ray indication could be guided by clinical symptoms. A retrospective single center study including all children with the diagnosis of transient synovitis of the hip between 2013 and 2018 was performed. 242 patients with the diagnosis of one or more transient synovitis episodes were included, 102 of whom underwent a follow up X-ray. Persistence or recurrence of symptoms were recorded for all patients, as well as the results of follow-up hip X-rays. 12 children did not remain symptom-free after the episode of transient synovitis. Of these patients 10 had a normal follow-up X-ray and 3 were diagnosed with Perthes disease. 1 patient of those 3 had a normal X-ray but was diagnosed with Perthes disease on MRI. Of the children which remained symptom-free after the episode of transient synovitis, none were diagnosed with Perthes disease afterwards. A follow-up X-ray to exclude Perthes disease after a diagnosis of transient hip synovitis appears to be necessary only in patients with persistent or recurrent symptomatology.
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Doença de Legg-Calve-Perthes , Sinovite , Criança , Articulação do Quadril/diagnóstico por imagem , Humanos , Doença de Legg-Calve-Perthes/diagnóstico por imagem , Radiografia , Estudos Retrospectivos , Sinovite/diagnóstico por imagemRESUMO
Air trapped in neonates' pulmonary ligament is often the consequence of positive pressure ventilation and its typical radiographic appearance must be recognized in order to prevent the use of aggravating factors. TEACHING POINT: Air trapped in neonates' pulmonary ligament is often the consequence of positive pressure ventilation; its typical waterdrop appearance must be recognized on radiographs to prevent unnecessary additional measures.
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Teaching Point: Ultrasound is the first-line examination for neck mass and may offer a reliable method to identify cervical ribs.
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Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/diagnóstico por imagem , Progressão da Doença , Paresia/diagnóstico por imagem , Paresia/etiologia , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Pré-Escolar , Humanos , Masculino , Paresia/genéticaRESUMO
Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the GPSM2 (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachnoid cysts, frontal subcortical heterotopia, and midline polymicrogyria. When hearing loss is managed early, most patients have minor or no impairment of motor and cognitive development, despite the presence of brain malformations. We report 2 cases of Chudley-McCullough syndrome, one presenting with congenital deafness and normal development except for speech delay and one presenting prenatally with ventriculomegaly and an atypical postnatal course characterized by epileptic spasms, deafness, and moderate intellectual disability. These highlight the challenges faced by clinicians when predicting prognosis based on pre- or postnatal imaging of brain malformations. We have also reviewed the phenotype and genotype of previous published cases to better understand Chudley-McCullough syndrome.
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Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/patologia , Cistos Aracnóideos/diagnóstico , Cistos Aracnóideos/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Adolescente , Agenesia do Corpo Caloso/genética , Cistos Aracnóideos/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Surdez/genética , Surdez/patologia , Diagnóstico Diferencial , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
Teaching Point: Typical imaging features of a vein of Galen aneurysmal malformation are enlarged intracranial arterial feeders to a dilated recipient vein.
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Orbital cellulitis is an infrequent but serious complication of sinus infections in children, as was the case of a 7-year-old who presented to the emergency room with ultrasound signs of preseptal cellulitis. Despite a well conducted antibiotic treatment a control ultrasound demonstrated associated signs of retro-septal extension. This case brings to light the essential role of ultrasound in suspected cellulitis, as a mean to differentiate between preseptal cellulitis and retroseptal (orbital) cellulitis. In the paediatric population ultrasound should be the first intention exam to diagnose the extension of the illness, and help guide the management and follow-up of the patients.
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Celulite Orbitária/diagnóstico por imagem , Ultrassonografia/métodos , Criança , Humanos , Órbita/diagnóstico por imagemRESUMO
We report a case of intra-articular osteoid osteoma (IAOO) of the elbow, in order to point out the clinical and imaging features which made the case challenging and caused a diagnostic delay.