Normal pediatric values of carotid artery intima-media thickness measured by B-mode ultrasound and radiofrequency echo tracking respecting the consensus: a systematic review.

BACKGROUND: Carotid artery intima-media thickness (IMT) is a sub-clinical radiologic marker of atherosclerosis in children. It is associated with adult-onset vascular disease. OBJECTIVE: To determine normal pediatric values of IMT from results observed in the literature. METHODS: Our systematic review was conducted according to PRISMA guidelines. We reviewed 2298 English articles from inception to February 2023. Inclusion criteria included studies evaluating B-mode and radiofrequency (RF)-based IMT measurements based on the American Heart Association, the Association for European Pediatric Cardiology, the Mannheim Consensus, and the American Society of Echocardiography recommendations. A meta-analysis of aggregate data was conducted to obtain the confidence interval (CI) for IMT, using a 95% confidence level. RESULTS: We obtained 88 B-mode-based IMT measurement studies with 6184 children and six radiofrequency echo-tracking-based studies with 766 children. Mean IMT in the pediatric population was 0.43 mm, 95% [CI] 0,42 to 0.44, using the B-mode technique, and 0.41 mm, 95% [CI] 0.36 to 0.45 using the radiofrequency technique. No significant relationship was detected between IMT and age (p value = 0.83). Finally, no significant effect of sex on IMT was found (p value = 0.82 for B-mode and p value = 0.62 for RF). CONCLUSION: Based on the studies selected in this literature review, we were unable to conclude that there was a significant difference between the average IMT of boys and girls. No relationship was demonstrated between age and IMT. IMT is technique-specific, and normal values should be interpreted according to recommendations of recognized consensus to counteract the current heterogeneity in literature. CLINICAL RELEVANCE STATEMENT: Technique and children-specific Intima media thickness measurements help clinicians and scientists to assess the risk of atherosclerosis in children. KEY POINTS: • Intima-media thickness (IMT) does not correlate with age in children without risk factors. • According to current literature, there is no difference in IMT between healthy boys and girls. • There is heterogeneity, even with studies abiding by the official consensus.

Behavioral-play familiarization for non-sedated magnetic resonance imaging in young children with mild traumatic brain injury.

BACKGROUND: Mild traumatic brain injury (mTBI) sustained in early childhood affects the brain at a peak developmental period and may disrupt sensitive stages of skill acquisition, thereby compromising child functioning. However, due to the challenges of collecting non-sedated neuroimaging data in young children, the consequences of mTBI on young children's brains have not been systematically studied. In typically developing preschool children (of age 3-5years), a brief behavioral-play familiarization provides an effective alternative to sedation for acquiring awake magnetic resonance imaging (MRI) in a time- and resource-efficient manner. To date, no study has applied such an approach for acquiring non-sedated MRI in preschool children with mTBI who may present with additional MRI acquisition challenges such as agitation or anxiety. OBJECTIVE: The present study aimed to compare the effectiveness of a brief behavioral-play familiarization for acquiring non-sedated MRI for research purposes between young children with and without mTBI, and to identify factors associated with successful MRI acquisition. MATERIALS AND METHODS: Preschool children with mTBI (n=13) and typically developing children (n=24) underwent a 15-minutes behavioral-play MRI familiarization followed by a 35-minutes non-sedated MRI protocol. Success rate was compared between groups, MRI quality was assessed quantitatively, and factors predicting success were documented. RESULTS: Among the 37 participants, 15 typically developing children (63%) and 10 mTBI (77%) reached the MRI acquisition success criteria (i.e., completing the two first sequences). The success rate was not significantly different between groups (p=.48; 95% CI [-0.36 14.08]; Cramer's V=.15). The images acquired were of high-quality in 100% (for both groups) of the structural images, and 60% (for both groups) of the diffusion images. Factors associated with success included older child age (Β=0.73, p=.007, exp(B)=3.11, 95% CI [1.36 7.08]) and fewer parental concerns (Β=-1.56, p=.02, exp(Β)=0.21, 95% CI [0.05 0.82]) about the MRI procedure. CONCLUSION: Using brief behavioral-play familiarization allows acquisition of high-quality non-sedated MRI in young children with mTBI with success rates comparable to those of non-injured peers.

Infected popliteal pseudoaneurysm in a youth basketball player: A case report and brief review of the literature.

INTRODUCTION: An infected popliteal pseudoaneurysm has never been described in the pediatric population. Physicians need to be aware of its presentation and management, in order to diagnose and treat this medical condition adequately. METHODS: We describe the case of a 14-year-old boy who developed myositis and cellulitis centered at the popliteal fossa after playing basketball. A treatment of intravenous cefazolin was started. 5 days later, he experienced a knee pain flare-up, which turned out to be a popliteal pyomyositis with a pseudoaneurysm of the popliteal artery. A saphenous vein graft bypass of the popliteal artery and an excision of the popliteal pseudoaneurysm were performed. Intravenous cefazolin was continued for 6 weeks and prophylactic acetylsalicylic acid for 6 months. RESULTS AND CONCLUSION: This case highlighted the importance of repeating radiologic investigations if a patient suffering from soft tissue infection has persistent pain after several days of appropriate antibiotics. A popliteal pseudoaneurysm can be diagnosed with ultrasound imaging and treated with a popliteal-popliteal bypass. Our patient needed a catheter-guided dilation of the anastomosis at the vein graft 6 months post-surgery, and then evolved favorably and went back to playing basketball 6 months post-dilation.

Non-Invasive Vascular Elastography as a One-Step Imaging Technique to Evaluate Early Vascular Changes in Children Compared to B-Mode-Based Intima-Media Thickness Technique : A Validation Study Using Inter- and Intra-Rater Reliability.

Background: Childhood obesity is linked to higher adult mortality and morbidity from atherosclerosis. It is primordial to detect at-risk children earlier-on to prevent disease progression. Carotid intima-media thickness (IMT) is a subclinical radiological marker for early atherosclerosis. B-mode ultrasound is a known technique to assess IMT, but no gold standard technique exists in children. Non-invasive vascular elastography (NIVE) using speckle statistics is an innovative alternative to evaluate IMT and adds by providing translation, strain and shear strain measurements. Validation studies for both techniques lack in children. Purpose: Validate the reproducibility of the 2 techniques in Canadian children. Methods: We conducted a prospective study where anthropometry, blood pressure, IMT and elastography were measured. Six operators obtained 2 measurements for both carotid arteries using both techniques, for a total of 720 measurements. Inter- and intra-class correlation coefficients (ICC) were calculated for each measurement technique and elastography parameters. Results: 30 participants (13.0 ± 1.26 years, 17 girls) were recruited. Twelve were overweight. No significant difference was found in mean IMT between weight groups for either technique (P = .15 and P = .60). We found excellent inter- (ICC = .98 [95% Confidence Interval (CI): .97; .99]) and intra- (ICC = .90-.93) operator reliability for the B-mode technique, and good inter (ICC = .70 [95% CI: .47; .85]) and intra- (ICC = .71-.91) operator reliability for the NIVE-based technique. Poor reliability was found between techniques (ICC = .30 [95% CI: -.31; .65). For elastography parameters, translation was the most reliable (ICC = .94-.95). Conclusion: IMT measurement is reproducible in children but not between techniques. NIVE gives the advantage of evaluating elastography.

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data.

Extensive venous malformations involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. But patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Available pharmacological treatments (e.g., sirolimus) are not universally effective. Novel therapies are urgently needed for patients with treatment-resistant venous malformations. We report three patients with TIE-2 receptor mutations treated with alpelisib for 6 months (daily dosing: 50 mg for children weighing <50 kg and 100 mg for those >50 kg). Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy dramatically improved. Drug exposure was highly variable, suggesting that alpelisib dosing should be individualized to patient's characteristics and guided by therapeutic drug monitoring.

Defining vascular anomaly phenotypes in children based on a systematic literature search: A critical step in developing a single severity score for interventional clinical trials.

INTRODUCTION: Genetically targeted drugs in vascular anomalies (VA) are used despite the absence of a validated severity score. The aim of this study was to evaluate the feasibility of grouping phenotypic VA clinical characteristics into a single severity score. METHODS: A systematic literature review including children treated with sirolimus accompanied by a detailed description of phenotype and management was conducted. Demographic data and clinical features were extracted to define distinct categories of phenotypes. RESULTS: Children with VA display two main phenotypes regardless of VA subtype, which may overlap. A systemic phenotype results from direct invasion and compression of vital structures generally leading to hospitalization and aggressive management in infancy. A functional phenotype is associated with chronic pain and disability manifesting mainly during early adolescence and managed in the outpatient setting. CONCLUSION: The two distinct phenotypes described could be the basis for developing a unified scoring system for VA severity assessment.

Current applications for measuring pediatric intima-media thickness.

Intima-media thickness is a known subclinical radiologic marker of the early manifestations of atherosclerotic disease. It is the thickness of the vessel wall, most often the carotid artery. Intima-media thickness is measured on conventional US manually or automatically. Other measurement techniques include radiofrequency US. Because there is variation in its measurement, especially in children, several recommendations have been set to increase the measurement's validity and comparability among studies. Despite these recommendations, several pitfalls should be avoided, and quality control should be performed to avoid erroneous interpretation. This article summarizes current literature in relation to the clinical applications for intima-media thickness measurement in children with known risk factors such as obesity, liver steatosis, hypercholesterolemia, diabetes, hypertension, systemic inflammatory diseases, cancer survival, kidney and liver transplant, and sickle cell disease or beta thalassemia major. Most potential indications for intima-media thickness measurement remain in the research domain and should be interpreted combined with other markers. The objective of diagnosing an increased intima-media thickness is to start a multidisciplinary treatment approach to prevent disease progression and its sequelae in adulthood.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

BACKGROUND: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life. METHODS: Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected. RESULTS: Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P = .007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P = .001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema. CONCLUSIONS: Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed.

Systemic, local, and sclerotherapy drugs: What do we know about drug prescribing in vascular anomalies?

Off-label drug prescribing, frequent in the treatment of vascular anomalies (VA), relies on the quality of the literature reporting drug efficacy and safety. Our objective is to review the level of evidence (LOE) surrounding drug use in VA, which is more prevalent in pediatric care. A list of drugs used in VA was created with a literature review in July 2020. For each drug listed, the article displaying the highest LOE was determined and then compared between efficacy/safety data, routes of administration, pharmacological categories and a subset of VA. The influence of research quality on study results was also explored. The median LOE for the 74 drugs identified poor methodological quality, with a predominance of retrospective studies or case reports. Drug safety is currently inadequately reported. This is alarming as many treatments display significant safety concerns. Also, current literature displays major publication bias that probably leads to overestimation of drug efficacy in VA.

PHACES Syndrome and Associated Anomalies: Risk Associated With Small and Large Facial Hemangiomas.

OBJECTIVE. PHACES syndrome includes posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal defect with or without supraumbilical raphe. Usually, brain imaging is performed when facial hemangiomas are larger than 5 cm. Data on associated anomalies regardless of hemangioma size are sparse. The objective of this study was to determine, first, the prevalence of PHACES-like associated anomalies in a large sample of infants with all sizes of segmental facial or periorbital focal infantile hemangioma and, second, whether the cutaneous localization of the hemangioma correlates with the type of anomalies present. MATERIALS AND METHODS. The records of all patients of a vascular anomalies practice who had a diagnosis of segmental facial or periorbital focal infantile hemangioma and who had clinical photographs and brain MRI available were reviewed. The clinical photographs were reviewed to determine the localization by segment and lateralization. MRI was reviewed by two experienced pediatric radiologists. If present, cardiovascular anomalies, sternal defects, and eye anomalies were recorded. The criteria for definite and possible PHACES were used. RESULTS. The study included 122 children (90 girls, 32 boys; mean age, 16.6 months). Forty-five (36.9%) children had a facial infantile hemangioma larger than 5 cm. Twenty-two patients (18.0%) had PHACES or possible PHACES syndrome. Cerebrovascular structural anomalies were seen in 14 of 22 and brain anomalies in 6 of 22 patients with PHACES syndrome but in none and one of the patients in the group without PHACES (p < .001). Cardiovascular anomalies were seen in six patients and ocular anomalies in eight patients. All but one of them had PHACES syndrome. CONCLUSION. Clinical concern about associated extracutaneous anomalies is warranted for all children with facial segmental or periorbital focal infantile hemangiomas, including those with small hemangiomas. Further studies are needed to correlate cerebrovascular anomalies with the clinical evolution of hemangiomas and their effects on cerebral perfusion.

Off-Label Use and Safety of Drug Use in Vascular Anomalies.

BACKGROUND: Off-label drug use is associated with an increased risk of adverse drug reactions. It is common in pediatrics and in rare diseases, which are two characteristics applying to vascular anomalies (VA). OBJECTIVES: The aim of this work was to quantify off-label drug use in VA and assess its safety. METHODS: A review was conducted to extract a list of drugs used in VA management. A drug was considered to have significant safety concerns if a black box warning was present or if a serious adverse drug reaction (SADR) was reported in at least 1% of the patients (SADR is defined as a noxious and unintended response to a drug that occurs at any dose and results in hospitalization, prolongation of existing hospitalization, congenital malformation, persistent or significant disability or incapacity, life-threatening condition, or death). The labelling status and safety of each drug was assessed based on the product monograph, Micromedex, and the FDA data. RESULTS: We found that 98.9% of the inventoried drugs were used off-label or unlicensed for VA management. Only the oral solution of propranolol hydrochloride (Hemangeol®) for the treatment of infantile hemangiomas is approved. Significant safety issues concerned 73% of the drugs and were more frequent among systemic than locally delivered drugs. CONCLUSIONS: Off-label drug use in VA is the rule and not the exception. Significant safety concerns are common. It is necessary to carefully weigh risk and benefits for every patient when using systemic and local treatments carrying safety concerns. Patients should be openly informed and involved in the decision-making process.

Intra-abdominal lymphatic malformation management in light of the updated International Society for the Study of Vascular Anomalies classification.

BACKGROUND: The International Society for the Study of Vascular Anomalies (ISSVA) classification distinguishes between common lymphatic malformations and complex lymphatic anomalies. These entities have overlapping features but differing responses to treatment. Surgery has been the mainstream treatment in intra-abdominal lymphatic malformation, with variable reported success in the literature. OBJECTIVE: The aim of this study was to review the outcome of different treatments for intra-abdominal lymphatic malformations in children. MATERIALS AND METHODS: We retrospectively reviewed all intra-abdominal lymphatic malformations from 1999 to 2019 in children treated by the surgical team or followed in the vascular anomalies clinic of our institution. Children were classified into one of three groups: group A, isolated intra-abdominal lymphatic malformation; group B, common lymphatic malformation in continuity with other regions; or group C, intra-abdominal involvement as part of a complex lymphatic anomaly or associated syndrome. RESULTS: Fifty intra-abdominal lymphatic malformations were diagnosed; five of these were excluded. In group A (n=28), the treatment was surgical resection (n=26) or sclerosing treatment (n=1), with one case of spontaneous regression; no recurrence was observed in 25 patients. In group B (n=7), three patients had partial resection and all had recurrence; four had sclerotherapy alone with good response. In group C (n=10), therapeutic options included surgery, sclerosing treatment and pharmacotherapy, with variable outcomes. CONCLUSION: The management of intra-abdominal malformations requires a team approach. Sclerotherapy is successful in treating macrocystic lymphatic malformation. Surgery is successful in treating isolated intra-abdominal common lymphatic malformation, albeit at times at the cost of intestinal resection, which could be avoided by combining surgery with preoperative sclerotherapy. With surgery there is often limited resectability, and therefore recurrence in intra-abdominal lymphatic malformations that are part of complex lymphatic anomalies associated with syndromes, or in common lymphatic malformations in continuity with other regions. Sclerotherapy is an effective modality in these instances along with pharmacotherapy.

Kaposiform hemangioendothelioma with overlapping features of rapidly involuting congenital hemangioma and a delayed complication of necrotizing fasciitis.

We report the case of a male infant born at term with kaposiform hemangioendothelioma (KHE) of the right forearm and coagulopathy. Our case was unusual as it involuted leaving subcutaneous atrophy and prominent veins, which are more commonly observed in rapidly involuting congenital hemangioma. At 3 years of age, the child developed recurrent superficial thrombophlebitis localized to the area where the KHE had regressed. Subsequently, he developed necrotizing fasciitis and thrombotic veins in the same location and group A streptococcal septic shock.

The value of non-invasive vascular elastography (NIVE) in detecting early vascular changes in overweight and obese children.

OBJECTIVES: Evaluate non-invasive vascular elastography (NIVE) in detecting vascular changes associated with obese children. METHODS: Case-control study to evaluate NIVE in 120 children, 60 with elevated body mass index (BMI) (≥ 85th percentile for age and sex). Participants were randomly selected from a longitudinal cohort, evaluating consequences of obesity in healthy children with one obese parent. Radiofrequency ultrasound videos of the common carotid artery were obtained. The carotid wall was segmented and NIVE applied to measure cumulated axial strain (CAS), cumulated axial translation (CAT), cumulated lateral translation (CLT), maximal shear strain (Max |SSE|), and intima-media thickness (IMT). Multivariate analyses were used controlling for age, sex, Tanner stage, blood pressure, and low-density lipoprotein. Statistical significance was set to 0.05-0.008. Participants were 10-13 years old (mean 11.4 and 12.0, for normal and elevated BMI groups, p < 0.001), 58% and 63% boys, respectively. Groups differed in age, Tanner stage, and blood pressure. In the normal BMI group, there was weak correlation between systolic blood pressure and Max |SSE| (r = 0.316, p = 0.01) and weak correlation between pulse pressure and Max |SSE| (r = 0.259, p = 0.045). After Bonferroni correction, CAT was significantly higher in the elevated BMI group (0.68 ± 0.24 mm vs. 0.52 ± 0.18 mm), p < 0.001. CAS/CAT was significantly lower in the elevated BMI group (9.54 ± 4.8 vs. 13.34 ± 6.46), p = 0.001. IMT was significantly higher in the elevated BMI group (0.36 ± 0.05 mm vs. 0.32 ± 0.05 mm) before Bonferroni correction, p = 0.013. CONCLUSIONS: NIVE detected differences in CAT and CAS/CAT in elevated BMI children. NIVE is a promising technique to monitor radiological markers of subclinical atherosclerosis. KEY POINTS: • NIVE is a non-invasive technique based on measurement of subsegmental focal deformation of vascular wall to detect subclinical changes in arterial wall compliance. • Children with elevated BMI showed increased carotid artery wall movement during systole, as compared to normal BMI children (mean 0.68 ± 0.24 mm vs. 0.52 ± 0.18 mm; p < 0.001) and a lower ratio of vascular wall strain to wall movement during systole (mean 9.54 ± 4.8 vs. 13.34 ± 6.46; p = 0.001). • The detection of these subclinical changes helps physicians in the stratification of children at risk of atherosclerosis and guides in the implementation of preventive measures.

Multifocal congenital hemangioma: Expanding the pathogenesis of "neonatal hemangiomatosis".

Congenital hemangiomas are benign vascular tumors, categorized by their postnatal behavior as rapidly involuting, non-involuting, or partially involuting. They are typically solitary, with a predilection for the head or limbs near a joint. We present two infants with small, multifocal congenital nonprogressive hemangiomas of the skin, one associated with hepatic and intracranial lesions, and another with an in utero intracranial hemorrhage and hydrocephalus. These cases further extend the differential diagnosis of congenital multifocal vascular lesions or "hemangiomatosis."

Non-involuting congenital hemangiomas (NICH) with postnatal atypical growth: A case series.

BACKGROUND: Non-involuting congenital hemangiomas (NICH) are fully formed vascular tumors at birth, with a distinctive clinical, radiologic, and histopathological profile, and classically lack expansion or involution over time. We describe a series of NICH cases with atypical postnatal growth. METHODS: The authors retrospectively analyzed all NICH cases diagnosed from 2007 to 2017. We reviewed charts and photographic databases from our Vascular Anomalies Clinic. We included in the study all NICH with an atypical postnatal growth. Clinical data, imaging, and histopathology were analyzed. RESULTS: Eighty cases of NICH were identified. Nine presented with atypical postnatal growth after a stable period, at ages from 2 to 10 years (mean: 5.3 years). Two patients had associated pain; 5 patients showed new red papules on the surface of the lesion; 2 reported bleeding from the papules; and 1 developed a pyogenic granuloma. All patients had Doppler ultrasound and/or MRI compatible with NICH, and a confirmatory biopsy was performed in 4 cases. In treatment, 2 patients received endovascular embolization, and one required further surgery. CONCLUSIONS: Non-involuting congenital hemangiomas (NICH) may develop significant postnatal growth over time (10% in our series), requiring closer follow-up for longer periods. The development of red papules, pyogenic granulomas, and superficial bleeding may be observed. Since this is a small series, we were not able to establish risk factors for NICH with postnatal growth.

Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.