SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic-related fetal hydrops and facial dysmorphology.

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

Magnetic resonance imaging of fetal vascular malformations.

Vascular anomalies develop during fetal life and can be detected on prenatal ultrasonography and fetal magnetic resonance imaging. Diagnosis of lymphatic, venous, and arteriovenous malformations, as well as congenital hemangiomas and other congenital vascular tumors, may be challenging. The benign vascular anomalies may be difficult to differentiate from malignancies with a similar appearance. In this manuscript, we present a succinct overview of the congenital vascular anomalies that may present in fetal or neonatal life.

An interesting case of thigh cellulitis: The streptococcal sex syndrome.

Streptococcal sex syndrome is a rare and under-recognised association between recurrent pubic, genital or thigh cellulitis, sexual intercourse and pelvic surgery or radiation. Lymphatic dysfunction may play a role in the aetiology of the syndrome. We describe a case of streptococcal sex syndrome and describe suggested management strategies.

Texture analysis of low-flow vascular malformations in the oral and maxillofacial region: venous malformation vs. lymphatic malformation.

Purpose: It is challenging for radiologists to distinguish between venous malformations (VMs) and lymphatic malformations (LMs) using magnetic resonance imaging (MRI). Thus, this study aimed to differentiate VMs from LMs using non-contrast-enhanced MRI texture analysis. Material and methods: This retrospective case-control study included 12 LM patients (6 men and 6 women; mean age 43.58, range 7-85 years) and 29 VM patients (7 men and 22 women; mean age 53.10, range 19-76 years) who underwent MRI for suspected vascular malformations. LM and VM patients were identified by histopathological examination of tissues excised during surgery. The texture features of VM and LM were analysed using the open-access software MaZda version 3.3. Seventeen texture features were selected using the Fisher and probability of error and average correlation coefficient methods in MaZda from 279 original parameters calculated for VM and LM. Results: Among 17 selected texture features, the patients with LM and VM revealed significant differences in 1 histogram feature, 8 grey-level co-occurrence matrix (GLCM) features, and 1 grey-level run-length matrix feature. At the cut-off values of the histogram feature [skewness ≤ -0.131], and the GLCM features [S(0, 2) correlation ≥ 0.667, S(0, 3) correlation ≥ 0.451, S(0, 4) correlation ≥ 0.276, S(0, 5) correlation ≥ 0.389, S(1, 1) correlation ≥ 0.739, S(2, 2) correlation ≥ 0.446, S(2, -2) correlation ≥ 0.299, S(3, -3) correlation ≥ 0.091] had area under the curves of 0.724, 0.764, 0.773, 0.747, 0.733, 0.759, 0.730, 0.744 and 0.727, respectively. Conclusions: Non-contrast-enhanced MRI texture analysis allows us to differentiate between LMs and VMs.

Prenatal Detection of a Sublingual Lymphatic Malformation in a Fetus: A Rare Case.

BACKGROUND: Lymphatic malformations are benign cystic lesions that, while rare, tend to affect the pediatric age group. There are no reported cases diagnosed prenatally. CASE: A 28-year-old G1 woman at 34 weeks gestation was scanned for placental localization at a community ultrasound clinic. A fetal cystic, sublingual structure was identified. The patient was referred to our tertiary care centre, where a small (1.3 cm) avascular, cystic structure under the tongue of the fetus was confirmed. Antenatal course and delivery were unremarkable. The lesion resolved spontaneously with time. CONCLUSION: This report highlights a unique case in which a sublingual lymphatic malformation was detected prenatally during a third-trimester ultrasound.

Morbidity and healthcare costs of vascular anomalies: a national study.

PURPOSE: This study aimed to define morbidities and costs related to modern-day medical care for children with vascular anomalies. METHODS: We reviewed the 2003-2009 Kids' Inpatient Database for pediatric patients (age < 21 years) hospitalized with hemangioma, arteriovenous malformation (AVM), or lymphatic malformation (LM). Patient characteristics, hospital complications, and hospital charges were compared by vascular anomaly type. Multivariable linear regression modeling was used to determine predictors of increasing hospital costs for patients with AVMs. RESULTS: In total, 7485 pediatric inpatients with vascular anomalies were identified. Frequently associated complications included chronic anemia (4.0%), sepsis (4.6%), and hypertension (2.4%). Children with AVM had the highest rate of in-hospital mortality, compared to those with hemangiomas or LM (1.0% vs. 0.1% vs. 0.3%, p < 0.001). AVMs were also associated with the highest median hospital charge, more than twice the cost for hemangiomas or LM ($45,875 vs. $18,909 vs. $18,919; p < 0.001). CONCLUSIONS: There is a significant rate of morbidity in children with vascular anomalies, most often from blood loss and infection. The greater cost of AVM care may be related to the higher mortality rate, associated complications, and complexity of procedures required treating them. Cost-effective management of vascular anomalies should target prevention and the early recognition of both chronic comorbidities and acute complications.

Intranodal Palisaded Myofibroblastoma: Radiological and Cytological Overview.

BACKGROUND: Intranodal palisaded myofibroblastoma is a benign and very rare mesenchymal neoplasm of the lymph nodes originating from differentiated smooth muscle cells and myofibroblasts. CASE REPORT: We report a case of intranodal palisaded myofibroblastoma in an 84-year-old woman with Parkinson's disease that presented as a left inguinal mass. The diagnosis was made using ultrasound-guided fine needle aspiration biopsy and consequent cytopathological examination that included immunohistochemical analysis. Herein, we discuss the presentation of a rare intranodal palisaded myofibroblastoma with emphasis on its ultrasonographic and cytopathologic features. CONCLUSIONS: Intranodal palisaded myofibroblastoma should be considered in the differential diagnosis of inguinal lymphadenopathy and the diagnosis is possible with cytopathologic exam and immunohistochemical analysis using ultrasound-guided FNA biopsy, guiding the clinician to nodal excision rather than aggressive measures.

Lymphedema in tuberous sclerosis complex.

Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC), with only six previous cases reported in the literature. TSC is an autosomal dominant, multisystem disorder connected to aberrant regulation of the mammalian target of rapamycin (mTOR) pathway. The aim of this study is to review cases of lymphedema in a large cohort of TSC patients. The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from 2002 to 2012 were retrospectively reviewed for reports of lymphedema or edema of unknown etiology. Genotypic and phenotypic data were collected in accordance with institutional review board (IRB) approval. This cohort presents two new cases of congenital lymphedema in TSC patients and acquired lymphedema was found in eight additional cases. Thus, we report 10 new cases of lymphedema in TSC (4%). The two patients with congenital lymphedema were female, as were the previous six reported cases. The frequency of lymphedema reported here (4%) is higher than the estimated prevalence in the general population (0.133-0.144%), suggesting a higher frequency of lymphedema in TSC. This study shows that patients with TSC and lymphedema are more likely to be females with renal AMLs and suggests that congenital lymphedema is a gender-specific (female) manifestation of TSC. Exploration of the potential role of mTOR antagonists may be important in treatment of lymphedema in TSC patients.

A Review of the Current State and Future Directions for Management of Scalp and Facial Vascular Malformations.

Vascular malformations are structural abnormalities that are thought to result from errors in vasculogenesis and angiogenesis during embryogenesis. Vascular malformations of the scalp present unique management challenges due to aesthetic and functional implications. This review examines the pathophysiology, clinical presentation, and management techniques for six common types of vascular malformations of the face and scalp : infantile hemangioma, capillary malformations, venous malformations, lymphatic malformations, arteriovenous malformations, and arteriovenous fistulas. These lesions range from common to rare, and have very different natural histories and management paradigms. There has been increasing understanding of the molecular pathways that are altered in association with these vascular lesions and these molecular targets may represent novel strategies of treating lesions that have historically been approached from a structural perspective only.

Association between lymphatic abnormalities in the neck and thorax in primary chylopericardium and surgical outcomes evaluated by non-enhanced magnetic resonance (MR) lymphangiography.

Background: Chylopericardium refers to the accumulation of chylous fluid in the pericardial cavity. Non-enhanced magnetic resonance lymphangiography (MRL) can show neck and thoracic lymphatic abnormalities in the primary chylopericardium. It is not clear whether there is a relationship between neck and thoracic lymphatic abnormalities in primary chylopericardium and thoracic duct terminal release surgery. This study aimed to explore the correlation between the severity of neck and thoracic lymphatic abnormalities observed in non-enhanced MRL and the surgical outcomes in primary chylopericardium. Methods: This is a retrospective cohort study. A retrospective analysis was conducted on fifty-six patients diagnosed with primary chylopericardium between January 2016 and December 2021, all of whom underwent thoracic duct terminal release surgery. Ultrasonography, chest computed tomography (CT) and non-enhanced MRL were performed prior to the surgical intervention. Patients were categorized into four types based on the severity of neck and thoracic lymphatic abnormalities observed in the non-enhanced MRL. Clinical and laboratory examinations and surgical outcomes were compared across different types using χ 2-test or Fisher's exact test, t-test, and Kruskal-Wallis H-test. Additionally, independent factors influencing surgical outcomes were analyzed. Results: Among primary chylopericardium cases (n=56), 22 (39.2%) were classified as type I or II, 17 (30.4%) as type III, and 17 (30.4%) as type IV. Surgical outcomes were more favorable for type I or II patients than those with type III or IV, accompanied by a reduction in postoperative primary chylopericardium volume (P=0.002). Postoperative chest CT scans indicated that type I or II patients had fewer instances of large grid shadows, small grid shadows, and bronchovascular bundle thickening compared to preoperative scans (P=0.001, P=0.02, P=0.03). Age and bronchomediastinal trunk dilation emerged as independent factors influencing surgical outcomes [odds ratio (OR) 0.03, 95% confidence interval (CI): 0.003-0.220, P=0.001; OR 11.10, 95% CI: 1.70-72.39, P=0.01, respectively]. Conclusions: A more severe degree of neck and thoracic lymphatic abnormalities is associated with worse surgical outcomes. Moreover, age and bronchomediastinal trunk dilatation are independent predictors of surgical outcomes. Preoperative utilization of non-enhanced MRL for severity of lymphatic abnormalities classification in primary chylopericardium patients offers a noninvasive means of assessing surgical risk.

Oral Lymphatic Malformations: A 21-Year Retrospective Study in a Single Institution.

Introduction. Oral lymphatic malformations are uncommon lesions. This study assessed the clinicopathological and sociodemographic features of oral lymphatic malformations in a Brazilian oral pathology service. Methods. Between 2000 and 2021, all oral lymphatic malformations diagnosed in a single oral pathology service were selected for the study. Clinical data, such as age, sex, site of the lesion, clinical presentation, diagnosis clinical, and the type of biopsy were recorded from the patient's clinical charts. Results. From 7554 oral lesions, 17 (0.22%) were oral lymphatic malformations. This lesion similarly affected both sexes, and the mean age of the patients was 16.5 years. The tongue was the most common site (n = 13; 76%). The mean size of the lesions was 17 mm. Oral lymphatic malformations were asymptomatic for 29% of the patients. Clinically, most lesions appeared as a reddish, sessile nodule, with a pebbly surface. In addition, the clinical and histopathological diagnoses agreed for most lesions (n = 11; 64%). The type of biopsy performed was excisional in 41% of lesions. Conclusions. In summary, oral lymphatic malformations present a low prevalence among the oral lesions diagnosed in an oral pathology service. Moreover, they affect equally both sexes, especially young patients, and usually appear as an asymptomatic or symptomatic nodular swelling on the tongue.

Prenatal Ultrasound Diagnosis of Klippel-Trenaunay Syndrome.

Klippel-Trenaunay syndrome (KTS) is a very rare vascular malformation syndrome also referred to as a capillary-lymphatic-venous malformation with unknown aetiology. The aim of our paper is to highlight interesting images, regarding a rare case of foetal Klippel-Trenaunay syndrome diagnosed prenatally in our department and confirmed postnatally with a favourable evolution during the gestation and neonatal periods. This case was diagnosed at 26 weeks gestation and characterised through ultrasound by the presence of superficial multiple cystic structures of different sizes spreading over the left leg with hemihypertrophy and reduced mobility. The cystic lesions were spreading to the left buttock and the pelvic area. The right leg and upper limbs had normal appearance with good mobility. There were no signs of hyperdynamic circulation or foetal anaemia, but mild polyhydramnios was associated. The ultrasound findings were confirmed postnatally, the left leg presented multiple cystic lesions and port wine stains, and there was hypertrophy and fixed position, with favourable evolution at 6 months of life, when the size of the lesions began to decrease and the mobility of the leg improved.

Visualizing the lymphatic vessels and flow with high-resolution ultrasonography and microvascular flow imaging.

Imaging of the lymphatic system has always encountered difficulties, such as high costs, timeconsuming procedures, and low-resolution images. Each method of imaging provides its own challenges. The use of high-resolution ultrasonography (HR-US) and microvascular flow imaging (MVFI) may prove to be the most effective method for visualizing the superficial lymphatic vessels. This study investigated the utilization of HR-US and MVFI in imaging inguinal lymph nodes and vessels, as well as the innovative use of an intranodal saline injection that acted as a contrast agent. This technical note aims to demonstrate that HR-US and MVFI, in combination with an intranodal saline injection, are applicable to the dynamic imaging of superficial inguinal lymph nodes and vessels.

Intramuscular epidermal cyst in the masticator space: a case report.

An epidermal cyst, also known as an epidermoid cyst or epidermal inclusion cyst, is the most prevalent type of cutaneous cyst. This noncancerous lesion can appear anywhere on the body, typically presenting as an asymptomatic dermal nodule with a visible central punctum. In the case presented herein, an epidermal cyst with uncommon features was misdiagnosed as a lymphatic malformation based on preoperative magnetic resonance imaging (MRI). A 61-year-old man came to us with a swollen left cheek that had been present for 11 months. The preoperative MRI revealed a 3 × 3.8 × 4.6 cm lobulated cystic lesion with thin rim enhancement in the left masticator space. The initial differential diagnosis pointed toward a lymphatic malformation. We proceeded with surgical excision of the lesion via an intraoral approach, and the specimen was sent to the pathology department. The pathological diagnosis revealed a ruptured epidermal cyst, indicating that the initial diagnosis of a lymphatic malformation based on preoperative MRI was incorrect. Epidermal cysts located under the muscle with no visible central punctum are uncommon, but should be considered if a patient presents with facial swelling.

Case report: Noonan syndrome with protein-losing enteropathy.

Background: Noonan syndrome (NS) is characterized by typical facial features, short stature, congenital heart defects and other comorbidities. Lymphedema and chylous pleural effusions are also common in NS, but protein-losing enteropathy (PLE) is rarely reported. Case presentation: We present the case of a 19-year-old Chinese woman presenting with PLE. Small intestine biopsy showed obvious expansion of lymphatic vessels. The gene mutation results of the patient indicated a c.184T>G missense mutation (p.Tyr62Asp) in the PTPN11 gene (NM_002834.3). Conclusion: NS accompanied by PLE is not common, but hypoproteinemia attributable to PLE may be more common in patients with NS than previously thought. It remains uncertain whether mutation of the PTPN11 gene is related to PLE, indicating that further research is needed.

Delaying Invasive Treatment in Unilateral Head and Neck Lymphatic Malformation Improves Outcomes.

OBJECTIVES: Large (De Serres stage [IV-V]) head and neck lymphatic malformations (HNLMs) often have multiple, high-risk, invasive treatments (ITs) to address functional compromise. Logically reducing HNLM ITs should reduce treatment risk. We tested whether delaying HNLM ITs reduces total IT number. MATERIALS: Consecutive HNLM patients (n = 199) between 2010 and 2017, aged 0-18 years. METHODS: ITs (surgery or sclerotherapy) were offered for persistent or dysfunction causing HNLMs. Treatment effectiveness categorized by IT number: optimal (0-1), acceptable (2-5), or suboptimal (>5). Clinical data were summarized, and outcome associations tested (χ2 ). Relative risk (RR) with a Poisson working model tested whether HNLM observation or IT delay (>6 months post-diagnosis) predicts treatment success (i.e., ≤1 IT). RESULTS: Median age at HNLM diagnosis was 1.3 months (interquartile range [IQR] 0-45 m) with 107/199(54%) male. HNLM were stage I-III (174 [88%]), IV-V (25 [13%]). Initial treatment was observation (70 [35%]), invasive (129 [65%]). Treatment outcomes were optimal (137 [69%]), acceptable (36 [18%]), and suboptimal (26 [13%]). Suboptimal outcome associations: EXIT procedure, stage IV-V, oral location, and tracheotomy (p < 0.001). Stage I-III HNLMs were initially observed compared with stage I-III having ITs within 6 months of HNLM diagnosis, had a 82% lower relative treatment failure risk ([i.e., >1 IT], RR = 0.09, 95% CI 0.02-0.36, p < 0.001). Stage I-III HNLMs with non-delayed ITs had reduced treatment failure risk compared with IV-V (RR = 0.47, 95% CI 0.33-0.66, p < 0.001). CONCLUSION: Observation and delayed IT in stage I-III HNLM ("Grade 1") is safe and reduces IT (i.e., ≤1 IT). Stage IV-V HNLMs ("Grade 2") with early IT have a greater risk of multiple ITs. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:956-962, 2023.

Quantification of lymphatic burden in patients with Fontan circulation by T2 MR lymphangiography and associations with adverse Fontan status.

AIMS: To quantify thoracic lymphatic burden in paediatric Fontan patients using MRI and correlate with clinical status. METHODS AND RESULTS: Paediatric Fontan patients (<18-years-old) with clinical cardiac MRI that had routine lymphatic 3D T2 fast spin echo (FSE) imaging performed from May 2017 to October 2019 were included. 'Lymphatic burden' was quantified by thresholding-based segmentation of the 3D T2 FSE maximum intensity projection image and indexed to body surface area, performed by two independent readers blinded to patient status. There were 48 patients (27 males) with median age at MRI of 12.9 (9.4-14.7) years, time from Fontan surgery to MRI of 9.1 (5.9-10.4) years, and follow-up time post-Fontan surgery of 9.4 (6.6-11.0) years. Intraclass correlation coefficient between two observers for lymphatic burden was 0.96 (0.94-0.98). Greater lymphatic burden correlated with post-Fontan operation hospital length of stay and duration of chest tube drainage (rs = 0.416, P = 0.004 and rs = 0.439, P = 0.002). Median lymphatic burden was greater in patients with chylous effusions immediately post-Fontan (178 (118-393) vs. 113 (46-190) mL/m2, P = 0.028), and in patients with composite adverse Fontan status (n = 13) defined by heart failure (n = 3), transplant assessment (n = 2), recurrent effusions (n = 6), Fontan thrombus (n = 2), and/or PLE (n = 6) post-Fontan (435 (137-822) vs. 114 (51-178) mL/m2, P = 0.003). Lymphatic burden > 600 mL/m2 was associated with late adverse Fontan status with sensitivity of 57% and specificity of 95%. CONCLUSION: Quantification of MR lymphatic burden is a reliable tool to assess the lymphatics post-Fontan and is associated with clinical status.

Milky Ascites: A Diagnostic Dilemma.

Chylous ascites is a milky-appearing, triglyceride-rich fluid within the abdominal cavity. It is a rare finding that arises from the disruption of the lymphatic system and can be caused by a wide variety of pathologies. Here, we present a diagnostically challenging case of chylous ascites. In this article, we discuss the pathophysiology and various etiologies of chylous ascites, explore the diagnostic tools available, and highlight the management strategies implemented in this rare finding.

Lymphatic Abnormalities on Magnetic Resonance Imaging in Single-Ventricle Congenital Heart Defects Before Glenn Operation.

Background In the palliative pathway of single-ventricle physiology, lymphatic abnormalities on T2-weighted magnetic resonance imaging have been shown after the Glenn operation. It is believed that postsurgical hemodynamic changes contribute to the lymphatic changes.However, little is known about how early these abnormalities occur. Our purpose was to determine if lymphatic abnormalities occur as early as before the Glenn operation. Methods and Results We retrospectively reviewed patients with single-ventricle physiology and a T2-weighted magnetic resonance imaging scan before their Glenn operation (superior cavopulmonary connection) at The Children's Hospital of Philadelphia from 2012 to 2022. Lymphatic perfusion patterns on T2-magnetic resonance imaging were categorized from type 1 (no supraclavicular T2-signal) to type 4 (supraclavicular, mediastinal, lung parenchymal T2-signal). Types 1 and 2 were considered normal variants. Distribution of lymphatic abnormalities were tabulated, as well as secondary outcomes including chylothorax and mortality. Comparison was done using analysis of variance, Kruskal-Wallis test, and Fisher's exact test. Seventy-one children were included: 30 with hypoplastic left heart syndrome and 41 with nonhypoplastic left heart syndrome. Lymphatic abnormalities were present before Glenn operation in 21% (type 3) and 20% (type 4), and normal lymphatic perfusion patterns (type 1-2) were seen in 59% of patients. Chylothorax was present in 17% (only types 3 and 4). Pre-Glenn mortality and mortality at any time was significantly increased when having a type 4 lymphatic abnormality compared with types 1 and 2 (P=0.04). Conclusions Lymphatic abnormalities can be found on T2-weighted magnetic resonance imaging in children with single-ventricle physiology before their Glenn operation. Mortality and chylothorax were more prevalent with advancing grade of lymphatic abnormality.