Erythematous capillary-lymphatic malformations mimicking blood vascular anomalies.

Superficial erythematous cutaneous vascular malformations are assumed to be blood vascular in origin, but cutaneous lymphatic malformations can contain blood and appear red. Management may be different and so an accurate diagnosis is important. Cutaneous malformations were investigated through 2D histology and 3D whole-mount histology. Two lesions were clinically considered as port-wine birthmarks and another 3 lesions as erythematous telangiectasias. The aims were (i) to demonstrate that cutaneous erythematous malformations including telangiectasia can represent a lymphatic phenotype, (ii) to determine if lesions represent expanded but otherwise normal or malformed lymphatics, and (iii) to determine if the presence of erythrocytes explained the red color. Microscopy revealed all lesions as lymphatic structures. Port-wine birthmarks proved to be cystic lesions, with nonuniform lymphatic marker expression and a disconnected lymphatic network suggesting a lymphatic malformation. Erythematous telangiectasias represented expanded but nonmalformed lymphatics. Blood within lymphatics appeared to explain the color. Blood-lymphatic shunts could be detected in the erythematous telangiectasia. In conclusion, erythematous cutaneous capillary lesions may be lymphatic in origin but clinically indistinguishable from blood vascular malformations. Biopsy is advised for correct phenotyping and management. Erythrocytes are the likely explanation for color accessing lymphatics through lympho-venous shunts.

Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts.

BACKGROUND: Primary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and therapeutics. The defining criteria for one such clinical syndrome, 'WILD syndrome' (Warts, Immunodeficiency, Lymphoedema and anogenital Dysplasia), have previously depended on a single case report. METHODS AND RESULTS: We present 21 patients (including the first described case) with similar clinical and immunological phenotypes. All had PL affecting multiple segments, with systemic involvement (intestinal lymphangiectasia/pleural or pericardial effusions) in 70% (n=14/20). Most (n=20, 95%) had a distinctive cutaneous lymphovascular malformation on the upper anterior chest wall. Some (n=10, 48%) also had hyperpigmented lesions resembling epidermal naevi (but probably lymphatic in origin). Warts were common (n=17, 81%) and often refractory. In contrast to the previous case report, anogenital dysplasia was uncommon-only found in two further cases (total n=3, 14%). Low CD4 counts and CD4:CD8 ratios typified the syndrome (17 of 19, 89%), but monocyte counts were universally normal, unlike GATA2 deficiency. CONCLUSION: WILD syndrome is a previously unrecognised, underdiagnosed generalised PL syndrome. Based on this case series, we redefine WILD as 'Warts, Immunodeficiency, andLymphatic Dysplasia' and suggest specific diagnostic criteria. The essential criterion is congenital multisegmental PL in a 'mosaic' distribution. The major diagnostic features are recurrent warts, cutaneous lymphovascular malformations, systemic involvement (lymphatic dysplasia), genital swelling and CD4 lymphopaenia with normal monocyte counts. The absence of family history suggests a sporadic condition, and the random distribution of swelling implicates mosaic postzygotic mutation as the cause.

Investigation of clinical characteristics and genome associations in the 'UK Lipoedema' cohort.

Lipoedema is a chronic adipose tissue disorder mainly affecting women, causing excess subcutaneous fat deposition on the lower limbs with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is currently unclear. A tightly phenotyped cohort of 200 lipoedema patients was recruited from two UK specialist clinics. Objective clinical characteristics and measures of quality of life data were obtained. In an attempt to understand the genetic architecture of the disease better, genome-wide single nucleotide polymorphism (SNP) genotype data were obtained, and a genome wide association study (GWAS) was performed on 130 of the recruits. The analysis revealed genetic loci suggestively associated with the lipoedema phenotype, with further support provided by an independent cohort taken from the 100,000 Genomes Project. The top SNP rs1409440 (ORmeta ≈ 2.01, Pmeta ≈ 4 x 10-6) is located upstream of LHFPL6, which is thought to be involved with lipoma formation. Exactly how this relates to lipoedema is not yet understood. This first GWAS of a UK lipoedema cohort has identified genetic regions of suggestive association with the disease. Further replication of these findings in different populations is warranted.

Systematic Review of Magnetic Resonance Lymphangiography From a Technical Perspective.

BACKGROUND: Clinical examination and lymphoscintigraphy are the current standard for investigating lymphatic function. Magnetic resonance imaging (MRI) facilitates three-dimensional (3D), nonionizing imaging of the lymphatic vasculature, including functional assessments of lymphatic flow, and may improve diagnosis and treatment planning in disease states such as lymphedema. PURPOSE: To summarize the role of MRI as a noninvasive technique to assess lymphatic drainage and highlight areas in need of further study. STUDY TYPE: Systematic review. POPULATION: In October 2019, a systematic literature search (PubMed) was performed to identify articles on magnetic resonance lymphangiography (MRL). FIELD STRENGTH/SEQUENCE: No field strength or sequence restrictions. ASSESSMENT: Article quality assessment was conducted using a bespoke protocol, designed with heavy reliance on the National Institutes of Health quality assessment tool for case series studies and Downs and Blacks quality checklist for health care intervention studies. STATISTICAL TESTS: The results of the original research articles are summarized. RESULTS: From 612 identified articles, 43 articles were included and their protocols and results summarized. Field strength was 1.5 or 3.0 T in all studies, with 25/43 (58%) employing 3.0 T imaging. Most commonly, imaging of the peripheries, upper and lower limbs including the pelvis (32/43, 74%), and the trunk (10/43, 23%) is performed, including two studies covering both regions. Imaging protocols were heterogenous; however, T2 -weighted and contrast-enhanced T1 -weighted images are routinely acquired and demonstrate the lymphatic vasculature. Edema, vessel, quantity and morphology, and contrast uptake characteristics are commonly reported indicators of lymphatic dysfunction. DATA CONCLUSION: MRL is uniquely placed to yield large field of view, qualitative and quantitative, 3D imaging of the lymphatic vasculature. Despite study heterogeneity, consensus is emerging regarding MRL protocol design. MRL has the potential to dramatically improve understanding of the lymphatics and detect disease, but further optimization, and research into the influence of study protocol differences, is required before this is fully realized. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Update and audit of the St George's classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis.

Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, there may be internal lymphatic dysfunction, for example, chylous reflux, or lymphatic malformations, including the thorax or abdomen. A number of causal germline or postzygotic gene mutations have been discovered. Some through careful phenotyping and categorisation of the patients based on the St George's classification pathway/algorithm. The St George's classification algorithm is aimed at providing an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling and associated clinical features. This has enabled the identification of new causative genes. This update brings the classification of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classification for vascular anomalies. The St George's algorithm considers combined vascular malformations and primary lymphatic anomalies. It divides the types of primary lymphatic anomalies into lymphatic malformations and primary lymphoedema. It further divides the primary lymphoedema into syndromic, generalised lymphatic dysplasia with internal/systemic involvement, congenital-onset lymphoedema and late-onset lymphoedema. An audit and update of the algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested.

Lymphoscintigraphic Abnormalities Associated with Milroy Disease and Lymphedema-Distichiasis Syndrome.

Background: Primary lymphedema is genetically heterogeneous. Two of the most common forms of primary lymphedema are Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS). This study aims to look further into the pathogenesis of the two conditions by analyzing the lymphoscintigram images from affected individuals to ascertain if it is a useful diagnostic tool. Methods and Results: The lymphoscintigrams of patients with MD and LDS were analyzed, comparing the images and transport parameters of the two genotypes against a control population. Lymphoscintigrams were available for 12 MD and 16 LDS patients (all genetically proven diagnoses). Eight of the 12 (67%) lymph scans performed on patients with MD demonstrated little or no uptake from the initial lymphatics and poor visualization of the inguinal lymph nodes. These changes were consistent with a "functional aplasia," that is, the lymphatic vessels were present but appeared to be ineffective in absorbing the interstitial fluid into the lymphatic system. In patients with LDS the lymphoscintigraphic appearances were different. In 12 of the 16 scans (75%), the lymph scans were highly suggestive of lymphatic collector reflux. Quantification revealed a significantly reduced uptake of tracer within the inguinal lymph nodes and a higher residual activity in the feet at 2 hours in MD compared with LDS and compared with controls. Conclusion: Lymphoscintigraphic imaging and quantification can be characteristic in specific genetic forms of primary lymphedema and may be useful as an additional tool for in-depth phenotyping, leading to a more accurate diagnosis and providing insight into the underlying mechanism of disease.

LIMPRINT in Australia.

Background and Study Objective: Australia was one of nine participating countries in the epidemiology Phase II Lymphoedema Impact and Prevalence - International (LIMPRINT) project to determine the number of people with chronic edema (CO) in local health services. Methods and Results: Data collection occurred through questionnaire-based interviews and clinical assessment with provided LIMPRINT tools. Four different types of services across three states in Australia participated. A total of 222 adults participated with an age range from 22 to 102 years, and 60% were female. Site 1 included three residential care facilities (54% of participants had swelling), site 2 was community-delivered aged care services (24% of participants had swelling), site 3 was a hospital setting (facility-based prevalence study; 28% of participants had swelling), and site 4 was a wound treatment center (specific patient population; 100% of participants had swelling). Of those with CO or secondary lymphedema, 93% were not related to cancer, the lower limbs were affected in 51% of cases, and 18% of participants with swelling reported one or more episodes of cellulitis in the previous year. Wounds were identified in 47% (n = 105) of all participants with more than half of those with wounds coming from the dedicated wound clinic. Leg/foot ulcer was the most common type of wound (65%, n = 68). Conclusions: Distances between services, lack of specialized services, and various state funding models contribute to inequities in CO treatment. Understanding the high number of noncancer-related CO presentations will assist health services to provide timely effective care and improve referral pathways.

The Lymphatic Response to Injury with Soft-Tissue Reconstruction in High-Energy Open Tibial Fractures of the Lower Extremity.

BACKGROUND: Severe compound tibial fractures are associated with extensive soft-tissue damage, resulting in disruption of lymphatic pathways that leave the patient at risk of developing chronic lymphedema. There are limited data on lymphatic response following lower limb trauma. Indocyanine green fluorescence lymphography is a novel, real-time imaging technique for superficial lymphatic mapping. The authors used this technique to image the superficial lymphatic vessels of the lower limbs in patients with severe compound tibial fracture. METHODS: Baseline demographics and clinical and operative details were recorded in a prospective cohort of 17 patients who had undergone bone and soft-tissue reconstruction after severe compound tibial fracture between 2009 and 2014. Normal lymphatic images were obtained from the patients' noninjured limbs as a control. In this way, the authors investigated any changes to the normal anatomy of the lymphatic system in the affected limbs. RESULTS: Of the 17 patients, eight had free muscle flaps with split-thickness skin grafting, one had a free fasciocutaneous flap, one had a full-thickness skin graft, six had local fasciocutaneous flaps, and one had a pedicled gastrocnemius flap. None of the free flaps demonstrated any functional lymphatic vessels; the fasciocutaneous flaps and the skin graft demonstrated impaired lymphatic vessel function and dermal backflow pattern similar to that in lymphedema. Local flaps demonstrated lymphatic blockage at the scar edge. CONCLUSION: Severe compound fractures and the associated soft-tissue injury can result in significant lymphatic disruption and an increased risk for the development of chronic lymphedema.

Development and validation of a custom made indocyanine green fluorescence lymphatic vessel imager.

Lymphoedema is a chronic progressive condition often producing significant morbidity. An in-depth understanding of an individual's lymphatic architecture is valuable both in the understanding of underlying pathology and for targeting and tailoring treatment. Severe lower limb injuries resulting in extensive loss of soft tissue require transposition of a flap consisting of muscle and/or soft tissue to close the defect. These patients are at risk of lymphoedema and little is known about lymphatic regeneration within the flap. Indocyanine green (ICG), a water-soluble dye, has proven useful for the imaging of lymphatic vessels. When injected into superficial tissues it binds to plasma proteins in lymph. By exposing the dye to specific wavelengths of light, ICG fluoresces with near-infrared light. Skin is relatively transparent to ICG fluorescence, enabling the visualization and characterization of superficial lymphatic vessels. An ICG fluorescence lymphatic vessel imager was manufactured to excite ICG and visualize real-time fluorescence as it travels through the lymphatic vessels. Animal studies showed successful ICG excitation and detection using this imager. Clinically, the imager has assisted researchers to visualize otherwise hidden superficial lymphatic pathways in patients postflap surgery. Preliminary results suggest superficial lymphatic vessels do not redevelop in muscle flaps.