Lymphatic Dysplasia Research Articles

Structural Analysis of Piezo1 Ion Channel Reveals the Relationship between Amino Acid Sequence Mutations and Human Diseases

Since first identified in 2010, Piezo proteins have been found to perform as poreforming mechanosensitive ion channels across a wide range of animals. As a Piezo ortholog primarily expressed in mammalian systems, Piezo1 has been observed to distribute mainly in nonsensory tissues, regulating osmotic homeostasis, proprioception, and light touch. With previous studies on the putative structure of Piezo1, the gating system and several mechanotransduction mechanisms have been proposed. Besides, mutations of specific amino acid sequences in Piezo1 have been linked to several human diseases such as dehydrated hereditary xerocytosis (DHS) and congenital lymphatic dysplasia (CLD). However, most of these mutations have not been well characterized. To further elucidate the relations between these mutations and diseases, UCSF Chimera is used as the tool to visualize the structural importance of each of these mutated amino acids. With the aid from UCSF Chimera, this study has recorded and interpreted clashes and contacts originated from each of the mutations. Accordingly, specific mechanisms between mutations and human diseases are proposed, which pave the way for healing.

CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease.

Primary intestinal lymphangiectasia (PIL) or Waldmann's disease was described in 1961 as an important cause of protein-losing enteropathy (PLE). PIL can be the sole finding in rare individuals or occur as part of a multisystemic genetic syndrome. Although genetic etiologies of many lymphatic dysplasia syndromes associated with PIL have been identified, the pathogenesis of isolated PIL (with no associated syndromic features) remains unknown. Familial cases and occurrence at birth suggest genetic etiologies in certain cases. Recently, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (the CHAPLE syndrome) has been identified as a monogenic form of PIL. Surprisingly, loss of CD55, a key regulator of complement system leads to a predominantly gut condition. Similarly to other complement disorders, namely paroxysmal nocturnal and hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), CHAPLE disease involves pathogenic cross-activation of the coagulation system, predisposing individuals to severe thrombosis. The observation that complement system is overly active in CHAPLE disease introduced a novel concept into the management of PLE; anti-complement therapy. While CD55 deficiency constitutes a treatable subgroup in the larger pool of patients with isolated PIL, the etiology remains to be identified in the remaining patients with intact CD55.

PLEURAL AND CHEST WALL LYMPHANGIOMATOSIS

SESSION TITLE: Disorders of the Mediastinum 2 SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/10/2018 10:45 am - 11:45 am INTRODUCTION: Recurrent pleural effusions of unclear etiology can be a challenging clinical scenario. We present a rare case of pleural Lymphangiomatosis with no lung parenchymal involvement, presenting atypically late in adult life. CASE PRESENTATION: A 66 year old lady presented to pulmonary clinic with subacute on chronic shortness of breath. She had a history of recurrent exudative right sided pleural effusions for the last 5 years. The effusions were consistently culture and cytology negative. She had no other cardiopulmonary symptoms, past history, exposures or family history. Pertinent exam findings included absent breath sounds in the right lower lung field. Chest X-ray revealed a moderate right-sided pleural effusion with associated right lower lobe atelectasis (Image 1). CT chest (Image 2) showed a large mediastinal cystic mass, cysts along the internal mammary wall and a small right pleural effusion with areas of pleural thickening. She underwent a diagnostic and therapeutic Video-assisted Thoracoscopy/Thoracotomy. Serosanguinous pleural fluid was drained and a pleural peel excision/pleurodesis/cyst excisions were performed. Histopathology revealed lymphangiomatosis with lymphangiectasia. She was symptom free post-procedure but presented a few years later with recurrent disease confirmed on CT chest (Image 3). She declined surgery and is being managed with therapeutic thoracenteses, propranolol, anti-Vascular Endothelial Growth Factor (VEGF) therapies and Sirolimus, with good response over the last few years. DISCUSSION: Lymphangiomatosis is a rare disorder characterized by lymphatic overgrowth along normal systemic lymphatic channels(1). While it has been reported to present over diverse age groups from birth to 80 years, with no clear gender predilection, it rarely presents after 20 years of age. In the chest, it can present as Diffuse Pulmonary Lymphangiomatosis, involving only pulmonary parenchyma and is clinically/histopathologically unique from Lymphangioleiomyomatosis. It may also present purely with mediastinal, pleural and chest wall involvement. CT chest usually shows interlobular septal thickening with mediastinal involvement (2). Factor 8 related antigen and CD31 are usually positive on immunohistochemistry. Chylous effusions, chyloptysis, chylopericardium and chylous ascites are common and complications include protein wasting enteropathy, lymphedema and Disseminated Intravascular Coagulation. Surgical interventions are complex given difficulty separating pathologic from normal lymphatics /other anatomic structures. Lymphoscintigraphy can often help to guide therapy. Anti-VEGF therapies and Sirolimus(3) are being increasingly used as therapeutic and maintenance measures. CONCLUSIONS: While a rare cause of pleural effusions in the adult population, Lymphangiomatosis can be a challenging condition to manage. Reference #1: Tazelaar, H.D., et al., Diffuse pulmonary lymphangiomatosis. Human Pathology. 24(12): p. 1313-1322. Reference #2: Faul, J.L., et al., Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med, 2000. 161(3 Pt 1): p. 1037-46. Reference #3: Reinglas, J., R. Ramphal, and M. Bromwich, The successful management of diffuse lymphangiomatosis using sirolimus: a case report. Laryngoscope, 2011. 121(9): p. 1851-4. DISCLOSURES: No relevant relationships by Augustine Lee, source=Admin input No relevant relationships by Divya Padmanabhan Menon, source=Web Response

Improved diagnosis in nonimmune hydrops fetalis using a standardized algorithm.

AbstractObjectiveThe aim of this study was to outline the disease etiology in a cohort of fetuses prenatally diagnosed with nonimmune hydrops fetalis (NIHF).MethodsBased on a literature review, we defined precise criteria to select the NIHF cases. Those were further classified into 14 categories. To complete this first step, a literature review was performed by using homogeneous criteria to compare our results.ResultsOver the 10‐year period, 102 fetuses were diagnosed with NIHF and included in the analysis. The etiology was identified in 86.3% (88/102) of them, with diagnostic distribution from the most prevalent to the least frequent (number of fetuses; %) being: chromosomal (33/102; 32.4%), lymphatic dysplasia (14; 13.7%), cardiovascular (10; 9.8%), “syndromic” (10; 9.8%), infection (8; 7.8%), and hematologic (8; 7.8%).ConclusionThis literature review enabled us to emphasize the absence of homogeneous criteria used to define NIHF. When compared with literature, our data analysis highlighted the relevance of applying our full diagnostic approach to decrease the rate of idiopathic NIHF cases.

Human phenotypes caused by PIEZO1 mutations; one gene, two overlapping phenotypes?

PIEZO1 is a large mechanosensitive ion channel protein. Diseases associated with PIEZO1 include autosomal recessive generalised lymphatic dysplasia of Fotiou (GLDF) and autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal oedema (DHS). The two disorders show overlapping features, fetal hydrops/perinatal oedema have been reported in both. Electrophysiological studies suggest opposite mechanisms of action: the mutations identified in GLDF patients cause a loss-of-function mechanism of disease and mutations in DHS patients cause gain of function. This raises the question: Is the pathogenic disease mechanism behind the fetal oedema the same in the two phenotypes? In this Symposium Review, we will discuss the two conditions and highlight key questions that remain to be answered. For instance, the perinatal oedema often resolves soon after birth and we are still at a loss to understand why. Are there any mechanisms which could compensate for the faulty PIEZO1 in these patients? Are there physiological changes at birth that are less reliant on the function of PIEZO1? Thus, there is a clear need for further studies into the two disorders, in order to fully understand the role of PIEZO1 in health and disease.

A Case of Congenital Lymphatic Dysplasia Complicated by Hydrops Fetalis

A Case of Congenital Lymphatic Dysplasia Complicated by Hydrops Fetalis

Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction.

Mutations in the genes encoding the mechanosensitive cation channels PIEZO1 andPIEZO2 are responsible for multiple hereditary human diseases. Loss-of-function mutations in the human PIEZO1 gene cause autosomal recessive congenital lymphatic dysplasia. Gain-of-function mutations in the human PIEZO1 gene cause the autosomal dominant hemolytic anemia, hereditary xerocytosis (also known as dehydrated stomatocytosis). Loss-of-function mutations in the human PIEZO2 gene cause an autosomal recessive syndrome of muscular atrophy with perinatal respiratory distress, arthrogryposis, and scoliosis. Gain-of-function mutations in the human PIEZO2 gene cause three clinical types of autosomal dominant distal arthrogryposis. This chapter will review the hereditary diseases caused by mutations in the PIEZO genesand will discuss additional physiological systems in which PIEZO channel dysfunction may contribute to human disease pathophysiology.

Comment on: A Pathologist’s Approach to Nonimmune Hydrops

I read with interest the excellent and truly valuable review article by WT Parks recently published in the Journal of Fetal Medicine [1], entitled ‘‘A Pathologist’s Approach to Nonimmune Hydrops’’ that describes the point of view of the pathologist approaching a fetus or a dead newborn affected by prenatally diagnosed nonimmune hydrops (NIH). In general, autopsy is recommended in all cases of fetal or neonatal death or pregnancy termination [2]. I fully agree with the author that ‘‘determining the cause of the NIH will be the primary question at autopsy’’ in particular, in cases for which no clinical diagnosis has been made. In Table 1, the author listed chylothorax among the ‘‘thoracic’’ causes of NIH, but neither the table nor the text touches upon lymphatic dysplasia as an important (and often underdiagnosed) cause of NIH. With regard to this issue, I would like to add a brief comment to the article [1]. The role of malformative development or impaired function of the lymphatic system in the fetus leading to hydrops formation has been discussed extensively [3] as also cited by the author. An unacceptably high number of NIH cases remain without a diagnosis, and among them, some degree of lymphatic involvement is extremely likely [4]. The usefulness of immunohistochemical staining techniques to discern between blood and lymphatic microcapillaries and vessels is now well established [4]. We previously recommended [5] the use of CD-31, CD-34, D2-40 (or podoplanin), smooth muscle actin (SMA), anti-LYVE-1 (antibodies against lymphatic endothelium), and VEGFR-3 in the pathological workup of NIH. I would like to underline and reaffirm the importance of immunohistochemical studies in the absence of a definite diagnosis of NIH or, as an alternative in case of a strong suspicion of lymphatic system involvement. I believe the inclusion of accurate immunohistochemical analysis of the lymphatic vessels in all NIH guidelines, might improve the existing value of the article.

Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.

Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.

Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.

Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant dehydrated hereditary stomatocytosis and non-immune hydrops of unknown aetiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.

Indocyanine Green Lymphography and Lymphaticovenous Anastomosis for Generalized Lymphatic Dysplasia with Pleural Effusion and Ascites in Neonates

The fatality rate of generalized lymphatic dysplasia (GLD) with chylous pleural effusion and ascites is particularly high when it persists over a prolonged period. The purpose of this report was to determine the utility of indocyanine green (ICG) lymphography and lymphaticovenous anastomosis (LVA) in GLD with chylous pleural effusion and ascites in neonates. We tested the lymphatic function in the 4 extremities for 8 GLD neonate patients using ICG lymphography, and on the basis of the results, we performed LVA for 5 of them. LVA was performed at the extremities under general anesthesia using incisions <1 cm in length. The outcome of LVA was evaluated with the amount of ascites discharged from thoracostomy tube or abdominal tube, except for 1 patient who had no drainage tube. In all cases, ICG lymphography showed varying degrees of dermal backflow in the limbs with lymphostasis. After LVA surgery, effusion stopped in 2 cases and decreased in 1 case. In the cases where effusion stopped, backflow as observed with ICG lymphography was minimal, and in the case where effusion decreased but did not stop, backflow was moderate. The application of ICG and LVA could possibly be used to diagnose and treat lymphatic pleural effusion or ascites.

Antenatal presentation of hereditary lymphedema type I

Fetal edema can present as limited subcutaneous edema, fluid accumulation in body cavities or hydrops fetalis. Hydrops fetalis is the end stage of a variety of fetal/maternal disorders and nonimmune etiology represents more than 3/4 of cases. Lymphatic dysplasia may account for a subset of patients with nonimmune and “idiopathic” hydrops fetalis, fetal chylous ascites or chylothorax. We present two unrelated patients with antenatal features of hereditary lymphedema syndrome, in whom Milroy disease was diagnosed after birth. At least, 20 genes have been identified to cause primary lymphedema, with sometimes antenatal features. Hereditary lymphedema syndrome should be considered in cases of nonimmune hydrops fetalis/fetal edema after ruling out the more common etiologies.

Etiology of non-immune hydrops fetalis: An update.

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases.

Pediatric lymphangiectasia: an imaging spectrum

Lymphangiectasia is a rarely encountered lymphatic dysplasia characterized by lymphatic dilation without proliferation. Although it can occur anywhere, the most common locations are the central conducting lymphatics and the pulmonary and intestinal lymphatic networks. Recent advances in lymphatic interventions have resulted in an increased reliance on imaging to characterize patterns of disease. To describe the patient populations, underlying conditions, and imaging features of lymphangiectasia encountered at a tertiary pediatric institution over a 10-year period and correlate these with pathology and patient outcomes. We retrospectively reviewed the pathology database from 2002 to 2012 to identify patients with pathologically or surgically proven lymphangiectasia who had undergone cross-sectional imaging. Medical records were reviewed for patient demographics, underlying conditions, treatment and outcome. Thirteen children were identified, ranging in age from 1month to 16years. Five had pulmonary lymphangiectasia, four intestinal and four diffuse involvement. Pulmonary imaging findings include diffuse or segmental interlobular septal thickening, pleural effusions and dilated mediastinal lymphatics. Intestinal imaging findings include focal or diffuse bowel wall thickening with central lymphatic dilation. Diffuse involvement included dilation of the central lymphatics and involvement of more than one organ system. Children with infantile presentation and diffuse pulmonary, intestinal or diffuse lymphatic abnormalities had a high mortality rate. Children with later presentations and segmental involvement demonstrated clinical improvement with occasional regression of disease. Three children with dilated central lymphatics on imaging underwent successful lymphatic duct ligation procedures with improved clinical course. Lymphangiectasia is a complex disorder with a spectrum of presentations, imaging appearances, treatments and outcomes. Cross-sectional imaging techniques distinguish segmental involvement of a single system (pulmonary or intestinal) from diffuse disease and may show dilated central conducting lymphatics, which may benefit from interventions such as ligation or occlusion.

Variable clinical presentation in primary lymphoedema

Lymphoedema is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system. Lymphoedema may be primary or secondary and can be inherited. Primary lymphoedema (primary lymphatic dysplasia) is a chronic oedema caused by a developmental abnormality of the lymphatic system. Primary lymphoedema most commonly affects the lower limbs, but other body parts can also be affected. It can be associated with some specific syndromes (i.e. Hennekam syndrome) and genetic disorders. In this article, we report on two patients with congenital multisegmental lymphoedema and Hennekam syndrome, both primary lymphoedemas.

Twin Infant with Lymphatic Dysplasia Diagnosed with Noonan Syndrome by Molecular Genetic Testing

Noonan Syndrome is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, dysmorphic facial features and occasional lymphatic dysplasias. The features of Noonan Syndrome change with age and have variable expression. The diagnosis has historically been based on clinical grounds. We describe a child that was born with congenital refractory chylothorax and subcutaneous edema suspected to be secondary to pulmonary lymphangiectasis. The infant died of respiratory failure and anasarca at 80 days. The autopsy confirmed lymphatic dysplasia in lungs and mesentery. The baby had no dysmorphic facial features and was diagnosed postmortem with Noonan syndrome by genomic DNA sequence analysis as he had a heterozygous mutation for G503R in the PTPN11 gene.

Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis

The VEGFC/VEGFR3 signaling pathway is essential for lymphangiogenesis (the formation of lymphatic vessels from pre-existing vasculature) during embryonic development, tissue regeneration and tumor progression. The recently identified secreted protein CCBE1 is indispensible for lymphangiogenesis during development. The role of CCBE1 orthologs is highly conserved in zebrafish, mice and humans with mutations in CCBE1 causing generalized lymphatic dysplasia and lymphedema (Hennekam syndrome). To date, the mechanism by which CCBE1 acts remains unknown. Here, we find that ccbe1 genetically interacts with both vegfc and vegfr3 in zebrafish. In the embryo, phenotypes driven by increased Vegfc are suppressed in the absence of Ccbe1, and Vegfc-driven sprouting is enhanced by local Ccbe1 overexpression. Moreover, Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of Ccbe1. Finally, CCBE1 is capable of upregulating the levels of fully processed, mature VEGFC in vitro and the overexpression of mature VEGFC rescues ccbe1 loss-of-function phenotypes in zebrafish. Taken together, these data identify Ccbe1 as a crucial component of the Vegfc/Vegfr3 pathway in the embryo.

Evaluation of Lymphatic Dysplasia in Patients with Congenital Pleural Effusion and Ascites Using Indocyanine Green Lymphography

To investigate the use of indocyanine green (ICG) lymphography in the diagnosis and assessment of the severity of lymphatic dysfunction in infants and neonates with congenital lymphatic pleural effusion and ascites. We performed ICG lymphography on 10 neonates and infants with congenital lymphatic pleural effusion and ascites. After the subcutaneous injection of ICG, circumferential fluorescent images of lymphatic drainage channels in the extremities and trunk were identified using an infrared camera system. The lymphographic findings were classifiable into 2 patterns-those showing a linear lymphatic pattern, suggesting normal lymphatic flow, and those showing lymphatic channels with retrograde lymphatic flow (dermal backflow pattern), suggesting an abnormal lymphatic flow. We analyzed the severity of the ICG lymphography findings and the clinical outcomes. Based on the ICG lymphography, the severity of lymphatic dysplasia were classified into 4 categories: mild dysplasia, moderate dysplasia, severe dysplasia, and lymphatic hypoplasia. All cases diagnosed with mild (n = 3) or moderate dysplasia (n = 2) survived, and 2 of the 4 cases diagnosed with severe dysplasia died. The duration of endotracheal intubation ranged from 1 to 17 days (median, 7) in the patients with mild or moderate dysplasia and from 25 to 110 days (median, 77) in those with severe dysplasia. The ICG lymphographic findings were consistent with the clinical conditions. This imaging technique may be important to the future clinical management of lymphatic dysplasia in neonates and infants.

Lymphatic dysplasia syndrome with chylothorax: a case report

Lymphedema is a disease that is caused by the blockage of flow of lymph and is generally characterized with swelling (edema) in the extremities. Primary lymphedema which is rarely seen can develop either at birth or symptoms can begin at puberty and is known as lymphedema praecox. Lymphedema praecox is the most common form of primer lymphedema and is diagnosed by the exclusion of secondary causes. Lymphatic Dysplasia Syndrome is defined as primary lymphedema with effusion in the third spaces of the body such as the pleura, pericardium and peritoneum. In this article, we present a rare case of a 14 year old girl who was diagnosed with lymphedema praecox/lymphatic dysplasia syndrome because she had edema in both her lower extremities and chylothorax in her right lung. Pam Med J 2014;7(3):234-238

Etiology and Outcome of Hydrops Fetalis: Report of 62 Cases

We aimed to define the etiologic and prognostic factors in live-born infants with hydrops fetalis (HF) in our tertiary neonatal intensive care unit over a 10-year period. Medical records of newborn infants with HF during 2002-2011 were reviewed retrospectively. Demographic data, prenatal interventions, clinical and laboratory findings, outcomes, and the results of postmortem examinations were analyzed. During the study period, 62 newborn infants with HF were identified from 16,200 live-born deliveries and the incidence of HF was 3.8/1000 live births in our hospital. Twenty-eight infants (45.2%) had immune HF, whereas 34 (54.8%) had nonimmune HF. An etiologic factor could be identified in 24 (70.5%) infants with nonimmune HF. Lymphatic dysplasias comprised the majority (23.5%) of the infants with nonimmune HF. Mortality rate was 50%. The presence of two or more serous cavity effusions and gestational age were independently associated with the risk of mortality. Despite the improvements in neonatal care, mortality rate in infants with HF is still high. Gestational age and the extent of serous cavity determine the risk of mortality. Timely and advanced prenatal or postnatal new therapeutic strategies may alter this fatal outcome in appropriate patients.