Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
2.
Medicine (Baltimore) ; 99(39): e21941, 2020 Sep 25.
Article in English | MEDLINE | ID: mdl-32991402

ABSTRACT

INTRODUCTION: Diffuse pulmonary lymphangiomatosis (DPL) is a rare condition. Most patients with DPL present dyspnea, cough, expectoration, and hemoptysis. There are few reports of DPL accompanied by thrombocytopenia, whose cause remains unknown. PATIENT CONCERNS: An 18-year-old male patient presented with recurrent cough, expectoration, and dyspnea for 5 years, and thrombocytopenia was observed during a 2-month follow-up. DIAGNOSIS: Chest computed tomography showed diffuse patchy shadows in both lungs, and pleural and pericardial effusions. Immunohistochemical lung tissue staining showed lymphatic and vascular endothelial cells positive for D2-40, CD31 and CD34. Routine blood test revealed platelets at 62 × 10 cells/L during follow-up. Bone marrow biopsy was normal. Ultrasound revealed no hepatosplenomegaly. Finally, the patient was diagnosed with DPL accompanied by thrombocytopenia. INTERVENTIONS: He was treated by subtotal pericardial resection, thoracocentesis, and anti-infective therapy. Oral prednisone was administered for 2 months. OUTCOMES: The symptoms of cough and shortness of breath were improved, but thrombocytopenia persisted. We investigated the cause of thrombocytopenia. Whole-exome sequencing identified a mutation in exon 3 of the TNFRSF13B gene in this patient. CONCLUSION: DPL may present with thrombocytopenia and DIC. Patients with thrombocytopenia but not DIC and splenomegaly should be screened for gene mutations.


Subject(s)
Lung Diseases/congenital , Lymphangiectasis/congenital , Thrombocytopenia/complications , Adolescent , Child , Humans , Lung Diseases/complications , Lung Diseases/diagnostic imaging , Lung Diseases/genetics , Lung Diseases/pathology , Lymphangiectasis/complications , Lymphangiectasis/diagnostic imaging , Lymphangiectasis/genetics , Lymphangiectasis/pathology , Male , Mutation, Missense , Thrombocytopenia/diagnosis , Tomography, X-Ray Computed , Transmembrane Activator and CAML Interactor Protein , Exome Sequencing
3.
Br J Ophthalmol ; 104(10): 1363-1367, 2020 10.
Article in English | MEDLINE | ID: mdl-31949094

ABSTRACT

AIMS: To investigate the relationship between the ophthalmic and systemic phenotypes in patients with hereditary transthyretin amyloidosis with the S77Y mutation (ATTRS77Y). METHODS: In this cross-sectional study, patients with genetically confirmed ATTRS77Y amyloidosis were enrolled. All patients underwent complete neurological examination, including staging with the Neuropathy Impairment Score (NIS), Polyneuropathy Disability (PND) score; complete cardiological evaluation, including echocardiography, cardiac MRI and/or cardiac scintigraphy and complete ophthalmic evaluation, including slit lamp examination and fundus examination. Ocular ancillary tests (fluorescein and indocyanine green angiography, and anterior segment optical coherence tomography) were performed in cases with abnormal findings. The Kruskal-Wallis test was used for quantitative outcomes and Fisher's exact test for qualitative outcomes. Statistical significance was indicated by p<0.05 (two tailed). RESULTS: The study sample was composed of 24 ATTRS77Y patients. The mean patient age was 58.4±12.4 years. None of the patients presented with amyloid deposits in the anterior chamber, secondary glaucoma or vitreous amyloidosis. Retinal angiopathy was observed in four patients, complicated with retinal ischaemia in one patient. Conjunctival lymphangiectasia (CL) was detected in 13 patients (54%), associated with perilymphatic amyloid deposits. The presence of CL was statistically associated with more severe neurological disease (NIS=43.3±31.9 vs 18.9±20.4; PND=2.6±1.0 vs 1.4±0.7 in patients with and without CL, respectively; both p<0.05) and amyloid cardiomyopathy (p=0.002). CONCLUSION: In ATTRS77Y patients, CL is common and could serve as a potential biomarker for severe systemic disease. There were neither anterior chamber deposits, secondary glaucoma nor vitreous deposits in ATTRS77Y patients.


Subject(s)
Amyloid Neuropathies, Familial/diagnostic imaging , Biomarkers , Conjunctival Diseases/diagnostic imaging , Lymphangiectasis/diagnostic imaging , Mutation , Prealbumin/genetics , Adult , Aged , Aged, 80 and over , Amyloid Neuropathies, Familial/genetics , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/genetics , Coloring Agents/administration & dosage , Conjunctival Diseases/genetics , Cross-Sectional Studies , Echocardiography , Female , Fluorescein Angiography , Genetic Association Studies , Humans , Indocyanine Green/administration & dosage , Lymphangiectasis/genetics , Magnetic Resonance Imaging , Male , Middle Aged , Radionuclide Imaging , Technetium , Tomography, Optical Coherence , Visual Acuity
4.
Front Immunol ; 10: 479, 2019.
Article in English | MEDLINE | ID: mdl-30936877

ABSTRACT

Background: HOIP is the catalytic subunit of the linear ubiquitination chain assembly complex (LUBAC) that is essential for NF-κB signaling and thus proper innate and adaptive immunity. To date only one patient with HOIP deficiency has been reported with clinical characteristics that include autoinflammation, immunodeficiency, amylopectinosis, and systemic lymphangiectasia. Case: We sought to identify a genetic cause of a disease for an 8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Methods: Targeted next generation sequencing of 352 immune-related genes was performed. Functional studies included transcriptome analysis, cytokine profiling, and protein analysis in patients' primary cells. Results: We identified biallelic variants in close proximity to splice sites (c.1197G>C and c.1737+3A>G) in the RNF31 gene. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells. Protein expression of HOIP and LUBAC was reduced in primary cells as shown by western blotting. Patient-derived fibroblasts demonstrated attenuated IL-6 production, while PBMCs showed higher TNF production after stimulation with proinflammatory cytokines. RNA sequencing of whole blood RNA and PBMCs demonstrated a marked transcriptome wide change including differential expression of type I interferon regulated genes. Conclusion: We report the second case of HOIP deficiency with novel compound heterozygous mutations in RNF31 and distinct clinical and molecular features. Our results expand on the clinical spectrum of HOIP deficiency and molecular signatures associated with LUBAC deficiency.


Subject(s)
Common Variable Immunodeficiency/genetics , Gene Expression Regulation , Inflammation/genetics , Polymorphism, Single Nucleotide , Transcriptome , Ubiquitin-Protein Ligases/deficiency , Alleles , Alternative Splicing , Child , Common Variable Immunodeficiency/diagnosis , Common Variable Immunodeficiency/immunology , Cytokines/biosynthesis , Cytokines/genetics , Exons/genetics , Female , Heterozygote , Humans , Lymphangiectasis/genetics , Lymphocyte Activation , NF-kappa B/physiology , Phenotype , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Signal Transduction , Transcription Factors/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/physiology , Ubiquitination/genetics , Ubiquitins/metabolism
5.
Klin Padiatr ; 229(4): 205-208, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28718185

ABSTRACT

Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder of the lung, characterized by dilation of pulmonary subpleural, interlobar, perivascular and peribronchial lymphatics. The incidence of CPL among stillborn and neonates was estimated to be <1%. The etiology of CPL is unknown. However, it has been suspected to be of a genetic background. Recent basic studies revealed that it might be caused by the FOXC2, Vegfr-3 and integrin α9ß1gene mutations. A clinical diagnosis of CPL can be made much easier in full-term neonates who present with respiratory distress, pleural (especially chylous) effusions with or without generalized edema. In infancy, the diagnosis seems to be more difficult due to the nonspecific respiratory symptoms like persistent tachypnea, cough and wheeze. Lung biopsy with subsequent histological and immunohistochemical studies is the golden diagnostic method of CPL. Immunohistochemical staining for endothelial cell markers CD31, CD34 and D2-40 confirms lymphatic origin. Therapeutic strategies include supportive, nutritional, investigational, aggressively interventional and surgical regimens, most of which have shown promising outcomes. Although CPL was once regarded as a disorder of very poor prognosis in neonatal onset cases, teenager and adult patients have shown good outcomes upon long-term follow-up.Die angeborene pulmonale Lymphangiektasie (CPL) ist eine seltene Entwicklungsstörung der Lunge, die durch eine Dilatation der pulmonalen subpleuralen, interlobären, perivaskulären und peribronchialen Lymphgefäße charakterisiert ist. Die Inzidenz der CPL bei Totgeburten und Neugeborenen wird <1% geschätzt. Die Ätiologie der CPL ist unbekannt. Allerdings wird ein genetischer Hintergrund vermutet. Neuere Grundlagenstudien zeigten, dass die CPL durch FOXC2, Vegfr-3 und Integrin α9ß1-Genmutationen verursacht sein könnte. Die klinische Diagnose der CPL ist sehr viel einfacher in Reifgeborenen zu stellen, die Atemnot, Pleuraergüsse (vor allem chylöse) mit und ohne generalisiertem Ödem aufweisen. In der frühen Kindheit ist die Diagnose aufgrund der unspezifischen respiratorischen Symptomatik wie persistierende Tachypnoen, Husten oder Röcheln schwerer zu stellen. Die Lungenbiopsie mit anschließenden histologischen und immunhistochemischen Untersuchungen ist der Goldstandard für die Diagnose der CPL. Die immunhistochemische Färbung der Endothelzellmarker CD31, CD34 und D2-40 bestätigt den lymphatischen Ursprung. Die Behandlungsstrategien umfassen unterstützende, alimentäre, in Erprobung befindliche, aggressiv-interventionelle und chirurgische Behandlungspläne, von denen die meisten ermutigende Ergebnisse zeigten. Obwohl die CPL einst bei Fällen mit Ausbruch im Neugeborenenalter als Erkrankung mit sehr schlechter Prognose galt, zeigen Teenager und erwachsene Patienten in der Langzeit-Nachbeobachtung gute Verläufe.


Subject(s)
Fetal Diseases/diagnosis , Infant, Newborn, Diseases/diagnosis , Lung Diseases/congenital , Lymphangiectasis/congenital , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , DNA Mutational Analysis , Female , Fetal Diseases/genetics , Fetal Diseases/pathology , Fetal Diseases/therapy , Forkhead Transcription Factors/genetics , Humans , Infant , Infant, Newborn , Infant, Newborn, Diseases/genetics , Infant, Newborn, Diseases/pathology , Infant, Newborn, Diseases/therapy , Integrins/genetics , Longitudinal Studies , Lung Diseases/diagnosis , Lung Diseases/genetics , Lung Diseases/pathology , Lung Diseases/therapy , Lymphangiectasis/diagnosis , Lymphangiectasis/genetics , Lymphangiectasis/pathology , Lymphangiectasis/therapy , Pregnancy , Prognosis , Stillbirth/genetics , Treatment Outcome , Vascular Endothelial Growth Factor Receptor-3/genetics , Young Adult
6.
Diagn Pathol ; 10: 27, 2015 Apr 16.
Article in English | MEDLINE | ID: mdl-25890230

ABSTRACT

INTRODUCTION: Nemaline myopathy is a rare genetic muscle disorder defined by the presence of nemaline rods in the muscle fibre sarcoplasm. Congenital nemaline myopathy is the most serious form of the disease's spectrum. CASE PRESENTATION: The affected newborn has no spontaneous movement, fractures at birth and respiratory insufficiency. The present case was a Thai male, floppy at birth with fractures of both humeri and femurs and ventilator-dependent respiration. The patient developed bilateral chylothorax two weeks later and died at the age of 6 weeks. Whole-body postmortem examination with informed consent and genetic analysis of ACTA1 mutation were performed. A skeletal muscle biopsy examined by light and transmission electron microscopy showed the features of nemaline myopathy. ACTA 1 heterozygous missense mutation (c.1127G > C) was identified. Histological examination of both lungs revealed primary pulmonary lymphangiectasia. CONCLUSION: To the best of our knowledge, congenital nemaline myopathy with primary pulmonary lymphangiectasia causing bilateral chylothrax has never been previously reported. Considering chylothorax as a poor prognostic index and an unusual clinical presentation of severe congenital NM are proposed. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9710506431489501 .


Subject(s)
Lung Diseases/congenital , Lymphangiectasis/congenital , Myopathies, Nemaline/diagnosis , Actins/genetics , Autopsy , Biopsy , Chylothorax/etiology , DNA Mutational Analysis , Fatal Outcome , Genetic Predisposition to Disease , Heterozygote , Humans , Infant , Infant, Newborn , Lung Diseases/complications , Lung Diseases/diagnosis , Lung Diseases/genetics , Lymphangiectasis/complications , Lymphangiectasis/diagnosis , Lymphangiectasis/genetics , Male , Mutation, Missense , Myopathies, Nemaline/complications , Myopathies, Nemaline/genetics , Myopathies, Structural, Congenital , Phenotype , Severity of Illness Index
7.
Circ Res ; 114(5): 806-22, 2014 Feb 28.
Article in English | MEDLINE | ID: mdl-24429550

ABSTRACT

RATIONALE: Lymphatic vessels in the respiratory tract normally mature into a functional network during the neonatal period, but under some pathological conditions they can grow as enlarged, dilated sacs that result in the potentially lethal condition of pulmonary lymphangiectasia. OBJECTIVE: We sought to determine whether overexpression of the lymphangiogenic growth factor (vascular endothelial growth factor-C [VEGF-C]) can promote lymphatic growth and maturation in the respiratory tract. Unexpectedly, perinatal overexpression of VEGF-C in the respiratory epithelium led to a condition resembling human pulmonary lymphangiectasia, a life-threatening disorder of the newborn characterized by respiratory distress and the presence of widely dilated lymphatics. METHODS AND RESULTS: Administration of doxycycline to Clara cell secretory protein-reverse tetracycline-controlled transactivator/tetracycline operator-VEGF-C double-transgenic mice during a critical period from embryonic day 15.5 to postnatal day 14 was accompanied by respiratory distress, chylothorax, pulmonary lymphangiectasia, and high mortality. Enlarged sac-like lymphatics were abundant near major airways, pulmonary vessels, and visceral pleura. Side-by-side comparison revealed morphological features similar to pulmonary lymphangiectasia in humans. The condition was milder in mice given doxycycline after age postnatal day 14 and did not develop after postnatal day 35. Mechanistic studies revealed that VEGF recptor (VEGFR)-3 alone drove lymphatic growth in adult mice, but both VEGFR-2 and VEGFR-3 were required for the development of lymphangiectasia in neonates. VEGFR-2/VEGFR-3 heterodimers were more abundant in the dilated lymphatics, consistent with the involvement of both receptors. Despite the dependence of lymphangiectasia on VEGFR-2 and VEGFR-3, the condition was not reversed by blocking both receptors together or by withdrawing VEGF-C. CONCLUSIONS: The findings indicate that VEGF-C overexpression can induce pulmonary lymphangiectasia during a critical period in perinatal development.


Subject(s)
Lung Diseases/congenital , Lymphangiectasis/congenital , Vascular Endothelial Growth Factor C/genetics , Animals , Female , Humans , Infant , Lung Diseases/genetics , Lung Diseases/metabolism , Lung Diseases/pathology , Lymphangiectasis/genetics , Lymphangiectasis/metabolism , Lymphangiectasis/pathology , Lymphatic Vessels/metabolism , Lymphatic Vessels/pathology , Male , Mice , Mice, Inbred Strains , Mice, Transgenic , Pregnancy , Pulmonary Edema/genetics , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , Signal Transduction/physiology , Trachea/metabolism , Trachea/pathology , Uteroglobin/genetics , Uteroglobin/metabolism , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolism
8.
J Clin Invest ; 123(3): 1202-15, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23391722

ABSTRACT

Lymphatic vessels are thought to arise from PROX1-positive endothelial cells (ECs) in the cardinal vein in response to induction of SOX18 expression; however, the molecular event responsible for increased SOX18 expression has not been established. We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1(S259A)) that is associated with Noonan syndrome. Expression of mutant RAF1(S259A) in ECs activated ERK and induced SOX18 and PROX1 expression, leading to increased commitment of venous ECs to the lymphatic fate. Excessive production of lymphatic ECs resulted in lymphangiectasia that was highly reminiscent of abnormal lymphatics seen in Noonan syndrome and similar "RASopathies." Inhibition of ERK signaling during development abrogated the lymphatic differentiation program and rescued the lymphatic phenotypes induced by expression of RAF1(S259A). These data suggest that ERK activation plays a key role in lymphatic EC fate specification and that excessive ERK activation is the basis of lymphatic abnormalities seen in Noonan syndrome and related diseases.


Subject(s)
Endothelium, Lymphatic/pathology , Human Umbilical Vein Endothelial Cells/metabolism , Lymphangiogenesis , MAP Kinase Signaling System , Animals , Aorta/pathology , Body Patterning , Butadienes/pharmacology , Cells, Cultured , Endothelium, Lymphatic/embryology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Gene Expression , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Human Umbilical Vein Endothelial Cells/physiology , Humans , Lymphangiectasis/genetics , Lymphangiectasis/metabolism , Lymphangiectasis/pathology , Male , Mice , Mice, Transgenic , Mutation, Missense , Nitriles/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/metabolism , SOXF Transcription Factors/genetics , SOXF Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Up-Regulation , Vascular Endothelial Growth Factor Receptor-3/metabolism
9.
PLoS One ; 7(9): e45261, 2012.
Article in English | MEDLINE | ID: mdl-23028890

ABSTRACT

Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrl(fl/fl)/CAGGCre-ER™ mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrl(fl/fl)/CAGGCre-ER™ mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE-cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrl(fl/fl)/CAGGCre-ER™ mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia.


Subject(s)
Calcitonin Receptor-Like Protein/genetics , Edema/genetics , Intestines/pathology , Limbus Corneae/pathology , Lymphangiectasis/genetics , Lymphatic Vessels/pathology , Skin/pathology , Adrenomedullin/genetics , Adrenomedullin/metabolism , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Cadherins/genetics , Cadherins/metabolism , Calcitonin Receptor-Like Protein/deficiency , Edema/etiology , Edema/metabolism , Edema/pathology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Gene Deletion , Gene Expression , Genetic Vectors , Intestinal Mucosa/metabolism , Intestines/drug effects , Limbus Corneae/drug effects , Limbus Corneae/metabolism , Lymphangiectasis/etiology , Lymphangiectasis/metabolism , Lymphangiectasis/pathology , Lymphatic Vessels/drug effects , Lymphatic Vessels/metabolism , Male , Mice , Mice, Transgenic , Signal Transduction , Skin/drug effects , Skin/metabolism , Tamoxifen/adverse effects , Zonula Occludens-1 Protein/genetics , Zonula Occludens-1 Protein/metabolism
10.
Eur J Pediatr ; 171(3): 447-50, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21918810

ABSTRACT

UNLABELLED: Non-immune hydrops fetalis may find its origin within genetically determined lymphedema syndromes, caused by mutations in FOXC2 and SOX-18. We describe a newborn girl, diagnosed with non-immune hydrops fetalis at a gestational age of 30 weeks. Family history revealed the presence of an autosomal dominant late-onset form of lymphedema of the lower limbs in her father, associated with an aberrant implantation of the eyelashes in some individuals. The newborn, hydropic girl suffered from severe pulmonary lymphangiectasia, resulting in terminal respiratory failure at the age of 3 months. Genetic analysis in both the father and the newborn girl demonstrated a heterozygous FOXC2 mutation, i.e., c.939C>A, p.Tyr313X. Her two older sisters are currently asymptomatic and the parents decided not to test them for the FOXC2 mutation. CONCLUSION: Patients with a mutation in the FOXC2 transcription factor usually show lower limb lymphedema with onset at or after puberty, together with distichiasis. However, the eye manifestations can be very mild and easily overlooked. The association between FOXC2 mutation and neonatal hydrops resulting in terminal respiratory failure is not reported so far. Therefore, in sporadic patients diagnosed with non-immune hydrops fetalis, lymphangiogenic genes should be systematically screened for mutations. In addition, all cases of fetal edema must prompt a thorough analysis of the familial pedigree, in order to detect familial patterns and to facilitate adequate antenatal counseling.


Subject(s)
Codon, Nonsense , Forkhead Transcription Factors/genetics , Hydrops Fetalis/genetics , Lung Diseases/congenital , Lymphangiectasis/congenital , Lymphedema/genetics , Fatal Outcome , Female , Genes, Dominant , Genetic Markers , Heterozygote , Humans , Hydrops Fetalis/diagnosis , Infant, Newborn , Lung Diseases/diagnosis , Lung Diseases/genetics , Lymphangiectasis/diagnosis , Lymphangiectasis/genetics , Lymphedema/diagnosis , Syndrome
12.
Nat Genet ; 41(12): 1272-4, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19935664

ABSTRACT

Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.


Subject(s)
Abnormalities, Multiple/genetics , Lymphangiectasis/genetics , Lymphedema/genetics , Mutation , Amino Acid Sequence , Animals , Consanguinity , Genes, Recessive , Heterozygote , Humans , Intellectual Disability/genetics , Male , Molecular Sequence Data , Pedigree , Phenotype , Syndrome , Young Adult
13.
Lymphat Res Biol ; 6(2): 65-8, 2008.
Article in English | MEDLINE | ID: mdl-18564920

ABSTRACT

BACKGROUND: Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance. Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes. METHODS AND RESULTS: The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals. CONCLUSIONS: The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.


Subject(s)
Hepatocyte Growth Factor/genetics , Lymphangiectasis/genetics , Lymphedema/genetics , Mutation , Proto-Oncogene Proteins/genetics , Receptors, Growth Factor/genetics , Exons , Humans , Lymphangiectasis/etiology , Lymphedema/etiology , Proto-Oncogene Proteins c-met
15.
Orphanet J Rare Dis ; 1: 43, 2006 Oct 30.
Article in English | MEDLINE | ID: mdl-17074089

ABSTRACT

Congenital pulmonary lymphangiectasia (PL) is a rare developmental disorder involving the lung, and characterized by pulmonary subpleural, interlobar, perivascular and peribronchial lymphatic dilatation. The prevalence is unknown. PL presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth. Most reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion. The diagnostic approach includes complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination. During the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL. Fetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL. At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage. Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.


Subject(s)
Lung Diseases/congenital , Lymphangiectasis/congenital , Rare Diseases , Diagnosis, Differential , Female , Humans , Hydrops Fetalis/diagnosis , Infant, Newborn , Infant, Newborn, Diseases/diagnosis , Lung Diseases/diagnosis , Lung Diseases/genetics , Lung Diseases/therapy , Lymphangiectasis/diagnosis , Lymphangiectasis/genetics , Lymphangiectasis/therapy , Male , Pregnancy , Prenatal Diagnosis/methods , Prognosis
17.
Am J Med Genet A ; 140(4): 368-72, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16419129

ABSTRACT

Pulmonary lymphangiectasia is an uncommon congenital anomaly, and familial occurrence has rarely been reported. We report on two sibs with bilateral pleural effusion/chylothorax and hydrops who died neonatally. One sib required prenatal intrauterine hemithoracic drainage. Autopsy confirmed congenital pulmonary lymphangiectasia (CPL) histologically in the first case. Hydrops, characterized as subcutaneous edema and effusions in two or more body cavities, may be due to a variety of factors, but the co-occurrence of CPL in one of these sibs, although rare, supports the notion that chylothorax and hydrops may be caused by structural lesions of lymph channels. Although most cases of CPL are sporadic, the reported sibs support autosomal recessive inheritance, with intrafamilial variability of a lymphatic disorder on a genetic basis. Mutations in vascular endothelial growth factor receptor-3 (VEGFR3) in families with Milroy disease, mutations of FOXC2 in the lymphedema-distichiasis syndrome, and fatal chylothorax in alpha9-deficient mice are potential candidate genes.


Subject(s)
Abnormalities, Multiple , Chylothorax/congenital , Edema/congenital , Lung Diseases/congenital , Lymphangiectasis/congenital , Lymphedema/congenital , Adolescent , Chylothorax/genetics , Edema/genetics , Fatal Outcome , Female , Genes, Recessive , Gestational Age , Humans , Infant, Newborn , Lung Diseases/genetics , Lymphangiectasis/genetics , Lymphedema/genetics , Male , Pleural Effusion , Pregnancy
18.
Am J Med Genet A ; 120A(1): 92-6, 2003 Jul 01.
Article in English | MEDLINE | ID: mdl-12794699

ABSTRACT

We report a female infant with congenital lymphedema, facial anomalies, intestinal lymphangiectasia consistent with a diagnosis of Hennekam syndrome. At birth the patient presented with severe respiratory distress due to nonimmune hydrops fetalis, a congenital chylothorax (CC), and pulmonary lymphangiectasia. Hydrops fetalis may be present in newborns with the Hennekam syndrome. Lymphoscintigraphy can be useful in explaining pleural-pulmonary involvement of this generalized lymph vessel malformation syndrome.


Subject(s)
Chylothorax/genetics , Hydrops Fetalis/genetics , Lung Diseases/genetics , Lymphangiectasis/genetics , Abnormalities, Multiple/genetics , Child, Preschool , Chylothorax/congenital , Chylothorax/diagnosis , Facies , Female , Humans , Hydrops Fetalis/diagnosis , Lung Diseases/diagnosis , Lymph Nodes/pathology , Lymphangiectasis/diagnosis , Lymphedema/diagnosis , Lymphedema/genetics , Radiography, Thoracic , Syndrome , Tomography, X-Ray Computed
19.
Am J Med Genet ; 93(4): 264-8, 2000 Aug 14.
Article in English | MEDLINE | ID: mdl-10946350

ABSTRACT

We report on four cases, three familial and one sporadic, with congenital pulmonary lymphangectasia and facial and lower limb lymphedema. Hydrops fetalis was observed in three cases and death occurred in one of those. This is the third report describing inherited pulmonary lymphangectasia with a clinical phenotype very similar to that described by Njolstad et al. [1998: Eur J Pediatr 157: 498-501], who reported three sibs with non-immune hydrops fetalis (NIHF), chylothorax, pulmonary lymphangectasia, distal lymphedema, and swelling of the face. We think that the present report and that of Njolstad et al. describe a new condition very similar to Hennekam syndrome, which is characterized by autosomal recessive inheritance, intestinal lymphangiectasia, lymphedema of the lower limbs and facial anomalies (flat face, hypertelorism, flat, broad nasal bridge, lymphedema, tooth anomalies, and ear defects). Similarity with our cases and Hennekam syndrome will be discussed.


Subject(s)
Hydrops Fetalis/genetics , Lung Diseases/genetics , Lymphangiectasis/genetics , Lymphedema/genetics , Child , Child, Preschool , Face/abnormalities , Female , Genes, Recessive , Humans , Infant
SELECTION OF CITATIONS
SEARCH DETAIL
...