CONGENITAL PULMONARY LYMPHANGIECTASIA
A congenital disease involving the lung characterized by greatly dilated lymphatic ducts throughout the lung.
age of onset:
neonatal period and after the neonatal period
TYPES (after Noonon (1970))*:
1. Group I
dilated pulmonary lymphatics are part of a generalized form of lymphangiectasis: thoracic and extrathoracic (intestinal) lymphangiectasia
diffuse angiomatosis in which bone is the most common site of involvement
less severe form and has a much better prognosis than the other two forms
2. Group II
due to a cardiac lesion
dilated pulmonary lymphatics are acquired in utero due to obstruction of the pulmonary venous flow secondary to a cardiac lesion which may interfere with the normal regression of the lymphatic tissue elements after the 16th week of fetal life
very poor prognosis
3. Group III
due to a defect in the primary development of the lung
Lawrence (1955) postulated that lymphangectasis is due to a developmental error in which the normal regression of connective tissue elements in the lung fails to occur after the 16th week of life. Subsequently the lymph vessels do not regress in size and remain enlarged in relation to the parenchyma of the lung (Noonan, 1970).
may be associated with congenital
malformations including cardiac lesions
clinical picture characterized by over expanded lungs with alveolar hypoventilation and periodic wheezing and a relapsing course
dilated lymphatics may result in marked restriction of respiratory movements
*first report of CPL by Virchow (1856) and first named by Lawarence in 1955
presents in two forms:
1. Neonatal Period
presents with respiratory distress and cyanosis at birth
(usually term) with rapid demise
can also present as a stillbirth
2. Post Neonatal Period
presents with respiratory difficulties
progressive relapsing course
associated with chylopericardium, chylothorax, chronic cough, congestive heart failure
3. Associated Abnormalities
congenital abnormalities in 50% of cases:
TAPVR, mitral valve atresia, hypoplastic left heart, aortic coarctation, VSD, PDA, ASD
cystic hygromas, diffuse angiomatosis (bones), pneumothorax
1. Lung Biopsy
cystic dilation of the lymphatics in the subpleural and intralobular regions and perivascular spaces give the lungs a subpleural reticulated pattern of fine interconnecting white lines with air-filled cystic areas
2. Imaging Studies
1. Chest X-Ray
diffuse reticular pattern
Pulmonary Lymphangiectasia, congenital
Lymphatic fluid in the lung is derived from normal leakage of fluid out of the blood capillaries in the lung and the intestines. In PL the channels (lymphatics) that carry lymph fluid are not properly connected and become dilated with fluid (lymphangiectasia). This fluid makes the lungs less elastic, which this causes breathing difficulties Mostly PL presents with severe respiratory distress in the newborn period, although later onset forms of PL have been described in a number of cases. The mortality of neonatal PL was previously reported to be nearly 100%. However, most of these reports were published nearly 30 years ago and neonatal care has advanced significantly since that time. Several recent case reports and case studies indicate that infants are now surviving the severe neonatal form of PL and the outcome is good for infants who present after the neonatal period. This report describes the latest concepts on what may cause this condition, its clinical presentation, how to make a diagnosis of PL, what successful strategies have been used to treat PL, and the outcome of PL.
The overall incidence of pulmonary lymphangiectasia is unknown. Autopsy studies suggest that approximately 1% of infants who are stillborn or die in the neonatal period have pulmonary lymphangiectasia. Most case series have reported that more males than females are affected. In most cases, there is no familial pattern, and in some PL may occur together with a number of genetic syndromes including Noonan, Down, Turner, and Fryns, yellow nail syndrome and congenital icthyosis. Most of these syndromes are associated with generalized abnormalities of the lymphatic system.
Pulmonary lymphangiectasia is broadly divided into 2 categories: primary pulmonary lymphangiectasia where there is an intrinsic abnormality of the lymph channels, and secondary pulmonary lymphangiectasia, where the lymph channels are normal, but there is some downstream blockage to lymph flow.
PL can be subdivided into
generalized, pulmonary, and syndromic forms. The generalized form
vessel changes in many organ systems including the subcutaneous tissue,
intestine, and lung. The major symptoms include generalized
loss from intestinal
vessels. Hemihypertrophy (enlargement of one limb) is
common. Lung involvement in typically not severe, and survival in
pulmonary involvement is reported to be better than with the other
pulmonary lymphangiectasia. The primary pulmonary form of
includes those patients with disease confined to the lung. This form is
classic congenital pulmonary lymphangiectasia previously described as
very poor prognosis. In the syndromic form, PL is associated with
unrelated congenital anomalies including the genetic syndromes
The cause of primary PL is not known. There is some evidence that the lung lymphatics are not properly “programmed” as they are developing in the fetus, so that the lymph systems in different parts of the lungs are never connected to the large channels that drain the fluid away. In some cases, there is evidence that the lymphatics may be normal at birth, and that subsequent abnormalities may result from a lung infection.
Secondary PL includes those forms that are due to downstream blockage of the lymphatics (e.g. surgery, trauma, lung disease) or congestion of the pulmonary veins, (usually from abnormal pulmonary veins on an abnormal heart).
The clinical symptoms of pulmonary lymphangiectasia can present prenatally, at birth (neonatal) or after an asymptomatic period (post-neonatal). In the prenatal period, pulmonary lymphangiectasia can be a cause of swelling of the fetus (non-immune hydrops fetalis) and excess amniotic fluid (polyhydramnios), and fluid in the chest cavity (pleural effusions). Many infants are stillborn. The neonatal presentation manifests as respiratory distress at, or within a few hours of birth. Mechanical ventilation is often required. The post-neonatal presentation can occur after weeks or months of mild or absent respiratory symptoms. A few cases have presented for the first time in childhood or adolescence. Typical presenting symptoms include rapid breathing, and recurrent cough or wheeze. Examination of the patient usually reveals the presence of fine crackles throughout the lungs. Although pleural effusions are reported in up to 15% of patients. Pleural effusions typically contain lymph (cloudy) fluid, but may be clear, particularly if the newborn infant has not yet been fed.
Diagnosis of pulmonary lymphangiectasia can be difficult, as many of the respiratory symptoms and radiological (X-rays, CT scan etc) findings are non-specific. Chest X-rays are usually abnormal, reflecting fluid in the chest cavity or lung tissue in infants, and overexpansion of the lungs in older infants and children. Chest computerized tomography (CT) scans of patients with pulmonary lymphangiectasia show patchy areas of fluid and over inflation of the lungs. Magnetic resonance imaging (MRI) may be used in the future for making a diagnosis of PL, but is not yet of proven value.
In many patients an open lung biopsy is helpful to distinguish pulmonary lymphangiectasia from other forms of lung disease. Care must be taken with the pathologic evaluation of the biopsy as the changes of pulmonary lymphangiectasia can be mistaken for interstitial emphysema or overlooked. Although dilated pleural lymphatics present a theoretical risk of chylothorax at the time of lung biopsy (leakage of lymph fluid from the incision site), this complication has not been reported .
In experienced hands, the diagnosis of PL can, in many cases, be made through a combination clinical and radiological evaluation, but a lung biopsy may be the only way to make the diagnosis of PL, particularly if there is concern that there may be another specific diagnosis (e.g. another type of interstitial lung disease).
Lung function studies show varying patterns of obstructive and restrictive disease with no deterioration over time. In infancy, patients present with recurrent with bronchitis, often caused by easily treatable pathogens including Streptococcus pneumonia and Moraxella cattharalis.
While there are undoubtedly infants whose PL is so severe that they cannot be saved, it is likely that many of the infants reported to have died previously with uncomplicated PL would have survived with current practices of neonatal intensive care. The oldest reported survivors in recent case series are 12 to 13 years old and are predicted to live into adulthood. Most patients who survive the neonatal and early infancy period continue to have respiratory problems (recurrent cough, wheeze and pneumonia) in the first several years of life with increased rates of hospitalization. A few patients require home supplemental oxygen for a period of time. Overall, respiratory condition and X-ray abnormalities improve during infancy and childhood, with many patients having minimal symptoms by age six. Of note, no deaths have occurred in the recent reported cohorts of patients who survived infancy.
Many patients with pulmonary lymphangiectasia who survive beyond infancy have other medical problems common to patients with chronic lung disease. Gastroesophageal reflux is frequent, poor growth is also not uncommon in the first few years of life, although most patients resume normal growth patterns by age 3 years. Both reflux and poor growth may be secondary to the increased work of breathing typical of patients with pulmonary lymphangiectasia rather than any specific abnormality.
There is no specific treatment for PL. The main strategy is to support the patient by treating respiratory failure in the neonatal period and lung infections later on in the expectation that he condition will improve over time. Mechanical ventilation is often required in the neonatal form of PL, and specific strategies (e.g. pressure support with high mean airway pressures) have been successfully used as a strategy for neonatal respiratory failure. Some infants develop rapidly expanding pleural effusions that require placement of chest tube that may drain large volumes of fluid over days or weeks, but in most cases, this problem resolves over time. Other specific therapies including nutritional therapy with medium chain triglycerides and total parenteral nutrition have been successfully employed for treatment of chylothorax.
Pulmonary lymphangiectasia can occur as a result of an intrinsic developmental anomaly, or from postnatal obstruction of pulmonary lymphatic or venous drainage. The timing and severity of the initial presentation is variable. Advances in neonatal care have significantly improved the outcome in even the most severe cases. PL can be diagnosed with a combination of clinical assessment, radiological studies and lung biopsy. Treatment is essentially supportive. The long-term outcome of PL is uncertain, but current evidence suggests that for the majority of patients with either neonatal or post-neonatal presentations, there is gradual improvement of clinical status over time, particularly if there are no significant co-existing abnormalities.
1- Isolated Pulmonary: The developmental defect is isolated to the pulmonary lymphatics. Felt to be related to failure of regression of the pulmonary lymphatics after the 16th week of gestation. It results in severe interstitial lung disease and has a poor prognosis. Rarely children may live beyond the neonatal period.
2- Secondary to Pulmonary Venous Obstruction: This form is associated with congenital heart disease and accounts for 30% of cases. Cardiac abnormalities include: Hypoplastic left heart, total anomalous pulmonary venous return type III, and pulmonic vein atresia.
3- Generalized: (Systemic)- Characterized by lymphangiectasia throughout the body. The pulmonary manifestations are typically mild. Patients may have an associated lymphangioma
pulmonary lymphangiectasia (PL) is a rare developmental disorder
lung and characterized by pulmonary subpleural, interlobar,
peribronchial lymphatic dilatation. The prevalence is unknown. PL
birth with severe respiratory distress, tachypnea and cyanosis, with a
mortality rate at or within a few hours of birth. Most reported cases
sporadic and the etiology is not completely understood. It has been
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
cardiac lesion. The diagnostic approach includes obtaining a complete
obstetric history, conventional radiologic studies, ultrasound and
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
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
wheeze are often necessary during childhood, sometimes associated with
pleural drainage. Recent advances in intensive neonatal care have
previously nearly fatal outcome of PL at birth. Patients affected by PL
survive infancy, present medical problems which are characteristic of
lung disease. *Authors: Drs C. Bellini, F. Boccardo, C. Campisi, E.
(October 2006)*. Reproduced from Congenital
lymphangiectasia. Orphanet J Rare Dis. 2006;1(1):43.
Full length article
Division of Pulmonary and Critical Care Medicine and the Department of Pathology, Stanford University School of Medicine, Stanford, California; and the Department of Pathology, Mayo Clinic, Scottsdale, Arizona
Javett, I Webster and JL Braudo
904 Medical Centre Jeppe Street, Johannesburg, South Africa
The disease variously referred to as congenital dilatation of the pulmonary, lymphatics congenital pulmonary cystic lymphangiectasis, and congenital lymphangiomatosis of the lung is a rarity known almost exclusively to pediatric pathologists. Up to 1959, 21 cases had appeared in world literature, with only two reports in clinical journals. Congenital dilatation of the pulmonary lymphatics has been observed as a chance finding in fetuses dying in utero, stillborn infants, and neonates, without any mention being made as to its possible significance. The great majority of those born alive have suffered in the immediate neonatal period from an acute respiratory disease exhibiting dyspnea and cyanosis, death following within a few hours. As a consequence, the opportunity for clinical observation and investigation has been strictly limited. Confirmation has been possible only by autopsy. With virtually no clinical information to work on, the pathologists have centered interest almost entirely on the identification of lymphatics, the histopathology, and theories of causation without being in a position to offer correlation between histologic findings and symptoms. In the absence of any clinical build-up, too, it is not surprising that the disease has escaped the attention of most clinicians. We have had the opportunity of observing and investigating a patient with congenital dilatation of the pulmonary lymphatics, still alive, albeit not well, at the age of 8 months. It is the purpose of this paper to describe as a clinical entity a condition hitherto regarded as a pathological curiosity.
Depts of 1 Paediatrics (Division of Paediatric Pulmonology), 2 Radiology, and 3 Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Correspondence: P.M. Barker, Division of Paediatric Pulmonology, Dept of Paediatrics, 200 Mason Farm Road, CB 7220, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Fax: 1 9199666179. E-mail: Pierre_Barker@med.unc.edu
Keywords: Growth, pathology, radiology, spirometry
February 4, 2004
Accepted May 20, 2004
C.R. Esther Jr is supported by a Parker B. Francis Pulmonary Fellowship.
Primary pulmonary lymphangiectasia (PPL) is a rare disorder of unknown aetiology characterised by dilatation of the pulmonary lymphatics. PPL is widely reported to have a poor prognosis in the neonatal period and little is known about the clinical features of patients who survive the newborn period.
The current authors report the outcome in nine patients diagnosed in infancy with PPL over a 15-yr period at a single university-based hospital clinic and followed for a median of 6 yrs.
Although all of the patients initially experienced respiratory distress, respiratory symptoms improved in most patients after infancy and were notably better by the age of 6 yrs. Many patients had poor weight gain in the first years of life, which eventually improved. Radiological scans showed progressive resolution of neonatal infiltrates, but were characterised by hyperinflation and increased interstitial markings in older children. Most patients had evidence of bronchitis and grew pathogenic organisms from quantitative bronchoalveolar lavage culture. Pulmonary function tests showed predominantly obstructive disease that did not deteriorate over time.
In conclusion, these results suggest that primary pulmonary lymphangiectasia does not have as dismal a prognosis as previously described and symptoms and clinical findings improve after the first year of life.
A female infant born at 28 weeks' gestation was found to have mild hydrops foetalis. Initial echocardiography showed a structurally normal heart. During the first week of life, episodic atrial tachycardia with 1:1 or 2:1 conduction was seen, requiring therapy with digoxin. The infant remained ventilator dependent, with a persistent, chylous pleural effusion which contained a preponderance of lymphocytes. Congenital pulmonary lymphangiectasia (CPL) was confirmed histologically. Worsening episodes of atrial tachycardia, including episodes of atrial fibrillation, were further investigated and a repeat echocardiogram revealed thickening of the entire right atrial wall. The cardiac findings of a thickened right atrial wall with the histological signs of myocarditis were thought to be the cause of paroxysms of atrial fibrillation, an extremely rare arrhythmia in the neonatal period. To the authors' knowledge there have been no previous reports of CPL in association with the cardiac abnormalities described herein.
University Hospital of Leuven, Herestraat 49, 3000, Leuven, Belgium, email@example.com.
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.
External Links and Resources
TAPVR, ASD, Pulmonary Lymphangiectasia
Ackowledgement: Congenital Heart Information Network
National Congenital Pulmonary Lymphangiectasia Foundation
National network. Founded 1995.Provides support and information for families and friends of persons with congenital pulmonary lymphangiectasia. Funds research projects. Information and referrals, phone support, pen pals, literature.
Nat'l CPL Fdn.
1202 S. Columbia Ave.
Somerset, PA 15501-9387
Paediapaedia: Neonatal Chest Diseases
Michael P. D'Alessandro, M.D.
Congenital Pulmonary Lymphangiectasia
New England Journal of Medicine
intestinal and thoracic lymphangiectasia: a response to antiplasmin
Congenital Pulmonary Lymphangiectasia
CONGENITAL PULMONARY LYMPHANGIECTASIA ASSOCIATED WITH CONGENITAL HEART DISEASE.
Chest, Oct, 2000, by JT Tuladhar, SA Storgion, MC Bugnitz, G Stidham, O Lasater
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ICD-9 - 748.9 (Unspecified anomalies of respiratory system)
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