Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Friday, February 24, 2006

Fresh theory on cause of Crohn's Disease

Friday, 24 February 2006, 00:11 GMT

A weakened immune system - not an over-active one as had been suspected - may cause the intestinal disorder Crohn's disease, research suggests.

However, work by University College London (UCL) suggests Crohn's is more likely to be due to a weakened immune system failing to destroy bacteria.

The Lancet study also suggests the anti-impotence drug Viagra may help to treat the disorder.
Viagra was found to correct low blood flow among Crohn's sufferers.

Crohn's disease is a chronic inflammatory disorder that causes ulcerations in the small and large intestines.

The UCL team compared the immune system response of Crohn's patients and healthy individuals to minor injuries, such as skin abrasions.

They found the Crohn's patients produced much lower numbers of infection-fighting white blood cells called neutrophils, and lower quantities of chemicals involved in the inflammatory process.

Blood cells taken from Crohn's patients also turned out to be abnormal when cultured in the laboratory.

E. coli infection

The UCL team also tested Crohn's patients' response to bacteria by injecting a harmless form of E. coli under their skin.

This resulted in a huge increase in blood flow to the inflamed area in healthy volunteers - but a much smaller increase in the Crohn's patients.

The researchers found this abnormally low blood flow could be corrected by treatment with Viagra.

The researchers believe that, because Crohn's patients have weakened immune systems, they are unable to destroy bacteria that penetrate the intestinal wall.

Thus the bacteria are left to build up in the tissue, stimulating the secretion of inflammatory chemicals that trigger the symptoms of Crohn's.

Dr Alistair Forbes, medical director of the gut disorder organisation Core, told the BBC News website the work was "very exciting" and consistent with other pieces of work which suggested Crohn's was linked to a weak immune response.


Dr Forbes said Crohn's patients had been reported to benefit from a treatment usually given to cancer patients to stimulate the production of white blood cells.

If Crohn's were an auto-immune disease then one would expect this treatment to make patients worse, rather than better.

In addition, a mutation of a gene linked to Crohn's was thought to weaken, rather than intensify the immune response.

He said: "The cause of Crohn's remains unknown, and although there are genetic factors, it is quite clear they don't explain the whole thing.

"Crohn's is clearly related to the bacterial flora in the gut, but how is not clear at all.

"There are several pieces of information that suggest Crohn's is linked to an abnormality of the immune response, rather than an excessive one in the first instance."

BBC Health News

Tuesday, February 21, 2006

Gorham-stout syndrome: a monocyte-mediated cytokine propelled disease.

February 2006

Colucci S, Taraboletti G, Primo L, Viale A, Roca C, Valdembri D, Geuna M, Pagano M, Grano M, Pogrel AM, Harris AL, Athanasou NN, Mantovani A, Zallone A, Bussolino F.

Istituto di Anatomia Umana Normale, Universita di Bari, Bari, Italy.

We studied the biological features and the immunophenotype of a cell culture established from the lesion of soft tissues of a woman affected by Gorham-Stout syndrome. We found that these cells belonged to a monocytic lineage with some characteristics of immature osteoclasts and were able to release large amounts of osteoclastogenic and angiogenic molecules that may contribute to disease progression.

INTRODUCTION: Gorham-Stout syndrome is a rare disease characterized by osteolysis and proliferation of vascular or lymphatic vessels, with a severe outcome. Its etiology and the identification of the cell types involved are completely unknown.

MATERIALS AND METHODS: A cell culture from a lesion of soft tissues was established, and its behavior in vitro and in immunodeficient mice was studied. We analyzed (1) the cell phenotype by flow cytometry; (2) the adhesive and migratory properties on different substrates; (3) the ability to differentiate into mature osteoclasts; (4) the production of osteclastogenic and angiogenic molecules; (5) the in vivo angiogenic activity of the cells subcutaneously implanted in mouse in a Matrigel plug; and (6) the ability to recapitulate the disease when transplanted in nude mice.

RESULTS AND CONCLUSIONS: The established culture consisted of a morphologically homogeneous cell population belonging to a monocytic lineage having some features of an osteoclast-like cell type. Cells had an invasive phenotype, were angiogenic, and produced osteoclastogenic (IL-6, TGF-beta1, IL-1beta) and angiogenic (vascular endothelial growth factor-A [VEGF-A], CXCL-8) molecules when challenged with inflammatory cytokines. Immunodeficient mice injected with these cells did not show any bone lesions or vascular alteration, but had high amounts of circulating human IL-6 and VEGF-A. Cells isolated from a cutaneous lymphangiomatosis did not show any of these findings. These data suggest that cells of monocyte-macrophage lineage play an essential role in the pathogenesis of Gorham-Stout disease, whose progression is propelled by cytokine circuits that accelerate angiogenesis and osteoclastogenesis.PMID: 16418776

[PubMed - in process]


Heterogenicity of Gorham-Stout syndrome: association with lymphatic and venous malformations

Somoza Argibay I, Diaz Gonzalez M, Martinez Martinez L, Ros Mar Z, Lopez-Gutierrez JC.Unidad de Cirugia Plastica Infantil. Servicio de Cirugia Pediatrica. Hospital Materno Infantil La Paz. Madrid. Espana.

INTRODUCTION: Gorham-Stout syndrome is a rare disorder of unknown etiology characterized by osteolysis and microscopic proliferation of abnormal vessels. We report two cases of this syndrome associated with lymphatic and venous malformations.

CASE REPORTS: The first case is a 5-year-old boy with disseminated lymphangiomatosis of poor prognosis, with significant pleural involvement and osteolytic lesions. The second case is a 5-year-old girl with a diagnosis of Klippel-Trenaunay syndrome with significant skeletal involvement of the lower extremities and secondary pathological fracture.

CONCLUSIONS: Gorham-Stout syndrome may occasionally be associated with various lymphatic and venous malformations. Osteolysis and bone resorption may be induced by lymphatic bone involvement.

Publication Types:
Case ReportsPMID: 12781118

[PubMed - indexed for MEDLINE]

Full Clinical Study in Original Spanish

Saturday, February 18, 2006

A Case of Gorham’s Disease with Chylothorax Treated Curatively with Radiation Therapy

Clin Med Res. 2005 May; 3(2): 83–86.

Clinical Medicine & Research

Bethany M. Duffy, BA, Rafael Manon, MD, Rakesh R. Patel, MD, and James S. Welsh, MD
Bethany M. Duffy, BA, University of Wisconsin Medical School, Madison, WI 53792.
Rafael Manon, MD and Rakesh R. Patel, MD, Department of Human Oncology, University of Wisconsin, Madison, WI 53792

James S. Welsh, MD, Department of Human Oncology, University of Wisconsin, Madison, WI 53792, and University of Wisconsin Cancer Center, 410 Dewey Street, Wisconsin Rapids, WI 54494

Reprint Requests: James S.Welsh, MD, University of Wisconsin Cancer Center, 410 Dewey Street, Wisconsin Rapids, WI 54494, Tel: 715-421-7442, Fax: 715-421-7408, Email:

Received February 10, 2005; Revised March 23, 2005; Accepted March 25, 2005.


Gorham’s disease, also known as vanishing bone disease or massive osteolysis, is a rare disorder of uncertain etiology. It is characterized by uncontrolled proliferation of vascular or lymphatic capillaries within bone, leading to resorption and replacement with angiomatous tissue. It can be complicated by chylous pericardial and pleural effusions, which can be life threatening. Patients are also at risk of mortality or serious morbidity due to bone destruction, especially when the disease involves the spine. We report the case of a 31-year-old female with Gorham’s disease involving several bones along with chylous pericardial and pleural effusions. She was effectively treated with definitive radiation therapy.

Keywords: Essential osteolysis, Chylothorax, Radiotherapy, Bone diseases, Bone resorption, Biopsy

Gorham’s disease, also known as vanishing bone disease and massive osteolysis is a very rare disorder of unknown etiology characterized by uncontrolled proliferation of vascular or lymphatic capillaries within bone.1 As the endothelial cells proliferate, they aggressively yet painlessly invade the adjacent bone, leading to resorption and replacement with angiomatous tissue. Surrounding soft tissues such as muscle, connective tissue, and viscera may also be affected. Chylous pleural and pericardial effusions can complicate the disease and lead to death in severe cases. In this report, we describe a case of Gorham’s disease involving the ribs, scapula, and thoracic spine, which resulted in chylous pericardial and pleural effusions. The patient was treated curatively with radiation therapy.

Case Report

A female, 31 years of age, presented with a 2-month history of exercise-induced dyspnea. Spirometry was characteristic of reactive airway obstruction, and therefore she was treated for a presumed diagnosis of asthma. Two weeks later she was hospitalized with pleural and pericardial effusions and signs of right ventricular impingement on echocardiogram. The pericardial effusion was drained, yielding 1.5 liters of chocolate-colored fluid consistent with hemo-chylopericardium. Cytology of this fluid identified reactive mesothelial cells and lymphocytes, but was negative for malignancy. Analysis of the pleural effusion revealed the same findings. Chest computed tomography (CT) revealed an anterior soft tissue mass and diffuse osteolysis of the right scapula, multiple thoracic and lumbar vertebral bodies, and multiple ribs on the right side. Hodgkin’s lymphoma or another metastatic neoplastic process was suspected. However, subsequent biopsy of the mediastinal mass revealed normal thymic tissue with no evidence of malignancy.

Six days after hospitalization the patient underwent an urgent pericardial window procedure to definitively drain the effusion. No abnormal pathology of the pericardium or removed xiphoid process was found. The chylothorax was initially managed with bilateral chest tube drainage and two attempts at talc pleurodesis, which failed to resolve the effusion.

Approximately 3 weeks into her hospitalization, the patient underwent biopsy of the clinically involved right 3rd and 4th ribs, which identified lymphangiomatosis and confirmed the suspected diagnosis of Gorham’s disease. Because the patient’s chylothorax persisted, thoracic duct ligation was considered. However, she was felt to be a poor surgical candidate due to extensive lymphatic collateralization and the absence of an obvious source of chylous leakage. She was referred to radiation oncology for primary treatment of her Gorham’s disease. She was treated with 15 Gy of 10 MV photons in 10 fractions over a 13-day period to the superior, middle, and inferior mediastinum. After receiving this initial low dose of radiation, the patient’s respiratory status improved significantly with no apparent toxicity. A follow-up CT scan 2 weeks later confirmed a significant decrease in the amount of thoracic lymphangiomatosis. Because prior published reports described successful outcomes in patients with Gorham’s disease using higher radiation doses, an additional 18 Gy in 10 fractions were delivered to the mediastinum and lower neck, bringing the total mediastinal dose to 33 Gy.

Shortly after completion of radiation therapy, the patient developed radiation pneumonitis, which was successfully controlled with steroids. While her pleural effusions never resolved completely, a gradual decline over the following months was observed, improving her respiratory function such that she was eventually able to resume a regular exercise regimen. Sequential CT scans and bone scans confirmed stabilization of her bony disease. Twenty months after completion of her radiation, the patient developed increased pleural effusions with worsening respiratory symptoms. This was treated with a second course of steroid therapy and antibiotics, which quickly resolved her symptoms. Now nearly 3 years since completion of her radiotherapy, the patient is doing remarkably well with no evidence of disease activity.


Gorham’s disease is a very rare disorder characterized by uncontrolled, destructive proliferation of vascular or lymphatic capillaries within bone and surrounding soft tissue.1 Most cases occur in children and young adults with no clear inheritance pattern or gender bias, although some authors have found males to be affected more often.2 , 3 Manifestations of Gorham’s disease vary depending on the affected site making clinical diagnosis of this uncommon disease difficult. Generally, laboratory studies are within normal limits, but radiographic and histopathologic findings are distinct and helpful in making the diagnosis.
Radiographically, Gorham’s disease progresses through four stages.
4 The disease initially presents as radiolucent foci resembling patchy osteoporosis. Next, bony deformity increases with further loss of bone mass. The cortex is then disrupted with endothelial invasion into adjacent soft tissues and/or across joints. Finally, there is shrinkage of the ends of affected bones producing a “sucked candy” appearance. Pathological fracture may develop at any stage, and bony regeneration is rarely seen. The diagnosis of Gorham’s disease must be confirmed by identifying vascular or lymphatic proliferation in early stages or fibrous tissue in late stages with a generous biopsy of the affected bone.1 , 5

The natural history of Gorham’s disease is unpredictable with spontaneous regression being known to occur.3 , 6 However, in many patients the disease is relentlessly progressive and involvement of vital structures may be fatal. Several therapeutic modalities have been utilized, including radiotherapy,79 surgical resection,7 , 1012 bone grafting,13 sympathectomy,14 and α-interferon.15 Recently, most patients have been treated with surgery and/or radiation therapy.

While Gorham’s disease has been reported throughout the body, commonly involved sites include the mandible (15%), ribs (12%), scapula (10%), humerus (8%), pelvis (10%), and femur (11%).
3 Disease of the ribs, scapula, or thoracic vertebrae leads approximately 17% of patients to develop chylothorax from direct extension of lymphangiectasia into the pleural cavity or invasion of the thoracic duct.16 This can have serious consequences, including hypoproteinemia, malnutrition, and immunosuppression with lymphocytopenia.16 , 17 Without surgical intervention, patients with Gorham’s disease who develop chylothorax have a mortality rate of approximately 64%. Tie and colleagues16 recently reported some success using thoracic duct ligation to treat chylothorax in Gorham’s disease patients. Of the eleven cases they reviewed, seven patients underwent successful thoracic duct ligation and survived, while four patients died following failed attempts to localize the thoracic duct during surgery. This intervention thus improved the survival rate from 36% to 64%.

However, thoracic duct ligation does not always produce lasting resolution of chylothorax
3 , 17 and not all patients are good candidates for the procedure. Our patient, for example, was determined to be a poor candidate due to extensive lymphatic collateralization with no clear source of chylous leakage. Other treatment modalities used in Gorham’s disease patients with chylothorax have included pleurodesis,10 , 1820 pleurectomy,21 , 22 α-interferon,15 and radiation therapy.8 , 9 , 20

For patients with Gorham’s disease with or without chylothorax, radiation therapy has been used with mixed success.
2 , 8 , 9 , 11 , 20 , 2326 Using escalating doses of radiation to treat Gorham’s disease assists in the eradication of increasing numbers of radiosensitive proliferating endothelial cells.26 Once an adequate dose has been reached, clones derived from remaining viable cells are spaced too irregularly to form an occlusive vessel. Moderate doses of 25–45 Gy have been reported as effective.7 , 24 After reviewing the 22 published cases of Gorham’s disease treated with radiotherapy prior to 1993, Dunbar and colleagues7 concluded that doses of 40–45 Gy at 1.8 Gy to 2 Gy per fraction produce a good outcome in a high proportion of patients with minimal long-term complications. Radiation therapy was successful in 14 of the 22 patients (64%) described in their review.

Prior to 1994, there were no reported cases of Gorham’s syndrome with chylothorax treated effectively with radiation.
16 In 1996, McNeil and colleagues8 reported a case treated with 40 Gy in 20 fractions, resulting in resolution of the chylothorax and arrest of bony destruction over 4 years of follow-up. In 2003, Fontanesi9 reported another case treated with 40 Gy in 20 fractions, which also achieved a curative result at 6 months of follow-up. Our patient received 33 Gy in 28 fractions and is currently without evidence of disease activity at nearly 3 years since completion of therapy.

There are several potential advantages of using radiation to treat Gorham’s disease. Early use of radiation therapy may arrest endothelial cell proliferation, and thereby limit the spread of disease and allow the patient to avoid relatively complicated surgery with its inherent risks.
7 , 26 Radiation therapy may also be used successfully in patients who are poor surgical candidates, such as the patient presented in this report, and patients who have failed surgical treatments. Finally, there have been reports of recalcification of affected bone following radiation therapy, a phenomenon that is exceedingly rare with other treatment modalities. A literature review conducted by Choma et al.3 in 1987 identified 18 cases of Gorham’s disease treated with radiotherapy, 11 of whom showed arrest or improvement of their disease and 5 with demonstrated regrowth of bone. One other patient in their review regenerated bone after treatment with splinting alone. Recently, an additional report of recalcification after radiation therapy was published.27

The major disadvantage to using radiation therapy for Gorham’s disease is the possibility for acute and long-term side effects that vary by treatment site. Our patient developed radiation pneumonitis that required treatment with steroids. While severe radiation-induced side effects are rare, the potential for secondary malignancy and growth restriction should be considered before administering high-dose radiation therapy to children, who represent a significant proportion of Gorham’s disease patients.

In conclusion, because spontaneous resolution has been described in Gorham’s disease, it is difficult to prove conclusively that any treatment modality has been curative in a given patient. However, radiation therapy has been documented to produce temporary or long-lasting arrest of osteolysis and symptomatic relief in numerous case reports over the years. In patients with chylothorax secondary to Gorham’s disease, radiation can be used as primary therapy or with thoracic duct ligation to halt the progression of osteolysis and provide the potential for regrowth of bone.


Gorham WL, Stout AP. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone): its relation to hemangiomatosis. J Bone Joint Surg 1955;37A:985–1004.

Heffez L, Doku HC, Carter BL, Feeney JE. Perspectives on massive osteolysis. Report of a case and review of the literature. Oral Surg Oral Med Oral Pathol 1983;55:331–343.

Choma ND, Biscotti CV, Bauer TW, Mehta AC, Licata AA. Gorham’s syndrome: a case report and review of the literature. Am J Med 1987;83:1151–1156.

Torg JS, Steel HH. Sequential roentgenographic changes occurring in massive osteolysis. J Bone Joint Surg Am 1969;51:1649–1655.

Ross JL, Schinella R, Shenkman L. Massive osteolysis. An unusual cause of bone destruction. Am J Med 1978;65:367–372
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Campbell J, Almond HG, Johnson R. Massive osteolysis of the humerus with spontaneous recovery. J Bone Joint Surg Br 1975;57:238–240.
PubMed] [Free Full Text].

Dunbar SF, Rosenberg A, Mankin H, Rosenthal D, Suit HD. Gorham’s massive osteolysis: the role of radiation therapy and a review of the literature. Int J Radiat Oncol Biol Phys 1993;26:491–497.

McNeil KD, Fong KM, Walker QJ, Jessup P, Zimmerman PV. Gorham’s syndrome: a usually fatal cause of pleural effusion treated successfully with radiotherapy. Thorax 1996;51:1275–1276.

Fontanesi J. Radiation therapy in the treatment of Gorham disease. J Pediatr Hematol Oncol 2003;25:816–817.
PubMed] [Full Text].

Feigl D, Seidel L, Marmor A. Gorham’s disease of the clavicle with bilateral pleural effusions. Chest 1981;79:242–244
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Gutierrez RM, Spjut HJ. Skeletal angiomatosis: report of three cases and review of the literature. Clin Orthop Relat Res 1972;85:82–97
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Turra S, Gigante C, Scapinelli R. A 20-year follow-up study of a case of surgically treated massive osteolysis. Clin Orthop Relat Res 1990;(250):297–302
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Woodward HR, Chan DP, Lee J. Massive osteolysis of the cervical spine. A case report of bone graft failure. Spine 1981;6:545–549.

King DJ. A case resembling hemangiomatosis of the lower extremity. J Bone Joint Surg 1946;28:623–628.

Hagberg H, Lamberg K, Astrom G. Alpha-2b interferon and oral clodronate for Gorham’s disease. Lancet 1997;350:1822–1823.

Tie ML, Poland GA, Rosenow EC 3rd. Chylothorax in Gorham’s syndrome. A common complication of a rare disease. Chest 1994;105:208–213.

Fujiu K, Kanno R, Suzuki H, Nakamura N, Gotoh M. Chylothorax associated with massive osteolysis (Gorham’s syndrome). Ann Thorac Surg 2002;73:1956–1957.

Patrick JH. Massive osteolysis complicated by chylothorax successfully treated by pleurodesis. J Bone Joint Surg Br 1976;58:347–349.
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Lee WS, Kim SH, Kim I, Kim HK, Lee KS, Lee SY, Heo DS, Jang BS, Bang YJ, Kim NK. Chylothorax in Gorham’s disease. J Korean Med Sci 2002;17:826–829.

Pedicelli G, Mattia P, Zorzoli AA, Sorrone A, De Martino F, Sciotto V. Gorham syndrome. JAMA 1984;252:1449–1451.

Miller GG. Treatment of chylothorax in Gorham’s disease: a case report and literature review. Can J Surg 2002;45:381–382.

Ricalde P, Ord RA, Sun CC. Vanishing bone disease in a five year old: report of a case and review of the literature. Int J Oral Maxillofac Surg 2003;32:222–226.
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Heyden G, Kindblom LG, Nielsen JM. Disappearing bone disease. A clinical and histological study. J Bone Joint Surgery Am 1977;59:57–61.

Lee S, Finn L, Sze RW, Perkins JA, Sie KC. Gorham Stout syndrome (disappearing bone disease): two additional case reports and a review of the literature. Arch Otolaryngol Head Neck Surg 2003;129:1340–1343.
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Handl-Zeller L, Hohenberg G. Radiotherapy of Morbus Gorham-Stout: the biological value of low irradiation dose. Br J Radiol 1990;63:206–208.

Mawk JR, Obukhov SK, Nichols WD, Wynne TD, Odell JM, Urman SM. Successful conservative management of Gorham disease of the skull base and cervical spine. Childs Nerv Syst 1997;13:622–625.
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Sunday, February 12, 2006

VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain.

Here is an interesting little side bar on the VEGF-C gene. This gene has long been identified with the development of the lymphatics. However, cutting edge research also has found a tie-in to the central nervous system.

The abstract:

From Nature Neuroscience

Feb 5, 2006

Le Bras B, Barallobre MJ, Homman-Ludiye J, Ny A, Wyns S, Tammela T, Haiko P, Karkkainen MJ, Yuan L, Muriel MP, Chatzopoulou E, Breant C, Zalc B, Carmeliet P, Alitalo K, Eichmann A, Thomas JL.

[1] Institut National de la Sante et de la Recherche Medicale (INSERM), U711, Paris F-75013, France.

[2] Universite Pierre & Marie Curie, Faculte de Medecine Pitie Salpetriere, IFR 70, Paris F-75005, France.

[3] These authors contributed equally to this work.

Vascular endothelial growth factor C (VEGF-C) was first identified as a regulator of the vascular system, where it is required for the development of lymphatic vessels. Here we report actions of VEGF-C in the central nervous system. We detected the expression of the VEGF-C receptor VEGFR-3 in neural progenitor cells in Xenopus laevis and mouse embryos. In Xenopus tadpole VEGF-C knockdowns and in mice lacking Vegfc, the proliferation of neural progenitors expressing VEGFR-3 was severely reduced, in the absence of intracerebral blood vessel defects. In addition, Vegfc-deficient mouse embryos showed a selective loss of oligodendrocyte precursor cells (OPCs) in the embryonic optic nerve. In vitro, VEGF-C stimulated the proliferation of OPCs expressing VEGFR-3 and nestin-positive ventricular neural cells. VEGF-C thus has a new, evolutionary conserved function as a growth factor selectively required by neural progenitor cells expressing its receptor VEGFR-3.PMID: 16462734 [PubMed - as supplied by publisher]

Saturday, February 04, 2006

Pulmonary Cystic Lymphangiectasis

Alternative titles; symbols


Frank and Piper (1959) described 2 affected infants who were not related. One was stillborn and the other lived only about 2 hours. In 1 case there were similar lesions in the heart, pancreas, kidneys, and mesentery. Scott-Emuakpor et al. (1981) described the disorder in 2 sisters who showed acute respiratory distress soon after birth and died in the neonatal period. Changes at autopsy were limited to the lungs.

Moerman et al. (1993) reported on 7 perinatal autopsy cases of primary congenital pulmonary lymphangiectasis (CPL) with bilateral chylothorax. They demonstrated that primary CPL is often complicated by chylous pleural effusions with ensuing pulmonary hypoplasia. Conversely, CPL appears to be a constant pathologic finding in spontaneous congenital chylothorax. These observations indicated a common pathogenesis for the 2 disorders. The basic defect is not an intrinsic lung abnormality, but a developmental error of the lymphatic system resulting in a pulmonary lymphatic obstruction sequence.

Moerman et al. (1993) concluded that the cause of CPL is heterogeneous. Most cases are apparently sporadic occurrences. They reported the second instance of CPL in sibs. Thus, some cases are genetically determined with autosomal recessive inheritance. CPL may also be part of a multiple congenital anomalies (MCA) syndrome, such as Noonan syndrome (163950), Turner syndrome, and Down syndrome.

Njolstad et al. (1998) reported the cases of 3 sibs with nonimmune hydrops fetalis (236750); 2 of them had congenital pulmonary lymphangiectasia.


1. Frank, J.; Piper, P. G. :
Congenital pulmonary cystic lymphangiectasis. J.A.M.A. 171: 1094-1098, 1959.PubMed ID :
2. Moerman, P.; Vandenberghe, K.; Devlieger, H.; Van Hole, C.; Fryns, J.-P.; Lauweryns, J. M. :
Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am. J. Med. Genet. 47: 54-58, 1993.PubMed ID :
3. Njolstad, P. R.; Reigstad, H.; Westby, J.; Espeland, A. :
Familial non-immune hydrops fetalis and congenital pulmonary lymphangiectasia. Europ. J. Pediat. 157: 498-501, 1998.PubMed ID :
4. Scott-Emuakpor, A. B.; Warren, S. T.; Kapur, S.; Quiachon, E. B.; Higgins, J. V. :
Familial occurrence of congenital pulmonary lymphangiectasis: genetic implications. Am. J. Dis. Child. 135: 532-534, 1981.PubMed ID :


Victor A. McKusick - updated : 2/20/1999Victor A. McKusick - updated : 8/21/1998


Victor A. McKusick : 6/4/1986


carol : 2/23/1999terry : 2/20/1999terry : 8/21/1998mimadm : 3/12/1994supermim : 3/17/1992supermim : 3/20/1990ddp : 10/27/1989marie : 3/25/1988reenie : 6/4/1986
Copyright © 1966-2004
Johns Hopkins University


Pulmonary cystic lymphangiectasis

Clinical Signs:

abnormal pleura/hydrothorax (Very frequent sign) autosomal recessive inheritance (Very frequent sign) respiratory distress (Very frequent sign) stillbirth/neonatal death (Very frequent sign) liver enlargement (excl. storage dis.) (Occasional sign) lymphoedema/oedema (Occasional sign) splenomegaly (Occasional sign)

Outpatient clinic(s)

Dysmorphology clinic

Genetic counselling clinic

Any outpatient pneumology clinic



Congenital pulmonary lymphangiectasis.

Report of four cases (author's transl)

Fidalgo I, Ortega F, Alustiza J, Pastor E, Cabrera A.

Four cases of congenital pulmonary lymphangiectasis were observed during a five year period. This represents an incidence of 1.11 per 10,000 cases among alive newborns and of 53 per 10,000 cases among pediatric necropsias performed during the same period. One case was observed in the clinical context of a generalized hemangiolymphangiomatosis, another was associated to tetralogy of Fallot and the remaining two cases were associated to obstruction of pulmonary venous return. Although one of the pathogenic theories generally accepted in the formation of pulmonary lymphangiectasis points to the presence of either hypertension or obstruction of pulmonary venous drainage, it is possible that such situation is only circumstantial. Among 40 personal cases of obstruction of pulmonary venous return proved anatomically, only in the two cases presented were pulmonary lymphangiectasis demonstrated.

The presence of dysplastic elements in pulmonary tissue in cases of lymphangiectasis suggests that a more possible mechanism is a primary defect in the development of pulmonary lymphatics.

Publication Types:
Case Reports
PMID: 7224372

[PubMed - indexed for MEDLINE]


Congenital pulmonary lymphangiectasis

Wockel W, Dietrich M.3 cases of congenital pulmonary lymphangiectasis are described. A girl, now 3 years old, underwent at the age of 4 weeks a resection of the left superior lobe of the lung which was singularly involved. A male newborn died 4 h after birth and showed the typical affection of both lungs. A second male infant died 19 d after birth and had an isolated involvement of the left lung. Post-mortem examination additionally revealed in both boys a cardiovascular malformation. Histologically, we especially observed a papillar endothelial hyperplasia in a dilated lymph vessel in case 1 and multinuclear giant cells of the foreign-body type in case 3. In the literature, there are reported 99 cases of congenital pulmonary lymphangiectasis. Including our case, a unilobar or unilateral involvement is described in only 8 cases.

The congenital pulmonary lymphangiectasis occurs more often in males than in females (1.8 : 1). 90 out of 93 life-born children suffering from this malformation died, 57 of them during the perinatal period. However, cardiovascular malformations, which were observed in 53 cases, are playing an important role as the cause of death. The aetiology of the congenital pulmonary lymphangiectasis remains unknown. There are 4 different theories concerning the pathogenesis, namely, a persistence of early-fetal lymphatic vessels, a missing connection between primitive lymphatic vessels, a hyperplasia of lymphatic ducts and, last but not least, a passive dilatation of the lymph vessels because of venous or lymphatic congestion.

Publication Types:

Case Reports

PMID: 6485606

[PubMed - indexed for MEDLINE]


Unusual diffuse pulmonary lymphatic proliferation in a young boy

Chest, August, 1991 by John M. Kelso, Daniel J. Kerr, J.T. Lie, Martin I. Sachs, Edward J. O'Connell

Several rare disorders may affect the pulmonary lymphatic vessels of children,including lymphangioma, lymphatic dysplasia, and congenital pulmonary lymphangiectasis. An additional disorder of pulmonary lymphatics, lymphangiomyomatosis, has been reported only in women of childbearing age. We report the case of a 4-year-old boy who died of a pulmonary lymphatic disorder, the clinical and pathologic characteristics of which seem to share features with several of these disorders.


A 3-year-old boy with an uncomplicated perinatal course was reported by his mother to have had a "rattle in the chest" since birth. Pneumonia was diagnosed at age 8 months and treated with antibiotics given orally. At age 18 months, frequent coughing and wheezing episodes developed and asthma was diagnosed. He was treated with bronchodilators and occasionally with prednisone, which produced significant improvement. A second case of penumonia was diagnosed at age 36 months and again treated with antibiotics given orally. Three months later, the patient had increasing cough, and a chest roentgenogram revealed an enlarged cardiac shadow, bilateral pleural effusions, and interstitial densities (Fig 1). An echocardiogram demonstrated pericardial effusion but normal cardiac anatomy.

He underwent pericardiocentesis; however, the pericardial effusion reaccumulated and thoracotomy was performed. A large mediastinal mass was identified and resected and pericardiectomy was performed. The tissue from the pericardium and mediastinum aggregated to 6.5x5.5x1.3 cm. This tissue was characterizied histologically by adipose and fibrous tissue of varying density, containing multiple poorly delimited spindle cell aggregates arranged asymmetrically around ectatic lymphatic channels and blood vessels. The nuclei were cytologically bland, and mitoses were rare. Occasional lymphoid follicles and a moderate number of hemosiderin-laden macrophages were scattered throughout the tissues. A biopsy specimen from the pulmonary trunk demonstrated an identical lesion of spindle cells and ectatic lymphatic channels. A normal 6-g thymus was removed.

Postoperatively, he continued to have bilateral pleural effusions and pulmonary infiltrates, and a second thoractomy was performed for lung biopsy and pleurodesis. Histologic study of the lung biopsy specimen demonstrated poorly demarcated spindle cell aggregates subpleurally, along interlobular septa, focally within alveolar walls, adjacent to pulmonary blood vessels, and adjacent to bronchioles distally to the level of respiratory bronchioles. The lesions were associated with ectatic lymphatic channels at all sites. A small amount of hemosiderin deposition was present in the pulmonary interstitium and in intra-alveolar histiocytes, although the interventing pulmonary parenchyma was normal (Fig 2). He was treated with a low-fat diet and diuretics with a subsequent decrease in pleural effusion but persistence of pulmonary infiltrates. He continued to have significant respiratory distress and wheezing. His airway obstruction was partially reversible, and he was treated with bronchodilators and diuretics.

At age 3 years 5 months, hemoptysis developed. Treatment with prednisone decreased the frequency and severity of the hemoptysis. Several attempts to taper the prednisone dose resulted in increased hemoptysis. At age 4 years 6 months, he continued to have daily hemoptysis and required daily prednisone. Therefore, he was treated with interferon alfa in an attempt to control the lymphatic proliferation in the lungs. He subsequently had a marked decrease in hemoptysis. However, this treatment was discontinued after 3 1/2 weeks because his platelet count had decreased to 53x[10.sup.9]/L. One month later, his platelet count had recovered to 94x[10.sup.9]/L.

At age 4 years 9 months, massive hemoptysis developed that was uncontrollable and he died. At autopsy, blood was found in the nasopharynx, trachea, and bronchi from terminal pulmonary hemorrhage. The pleural sacs and mediastinum were extensively encased by dense fibrious adhesions. Histologically, poorly demarcated spindle cell aggregates were arranged asymmetrically around ectatic lymphatic spaces in the lung adjacent to bronchioles and blood vessels, within interlobular septa, covered the surface of the lungs, permeated the mediastinum, and were confined to the thoracic cavity (Fig 3).

The spindle cells resembled vascular smooth muscle, exhibiting elongated, blunt-ended nuclei and a pattern of staining with Masson's trichrome stain consistent with smooth muscle. Immunohistochemical studies with anti-desmin and anti-actin on formadehyde solution-fixed, paraffin-embedded tissue obtained at autopsy were noncontributory, however, because both appropirate internal controls and the spindle cells failed to stain. The thoracic duct could not be identified. Thus, the pulmonary distribution and histologic features had remained unchanged, although the lesions had increased in size since the pericardiectomy and lung biopsy. The amount of hemosiderin deposited in the pulmonary intersititium and number of intra-alveolar histiocytes had increased, and acute intrapulmonary hemorrhage was also present. The heart and all extrathoracic viscera were grossly and histologically normal.


This case emphasizes the complex nature of disorders of lymphatics that may manifest as lymphangiomas (tumors of lymphatic vessels), lymphangiectasis (dilation of lymphatic vessels), or lymphangiomyomatosis (proliferation of lymphatic smooth muscle). When these manifestations occur together, the distinction between them is often arbitrary. Distinction between lymphangioma and hemangioma may also be difficult. Lymphatic disorders may occur secondary to congenital maldevelopment of, or an acquired blockage in, the lymphatic system.

These conditions often lead to abnormal collections of chyle outside the lymphatic system, such as chylothorax.

Review of the literature [1-12] reveals several categories of rare lymphatic disorders that can affect the lungs and that can present in childhood. The first category is lymphangioma. This tumor may occur in the neck (cystic hygroma), axilla, subcutaneous tissue, liver, spleen, bone, lung, pleura, or mediastinum. These lesions may be isolated or may occur in association with other lymphatic dysplasia and freqeuntly result in the leakage of chyle. A recent review [1] of intrathoracic lymphangiomas did not describe pulmonary parenchymal involvement. However, there are rare reports [2-4] of pulmonary lymphangiomas confined to one or two lobes. When multiple lymphangiomas are present, the condition is termed lymphangiomatosis. Such multiple lesions almost always involve bone in which they may cause pathologic fractures or "disappearing bones." Lymphangiomatosis often causes chylothorax, frequently from a mediastinal lymphangioma, but to our knowledge, pulmonary parenchymal involvement has been described in only one such case. [5]

The second category of lymphatic disorders is lymphatic dysplasia. Dysplastic or ectatic lymphatics may cause leakage of chyle where these lesions occur. Lymphedema describes a swollen extremity or body region secondary to such a lymph accumulation. A congenital form occurs in patients younger than 3 months of age; if familial, it is called Milroy's disease.

Lymphedema praecox presents in patients older than 3 months of age; if familia, it is called Meige's disease. Intestinal lymphangiectasis describes dilation of intestinal lymphatics with leakage of chyle into the bowel lumen. Chyloperitoneum, chylothorax, and chylopericardium represent leakage of lymphatics in those cavities. In generalized lymphatic dysplasia or lymphangiectasis, the process occurs in several sites and may cause chyle accumulations in multiple locations. Generalized lymphatic dysplasia can involve the lung. [6-8] Lymphangiectasis may also be secondary to operation, trauma, infection, or neoplasm.
The third category is congenital pulmonary lymphangiectasis. This condition is most commonly associated with cardiac anomalies that cause pulmonary venous obstruction and dilated lung lymphatics. It also may occur as an isolated lesion. With or without cardiac anomalies, the disorder usually presents with severe respiratory distress at the time of birth. Congenital pulmonary lymphangiectasis is usually fatal in the newborn period whether or not it is secondary to heart lesions; however, prolonged survival has been reported. [9-11]


Wednesday, February 01, 2006

Nearly 8 million children born with defects: study

Reuters Health
Tuesday, January 31, 2006

WASHINGTON (Reuters) - Nearly 8 million children are born with birth defects around the world every year and most of them either die or are disabled for life as a result, according to a report released on Monday.

With proper medical care up to 70 percent of these defects could be prevented, or at least treated, the report from the March of Dimes said.

"An estimated 7.9 million children are born annually with a serious birth defect of genetic or partially genetic origin," the report said.

"More than 90 percent of all infants with a serious birth defect are born in middle- and low-income countries," the report added.

"Because most of these countries do not have adequate services to care for infants and children with birth defects, many of them will die young."

The March of Dimes, a charity whose goal is to eliminate birth defects, said 3.3 million deaths every year are associated with birth defects and another 3.2 million children born with defects become disabled.

Proper medical care and nutrition could prevent many of these, the report said. "For example, structural birth defects including congenital heart defects, congenital cataracts, cleft lip and palate and clubfoot, can be corrected with pediatric surgery," it said.

Treatments are also available for sickle cell disease, which causes misshapen red blood cells, thyroid disease and other problems.

"In the United States alone, fortification of the grain supply with folic acid has produced a one-third decline in neural tube defects each year, with an overall cost savings calculated at $400 million annually," the report said.

In the United States, the infant mortality rate from birth defects fell 46 percent between 1980 and 2001, the March of Dimes said.

Four of the most common defects seen in 2001 were congenital heart defects, affecting more than a million newborns; neural tube defects which affected more than 300,000; Down's syndrome; and the blood diseases thalassemia and sickle cell disease.

Sudan had the highest rate of birth defects, with 82 per 1,000 live births. Saudi Arabia and Benin followed. The three countries with the lowest rates of birth defects were Australia, Austria and France, with around 40 per 1,000 live births.