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Lymphedema Cholestasis Syndrome

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Synonyms: CLS; CHLS; LCS; LCS1; Aagenaes Syndrome

Classified as a rare disorder by Orphanet, Aagenaes Syndrome is an autosomal recessive condition and presents with chronic and sever lymphedema and severe neonatal cholestasis, (Any condition in which the release of bile from the liver is blocked The blockage can occur in the liver (intrahepatic cholestasis) or in the bile ducts (extrahepatic cholestasis).

The condition has only been studied in six families with most of them being from Norway.  These studies are included below.

The most  common feature is a generalised lymphatic anomaly which is why we have placed it under our Syndromes of Lymphatic Dysplasia section.  The cause appears to be a defect in lymphangiogenesis, but the specifics are as yet unknown.  

Clinical Signs (Symptoms and Complications)

Very Frequent

Frequent

Hemangioma-capillary

Other

Liver scarring, jaundice, insufficient bile secretion and and enlarged liver are also mentioned as symptoms.

Diagnosis

Diagnosis may be achieved by testing for the cause of the specific symptoms, especially in conjunction with the lymphedema.

Treatment

There is no "cure" and treatment would specifically focus on the complications such as lymphedema, possible cirrhosis of the liver, and/or a hemangioma.

Support Organizations and help:

Because of its rarity, there are no support groups for this syndrome.  There are however support groups for the complications such as lymphedema such as our organization and website.

There are three help lists/site available for rare conditions:

Office of Rare Diseases Database (Database available to search)

http://rarediseases.info.nih.gov/RareDiseaseList.aspx?PageID=1

Rareshare (RareShare is unique social hub building communities for patients, families, and healthcare professionals affected by rare disorders.)

http://www.rareshare.org/

Genetic and Rare Diseases Information Center (Database available to search)

By Telephone
Monday - Friday, 12:00 p.m. to 6:00 p.m. Eastern Time
(888) 205-2311 (Phone)
(888) 205-3223 (TTY)
(301) 519-3194 (International Telephone Access Number)

By E-mail Form
(Answered within 5 to 10 working days)

By U.S. Mail or Fax
(Answered within 5 to 10 working days)
The Genetic and Rare Diseases Information Center
P.O. Box 8126
Gaithersburg, MD 20898-8126

http://rarediseases.info.nih.gov/GARD/Default.aspx?PageID=4

Prognosis

Because of the variables, and complications, it is not possible to make a generalized prognosis.

Pat O'Connor

May 26, 2008

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CHOLESTASIS-LYMPHEDEMA SYNDROME

%214900

Alternative titles; symbols

CHLS
AAGENAES SYNDROME
LYMPHEDEMA-CHOLESTASIS SYNDROME; LCS; LCS1
Gene map locus 15q

TEXT

In 2 Norwegian kindreds, Aagenaes et al. (1968, 1970) described a syndrome of hereditary recurrent cholestasis and lymphedema. Jaundice became evident soon after birth and recurred in episodes throughout life. Edema in the legs, which was due to hypoplasia of the lymphatic vessels, began at about school age and progressed. In 1 kindred, 16 individuals in 7 interconnected sibships appear to have been affected. One instance of affected mother and daughter may have resulted from the fact that the father was a heterozygote. Aagenaes (1974) described 2 additional unrelated families. In 1 family, with a single affected individual, the parents were first cousins once removed; in the other, nonconsanguineous family, 3 of 6 sibs were affected. Liver histology showed giant cell transformation in infancy and some fibrosis or cirrhosis in later childhood. The family reported by Sharp and Krivit (1971) was also Norwegian, living in Minnesota. Aagenaes (1974) therefore suggested the designation 'hereditary cholestasis of Norwegian type,' when cholestasis is combined with lymphedema. 

Morris et al. (1997) reported an affected mother and daughter in a nonconsanguineous family of British origin. Morris et al. (1997) suggested that the most likely explanation was a de novo autosomal dominant mutation in the mother, either allelic with or at a locus distinct from that in the previously described families. 

Aagenaes (1998) gave a comprehensive review of the syndrome that bears his name with a description of new cases and follow-up from infancy to adulthood. The original observations (Aagenaes et al., 1968) involved 16 patients from the southwest of Norway. The patients belonged to 7 sibships; consanguinity was frequent, and autosomal recessive inheritance was proposed. Fourteen patients had been diagnosed in Norway since 1970. Nine of these belonged to the first large family reported. Two brothers of consanguineous parents belonged to a small family described in 1974 (Aagenaes, 1974); 2 sibs and 1 other sporadic patient appeared to be unrelated to any of these other families. A complicated pedigree of the original family showing the multiple affected individuals was displayed (Figure 8). Of the 21 patients born before 1970, 11 died in early childhood. Nine of these died in early infancy, mainly of bleeding because of unavailability of vitamin K at the time. Two died of cirrhosis in later childhood. Of the patients born before 1970, 6 women and 4 men survived childhood. One woman died at the age of 50 years, and 9 were still alive at ages ranging from 30 to 61 years. There had been no new Norwegian cases identified in the previous 6 years. 

Aagenaes (2001) pointed out that the common denominator of the syndrome that bears his name is a 'relatively generalized' lymphatic anomaly. This appears to indicate that the defect resides in lymphangiogenesis.

Bull et al. (2000) performed a genome screen, using DNA from 8 Norwegian patients with cholestasis-lymphedema syndrome and from 7 unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifested extensive allele and haplotype sharing over a 6.6-cM region on chromosome 15 between markers D15S979 and D15S652. 

REFERENCES

1. Aagenaes, O. :
Personal Communication. Oslo, Norway, 2/28/2001.
2. Aagenaes, O. :
Hereditary cholestasis with lymphoedema (Aagenaes syndrome, cholestasis-lymphoedema syndrome): new cases and follow-up from infancy to adult age. Scand. J. Gastroent. 33: 335-345, 1998.
PubMed ID : 9605254
3. Aagenaes, O. :
Hereditary recurrent cholestasis with lymphoedema--two new families. Acta Paediat. Scand. 63: 465-471, 1974.
PubMed ID : 4857709
4. Aagenaes, O.; Sigstad, H.; Bjorn-Hansen, R. :
Lymphoedema in hereditary recurrent cholestasis from birth. Arch. Dis. Child. 45: 690-695, 1970.
PubMed ID : 5477684
5. Aagenaes, O.; Van der Hagen, C. B.; Refsum, S. :
Hereditary recurrent intrahepatic cholestasis from birth. Arch. Dis. Child. 43: 646-657, 1968.
PubMed ID : 5702224
6. Bull, L. N.; Roche, E.; Song, E. J.; Pedersen, J.; Knisely, A. S.; van der Hagen, C. B.; Eiklid, K.; Aagenaes, O.; Freimer, N. B. :
Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q. Am. J. Hum. Genet. 67: 994-999, 2000.
PubMed ID : 10968776
7. Morris, A. A. M.; Sequeira, J. S. S.; Malone, M.; Slaney, S. F.; Clayton, P. T. :
Parent-child transmission of infantile cholestasis with lymphoedema (Aagenaes syndrome). J. Med. Genet. 34: 852-853, 1997.
PubMed ID : 9350821
8. Sharp, H. L.; Krivit, W. :
Hereditary lymphedema and obstructive jaundice. J. Pediat. 78: 491-496, 1971.
PubMed ID : 5544157

CONTRIBUTORS

Victor A. McKusick - updated : 10/20/2000
Victor A. McKusick - updated : 7/10/1998
Michael J. Wright - updated : 6/5/1998

OMIM

http://omim.org/entry/214900

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Prognosis, with evaluation of general biochemistry, of liver disease in lymphoedema cholestasis syndrome 1 (LCS1/Aagenaes syndrome).

Scand J Gastroenterol. 2006 Apr

Drivdal M, Trydal T, Hagve TA, Bergstad I, Aagenaes O.

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. monica.drivdal@uus.no

OBJECTIVE: To investigate the prognosis of liver disease in Aagenaes syndrome (lymphoedema cholestasis syndrome 1 (LCS1)), which is an autosomal recessive inherited syndrome consisting of neonatal cholestasis with intermittent cholestatic episodes in childhood into adulthood and development of lymphoedema. Forty Norwegian patients are known to have this condition, 25 of whom are alive. A clinical description of the liver disease is supplied with a case-control study. 

MATERIAL AND METHODS: In this paper we review the course of the liver disease in the Norwegian cohort of patients and present results from a case-control study in the patients above 10 years of age. The case-control study was performed on 15 patients without clinical cholestasis (itching and sometimes jaundice) at the time of the study. An evaluation of 11 patients above 15 years of age without chronic biochemical cholestasis (increased alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and/or serum bile acids) was also carried out. For each patient one randomly identified control person was included (15 in one study, 11 in the other). 

RESULTS: Cirrhosis with either transplantation or death in infancy or early childhood occurred in six patients; slowly developing cirrhosis occurred in three patients. Two patients may be in the process of developing cirrhosis. Significantly increased ALP and GGT levels were found in patients with normal liver biochemistry in the preceding years when compared with the case control group. Additionally, albumin was found to be lower in older patients. 

CONCLUSIONS: Compared with that for other types of hereditary neonatal cholestasis, patients with LCS1 have a relatively good prognosis. More than 50% can expect a normal life span.

http://informahealthcare.com/doi/abs/10.1080/00365520500335183

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Cholestasis with lymphedema (Aagenaes syndrome): Genome screen and evaluation of candidate regions. L. Bull1, E. Roche1, K. Eiklid2, C. van der Hagen2, A. Knisely3, O. Aagenaes2, N. Freimer1. 1) UCSF, San Francisco, CA; 2) University of Oslo, Oslo, Norway; 3) University of Texas Medical Branch, Galveston, TX.

   Cholestasis with lymphedema (CL), or Aagenaes syndrome, was first described in a Norwegian pedigree, in which the disease demonstrates probable autosomal recessive inheritance. Most Norwegian patients come from the same region, and are descended from a couple born circa 1570. CL is characterized by neonatal-onset cholestatic jaundice, accompanied by elevated levels of serum bile acids, bilirubin, and ALAT, and lasting 1-5 years. Recurrent cholestatic episodes occur in later childhood and adulthood. Lymphedema may be apparent at birth, or begin during childhood, and becomes chronic. Studies on urinary bile acids suggest no inborn bile acid metabolism abnormality. To identify the CL gene, we performed a genome screen using DNA from members of the Norwegian pedigree, and 385 autosomal microsatellite markers. A standard linkage analysis was not feasible because the structure of the pedigree is too complex, and too many samples are unavailable. Therefore, we designed a screening strategy to identify genome regions potentially shared identical by descent among several of these distantly related patients; two sib-pairs and a cousin pair were included. We identified candidate regions based on: 1) data consistent with linkage in the two sib pairs, 2) data consistent with linkage in the cousin pair, 3) evidence for marker haplotypes shared by affected individuals, and 4) evidence that particular marker alleles are more frequent than expected on the disease chromosomes. We paid particular attention to 5 regions containing genes previously found to be mutated in forms of hereditary liver disease or lymphedema (BSEP, FLT4, PGY3, FIC1, and JAG1). We have obtained no genetic evidence that CL is due to mutation in any of these candidate genes. We are currently evaluating 20 candidate regions identified in the genome screen on the basis of the genetic criteria outlined above. These regions are being evaluated by additional genotyping of the samples included in the genome screen, as well as in a larger sample of Norwegian CL patients.

http://genetics.faseb.org/genetics/ashg99/f1358.htm

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Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q.

Bull LN, Roche E, Song EJ, Pedersen J, Knisely AS, van Der Hagen CB, Eiklid K, Aagenaes O, Freimer NB.

Liver Center Laboratory, San Francisco General Hospital, San Francisco, CA 94110, USA. lbull@medsfgh.ucsf.edu

Patients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979-D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor.

PMID: 10968776 [PubMed - indexed for MEDLINE]

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Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome.

Fruhwirth M, Janecke AR, Muller T, Carlton VE, Kronenberg F, Offner F, Knisely AS, Geleff S, Song EJ, Simma B, Konigsrainer A, Margreiter R, van der Hagen CB, Eiklid K, Aagenaes O, Bull L, Ellemunter H.

Department of Pediatrics, University Hospital Innsbruck, the Institute of Medical Biology and Human Genetics, University of Innsbruck, Austria.

Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis. A locus, LCS1, has recently been mapped to chromosome 15q in a Norwegian kindred. In a consanguine Serbian Romani family with a neonate who had a combination of lymphedema and cholestasis with features atypical for Norwegian LCS, haplotype and linkage analysis of markers spanning the LCS1 region argue that a second LCS locus may exist. The infant may represent an instance of a previously undescribed lymphedema-cholestasis syndrome.

Publication Types:

PMID: 12712065 [PubMed - indexed for MEDLINE]

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Aagenaes syndrome--lymphedema and intrahepatic cholestasis

Tidsskr Nor Laegeforen. 2001 May

Heiberg A.

Avdeling for medisinsk genetikk Rikshospitalet 0027 Oslo.

The combination of neonatal intrahepatic cholestasis and lymphoedema in feet and legs is a specific syndrome named after the Norwegian paediatrician Øystein Aagenaes, who described the syndrome in 1968. The condition is autosomal recessively inherited and the gene is located to 15q, but not yet identified. The condition is particularly frequent in the southern most part of Norway and the gene frequency is estimated to be about 3%. The development of small lymphoid vessels is probably deficient around the small biliary tracts and in general. Aagenaes' syndrome is found in patients from other parts of Europe and the US, but more than half of the cases are of Norwegian origin.

PubMed

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Analysis of Lymphedema Cholestasis Syndrome I

http://www.bork.embl-heidelberg.de/g2d/exam_disease.pl?U84565

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Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes?

Aug 2010

Drivdal M, Løken EB, Hagve TA, Bergstad I, Aagenaes Ø.

Source

Regional Department of Eating Disorders, Division of Psychiatry, Building 37A, Oslo University Hospital, Ullevaal, N-0407 Oslo, Norway. ildr@uus.no

Abstract

AIMS:

Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed.

METHODS:

Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations.

RESULTS:

The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p=0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of alpha-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges.

CONCLUSIONS:

The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and alpha-tocopherol levels within reference  ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended.

Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

Keywords: Intrahepatic cholestasis, Lymphoedema, Nutrition assessment, Nutrient intake, Syndrome

Abbreviations: LCS1, Lymphoedema Cholestasis Syndrome 1, C.I., Confidence Interval, 25-OH D, 25-hydroxy vitamin D, E%, Percentage of energy, EPA, eicosapentaenoic acid, DHA, docosahexaenoic acid, MCT, Medium chain triglycerides, MJ, Mega joule

http://www.clinicalnutritionjournal.com/article/S0261-5614(10)00028-2/abstract

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Classification and Codes:

Orpha number ORPHA1414
Prevalence Exceptional
Inheritance
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD 10 code
  • K83.1
  • Q82.0
MIM number

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Classification and Codes:

Orpha number ORPHA1414
Prevalence Exceptional
Inheritance
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD 10 code
  • K83.1
  • Q82.0
MIM number

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Join us as we work for lymphedema patients everywhere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

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Pat O'Connor

Lymphedema People / Advocates for Lymphedema

===========================

For information about Lymphedema

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For Information about Lymphedema Complications

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For Lymphedema Personal Stories

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For information about How to Treat a Lymphedema Wound

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For information about Lymphedema Treatment 

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For information about Exercises for Lymphedema 

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For information on Infections Associated with Lymphedema

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For information on Lymphedema in Children

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Lymphedema Glossary

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

http://health.groups.yahoo.com/group/childrenwithlymphedema/

Subscribe: childrenwithlymphedema-subscribe@yahoogroups.com

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

http://health.groups.yahoo.com/group/lipedema_lipodema_lipoedema/?yguid=209645515

Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

http://health.groups.yahoo.com/group/menwithlymphedema/

Subscribe: menwithlymphedema-subscribe@yahoogroups.com

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

Subscribe: allaboutlymphangiectasia-subscribe@yahoogroups.com

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

===========================

Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet?  Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more.  Come and take a stroll! 

Lymphedema Glossary 

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing 

Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema 

Arm Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=arm_lymphedema 

Leg Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=leg_lymphedema 

Acute Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=acute_lymphedema 

The Lymphedema Diet 

http://www.lymphedemapeople.com/wiki/doku.php?id=the_lymphedema_diet 

Exercises for Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema 

Diuretics are not for Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=diuretics_are_not_for_lymphedema 

Lymphedema People Online Support Groups 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_people_online_support_groups 

Lipedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lipedema 

Treatment 

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment 

Lymphedema and Pain Management 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pain_management 

Manual Lymphatic Drainage (MLD) and Complex Decongestive Therapy (CDT)

http://www.lymphedemapeople.com/wiki/doku.php?id=manual_lymphatic_drainage_mld_complex_decongestive_therapy_cdt 

Infections Associated with Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema 

How to Treat a Lymphedema Wound 

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound 

Fungal Infections Associated with Lymphe dema 

http://www.lymphedemapeople.com/wiki/doku.php?id=fungal_infections_associated_with_lymphedema 

Lymphedema in Children 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children 

Lymphoscintigraphy 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphoscintigraphy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Extraperitoneal para-aortic lymph node dissection (EPLND) 

http://www.lymphedemapeople.com/wiki/doku.php?id=extraperitoneal_para-aortic_lymph_node_dissection_eplnd 

Axillary node biopsy 

http://www.lymphedemapeople.com/wiki/doku.php?id=axillary_node_biopsy

Sentinel Node Biopsy 

http://www.lymphedemapeople.com/wiki/doku.php?id=sentinel_node_biopsy

Small Needle Biopsy - Fine Needle Aspiration 

http://www.lymphedemapeople.com/wiki/doku.php?id=small_needle_biopsy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Lymphedema Gene FOXC2

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_foxc2

 Lymphedema Gene VEGFC

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_vegfc

 Lymphedema Gene SOX18

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_sox18

 Lymphedema and Pregnancy

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pregnancy

Home page: Lymphedema People

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Page Updated: Dec. 28, 2011