Aagenaes Syndrome
.....................................
Synonyms: Cholestasis-lymphedema syndrome (CLS); CHLS; LCS; LCS1; Lymphedema - cholestasis 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.)
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.
May 26, 2008
===========================
Clinical Studies and Abstracts:
==============
CHOLESTASIS-LYMPHEDEMA SYNDROME |
Alternative titles; symbols
CHLSIn 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.
Victor A.
McKusick - updated : 10/20/2000
Victor A. McKusick - updated : 7/10/1998
Michael J. Wright - updated : 6/5/1998
Victor A. McKusick : 6/3/1986
mgross : 3/17/2004
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=214900
.....................................
Prognosis, with evaluation of general biochemistry, of liver disease in lymphoedema cholestasis syndrome 1 (LCS1/Aagenaes syndrome).
Scand J Gastroenterol. 2006 Apr
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://www.informaworld.com/smpp/content~db=all?content=10.1080/00365520500335183
.....................................
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
.....................................
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]
.....................................
Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome.PMID: 12712065 [PubMed - indexed for MEDLINE]
.....................................
Aagenaes syndrome--lymphedema and intrahepatic cholestasis
Tidsskr Nor Laegeforen. 2001 May
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.
===========================
Classification and Codes:
Orpha number | ORPHA1414 |
Prevalence | Exceptional |
Inheritance |
|
Age of onset | Neonatal/infancy |
ICD 10 code |
|
MIM number |
===========================
Join us as we work for lymphedema patients every where:
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
http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema\
For Information about Lymphedema Complications
http://www.lymphedemapeople.com/wiki/doku.php?id=complications_of_lymphedema
For Lymphedema Personal Stories
http://www.lymphedemapeople.com/phpBB2/viewforum.php?f=3
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
http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema
For information on Infections Associated with Lymphedema
http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema
For information on Lymphedema in Children
http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children
Lymphedema Glossary
http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing
===========================
Lymphedema People - Support Groups
-----------------------------------------------
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
......................
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!
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Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com
......................
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
......................
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/
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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
......................
All
About Lymphedema
For
our Google fans, we have just
created this online support group in Google Groups:
Homepage: http://groups-beta.google.com/group/All-About-Lymphedema
Group email: All-About-Lymphedema@googlegroups.com
......................
Lymphedema Friends
http://groups.aol.com/lymphedemafriend
If you an AOL fan and looking for a
support group in AOL
Groups, come and join us there.
===========================
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)
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
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)
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
http://www.lymphedemapeople.com
Page Updated: Nov. 16, 2011