Sharp 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)
Liver scarring, jaundice, insufficient bile secretion and and enlarged liver are also mentioned as symptoms.
Diagnosis may be achieved by testing for the cause of the specific symptoms, especially in conjunction with the lymphedema.
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)
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)
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)
(Answered within 5 to 10 working days)
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
Because of the variables, and complications, it is not possible to make a generalized prognosis.
May 26, 2008
Clinical Studies and Abstracts:
Alternative titles; symbolsCHLS
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.
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
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. email@example.com
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.
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.
Mapping of the locus for
cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM
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. firstname.lastname@example.org
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 Řystein 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:
|Age of onset||Neonatal/infancy|
|ICD 10 code||
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