Developmental Disorders of the Lymphatics

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Wednesday, November 30, 2005

Aagenaes Syndrome



Alternative titles; symbols



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.


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 :
3. Aagenaes, O. :
Hereditary recurrent cholestasis with lymphoedema--two new families. Acta Paediat. Scand. 63: 465-471, 1974.PubMed ID :
4. Aagenaes, O.; Sigstad, H.; Bjorn-Hansen, R. :
Lymphoedema in hereditary recurrent cholestasis from birth. Arch. Dis. Child. 45: 690-695, 1970.PubMed ID :
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 :
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 :
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 :
8. Sharp, H. L.; Krivit, W. :
Hereditary lymphedema and obstructive jaundice. J. Pediat. 78: 491-496, 1971.PubMed ID :


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

Victor A. McKusick : 6/3/1986

mgross : 3/17/2004

Pub Med


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 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.eduPatients 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.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 - Pub Med:

Case Reports
PMID: 12712065 [PubMed - indexed for MEDLINE]


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