Cholestasis-Lymphedema Syndrome

Clinical Features

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, suggesting that the defect resides in lymphangiogenesis.

Drivdal et al. (2006) stated that 40 Norwegian patients have been known to have cholestasis-lymphedema syndrome, of whom 25 were still alive at the date of the report. Nine died in infancy or early childhood, mainly of bleeding before vitamin K treatment was available; 4 died of cirrhosis at ages 2, 7, 8, and 50 years, respectively; and 2 died of unrelated causes in late adulthood. Of those patients still living, 3 underwent liver transplantation in infancy, and 2 had slow progression to cirrhosis. Analysis of 15 Norwegian patients over age 10 years with the disorder but without signs or symptoms of cholestasis showed significantly increased serum transaminase levels compared to controls, and albumin was decreased in older patients. Lymphedema ranged from moderate to massive. Retrospectively, it appeared that those with remission of liver disease by about 2 to 2.5 years of age showed a better prognosis. Drivdal et al. (2006) concluded that more than 50% of patients with Norwegian cholestasis-lymphedema syndrome can expect a normal life span given proper nutritional and vitamin treatment and that most patients have a relatively good prognosis compared to patients with other types of hereditary neonatal cholestasis.

Mapping

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.