Klatskin-like presentation of lymphedema cholestasis syndrome associated with compound heterozygous CCBE1 mutation

Lymphedema cholestasis syndromes (LCS) are genetically heterogeneous conditions characterized by chronic cholestasis with recurrent cholangitis and generalized lymphedema with more severe lower limb affection, which typically manifests in infants and young children. LCS1/Aagenes syndrome is inherited as an autosomal recessive trait and although the exact genetic defect causing LCS1 is yet unknown, it was mapped to chromosome 15q. Genetic heterogeneity can be inferred from the observation that the LCS1 locus on chromosome 15q is not implicated in all patients with this disease phenotype. Similar to portal biliopathy, where reduced venous outflow in large biliary duct veins is thought to result in impaired biliary drainage, in LCS cholestasis is thought to result from impaired lymphatic drainage.

We here report a fifty eight year old patient presenting with peripheral edema, mechanical cholestasis and relapsed cholangitis resulting from a Klatskin-like biliary stenosis to whom a compound heterozygosity (c.310G>A, c.684_685insT) in the CCBE1 gene was identified. CCBE1 is a secreted protein composed of 2 EGF and 2 collagen domains proved to be essential for the activation of VEGFC and thus lymphatic vascular development. Hennekam syndrome is a lymphatic development disorder characterized by dysmorphic features and variable cognitive impairment in which recessive mutations in CCBE1 are encountered in about 25% of patients. In contrast to the usual earlier and more severe manifestation in patients with Aagenes or Hennekam syndromes, we hypothesize that our patient's mild phenotype could be due to the compound heterozygosity.