CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops

Sohela Shah,Luis Gomez,Randolph P Matthews,Laura K Conlin,Nancy B Spinner,A S Knisely,Michael T Mennuti,Øystein Aagenaes,Laura N Bull,Kristin Eiklid

doi:10.1371/journal.pone.0075770

Abstract

BackgroundLymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS.MethodsConsanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes.ResultsBoth siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known ‘cholestasis genes’ did not demonstrate homozygosity in the LCS patient.ConclusionsMutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.

Highlights

Lymphedema cholestasis syndrome (LCS; Aagenaes syndrome) is characterized by neonatal intrahepatic cholestasis and severe chronic lymphedema that mainly affects the lower limbs
CCBE1 is mutated in some patients with Hennekam syndrome, and in two families with multiple members having generalized lymphatic dysplasia (GLD), sometimes with fetal hydrops [7,8,9,10]
To evaluate the possibility that Patient 1 carried homozygous mutation in a gene implicated in cholestasis, and potentially responsible for his cholestasis independently of the homozygous mutation in the known lymphedema gene CCBE1, we evaluated the whole-genome single nucleotide polymorphism (SNP) data for evidence of homozygosity in the following genes already known to be mutated in forms of cholestasis: ABCB11/BSEP, ABCB4/ MDR3, EPHX1, TJP2, CLDN1, NR1H4/FXR, BAAT, SLC27A5, CIRH1A, VPS33B, VIPAR, ABCC2, HSD3B7, and AKR1D1 [20,21,22,23,24,25,26,27,28,29,30,31,32]

Summary

Introduction

Lymphedema cholestasis syndrome (LCS; Aagenaes syndrome) is characterized by neonatal intrahepatic cholestasis and severe chronic lymphedema that mainly affects the lower limbs. Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS. Results: Both siblings harbored a homozygous mutation in CCBE1, c.398. Regions containing known ‘cholestasis genes’ did not demonstrate homozygosity in the LCS patient. Conclusions: Mutations in CCBE1 may yield a phenotype of lymphatic dysplasia, and of LCS or fetal hydrops; the possibility that the sibling with LCS carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded

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Results

Conclusion