Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations

Abstract

The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.

Keywords: Autosomal recessive; CCBE1; Genotype-phenotype; Hennekam syndrome; Lymphangiectasia; Lymphatic dysplasia; Lymphedema.

Fig. 1

a Phenotype of patient 10 with a CCBE1 mutation at age 2 years showing hair whorl in anterior hairline, hypertelorism, thick lateral eyebrows, epicanthi, depressed nasal bridge, and (pitting) lymphedema of distal limbs. b Changes in facial phenotype and lower limbs lymphedema in patient 11 with a CCBE1 mutation at age 3 months, 2 years, 8 years and 15 years. Note similarities with patient in figure 1a, and variation in facial lymphedema. c Lower limb lymphedema in patient 11 at age 3 months, 2 years and 8 years.

Fig. 2

Overview of the mutations described in CCBE1. The upper panel represents the 11 exons of the CCBE1 gene; the lower panel represents the CCBE1 protein. Functional domains in the protein (according to Uniprot) and the location of the mutations are indicated.