CCBE1 – Hennekam Syndrome

The association between CCBE1 and Hennekam syndrome is supported by multiple independent studies and is classified as a strong gene‑disease relationship. Multiple case reports and family studies have identified autosomal recessive mutations in CCBE1 in patients with lymphatic dysplasia, manifesting as generalized edema, ascites, and hypoalbuminemia (PMID:25925991). This clinical phenotype is consistent with the variable expressivity observed in Hennekam syndrome, where some individuals exhibit only mild lymphatic abnormalities while others demonstrate the full spectrum including dysmorphic features and protein‑losing enteropathy.

Genetic evidence from several studies demonstrates compound heterozygous and homozygous mutations in CCBE1 across unrelated probands. In one representative study, a pathogenic variant, c.294T>G (p.Cys98Trp), was identified, and similar mutations have been recurrently observed in independent families (PMID:25925991; PMID:27345729). Segregation analyses in these families further strengthen the association, with affected relatives in multiple pedigrees carrying the pathogenic variants.

Functional studies have provided robust support for CCBE1’s role in lymphangiogenesis. In murine models, CCBE1 deficiency leads to a complete lack of definitive lymphatic structures, while in vitro assays demonstrate that the recombinant CCBE1 protein enhances VEGF‑C-mediated lymphatic vessel formation (PMID:21778431; PMID:25814692). These findings clearly indicate that loss‑of‑function mutations in CCBE1 disrupt lymphatic vascular development, recapitulating the clinical features of Hennekam syndrome.

Although mutations in other genes such as FAT4 have been reported in overlapping lymphatic dysplasia phenotypes, the genetic and functional data for CCBE1 are consistent and robust. Evidence from multiple case reports, multi‑patient studies, and experimental assessments converge on a pathogenic mechanism involving impaired lymphatic endothelial cell budding and migration, without significant conflicting findings.

The integrated data from clinical, genetic, and functional studies provide a coherent narrative that supports the strong clinical validity of CCBE1 in Hennekam syndrome. Additional evidence from extended family studies and experimental systems further underscores the clinical utility of CCBE1 testing for diagnostic decision‑making in patients presenting with congenital lymphatic dysplasia.

Key take‑home: CCBE1 mutations represent a strong, well‐validated genetic cause of autosomal recessive Hennekam syndrome, with significant implications for diagnostic evaluation and potential targeted therapeutic interventions.

References

• BMC medical genetics • 2015 • A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature. PMID:25925991
• American journal of medical genetics. Part A • 2016 • Expanding the genotypic spectrum of CCBE1 mutations in Hennekam syndrome. PMID:27345729
• Circulation research • 2011 • CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor‑C in vivo. PMID:21778431
• Circulation research • 2015 • Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain. PMID:25814692

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