CDH1-associated Blepharocheilodontic Syndrome Registry

Recruiting

• Conditions: Blepharocheilodontic Syndrome

• Registration Number: NCT07133464
• Lead Sponsor: Ohio State University

Brief Summary

The aim of the CDH1-associated Blepharocheilodontic Syndrome (BCDS) registry is to better characterize the clinical features of this condition and exploring whether CDH1 variants linked to BCDS may also increase cancer risk.

Detailed Description

Blepharocheilodontic Syndrome (BCDS) is a rare genetic disorder characterized by cleft lip and/or palate (CL/P), eyelid malformations, and features suggestive of ectodermal dysplasia. Variants in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been implicated in BCDS. Functional studies have demonstrated that CDH1 plays a critical role in lip and palate development during embryogenesis (Ghoumid 2017; Figueiredo 2019).

In the hereditary cancer genetics community, CDH1 is more commonly associated with hereditary diffuse gastric and lobular breast cancer syndrome (DGLBC). CDH1 variants linked to DGLBC are typically truncating mutations, resulting in a null allele. In contrast, CDH1 variants observed in individuals with BCDS are often missense mutations located in the EC1-EC2 linker region (amino acids 254-257) or exon 9 donor splice site variants (e.g., c.1320G\>T, c.1320+1G\>A, c.1320+1G\>T, c.1320+1G\>C, c.1320+5G\>A) (Ghoumid 2017; Kievit 2018).

Historically, it was believed that individuals with BCDS-associated CDH1 missense variants were not at increased risk for DGLBC-associated cancers. This assumption was based on the absence of reported cancer cases in published BCDS families and epidemiological data from the CDH1 ClinGen Variant Curation Expert Panel (VCEP), which suggested that missense variants may not confer elevated cancer risk (Ghoumid 2017; Kievit 2018; Lee 2018).

However, a 2020 case report by LeBlanc et al. described a family with a known BCDS-associated CDH1 missense variant (c.768T\>A, p.N256K), in which a 37-year-old male developed diffuse gastric cancer. This report raised concerns about potential cancer risks in individuals with BCDS-associated CDH1 variants and prompted questions regarding the need for endoscopic screening and other surveillance measures.

Currently, data regarding cancer risk in individuals with CDH1 variants and the BCDS phenotype are limited. The condition is rare, and affected individuals are often identified through exome sequencing due to multiple congenital anomalies. The interpretation of familial cancer risk is further complicated by a high rate of de novo mutations and limited family history.

To address these gaps, this registry aims to establish a centralized, international cohort of individuals with CDH1-associated BCDS. The goal is to better characterize the genotype-phenotype correlations, define the clinical spectrum, and assess the potential cancer risks associated with these variants.

Study Timeline

• Study Start: 2025-06-17
• Status Verified: 2025-08
• Study First Submitted: 2025-08-08
• Study First Submitted QC: 2025-08-18
• Last Update Submitted: 2025-08-18
• Study First Posted: 2025-08-21
• Last Update Posted: 2025-08-21
• Primary Completion: 2040-01
• Study Completion: 2040-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• A documented pathogenic, likely pathogenic or a variant of uncertain significance in the CDH1 gene
• Clinical features that are diagnostic for, or suggestive of, BCDS (cleft lip and/or palate, eyelid anomalies, dental abnormalities, webbed toes, imperforate anus, etc)

Exclusion Criteria

• Non-English-speaking individuals

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Comprehensive characterization of the clinical phenotype associated with CDH1-associated blepharocheilodontic syndrome (BCDS)	5 years	Reporting of currently known clinical characteristics of CDH1-associated Blepharocheilodontic Syndrome (BCDS), including but not limited to cleft lip and/or palate, eyelid anomalies, dental abnormalities, webbed toes, and imperforate anus. The study will also document additional clinical features that may not have been previously reported in the literature, with the goal of expanding the phenotypic understanding of this rare condition.

Secondary Outcome Measures

Name	Time	Method
Development of evidence-based cancer surveillance recommendations for individuals with CDH1-assocaited blepharocheilodontic syndrome.	10 years	Personal and family cancer history will be collected and reviewed annually to evaluate potential cancer risks associated with CDH1 variants in individuals with blepharocheilodontic syndrome (BCDS). For participants who are of appropriate age and undergoing endoscopic surveillance as part of their routine medical care, relevant endoscopic and pathology reports will be obtained and analyzed to assess the presence and prevalence of signet ring cells, a hallmark of diffuse gastric cancer. This comprehensive data collection will support efforts to develop evidence-based cancer surveillance recommendations tailored to individuals with CDH1-associated BCDS.

Trial Locations

Locations (1)

The Ohio State University; 🇺🇸 Columbus, Ohio, United States