Blepharo-cheilo-odontic syndrome (ORPHA:1997)
A rare ectodermal dysplasia syndrome characterized by the association of lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth.
Epidemiology
Over 50 cases have been described in literature to date.
Clinical description
Blepharocheilodontic syndrome (BCD) syndrome is characterized by eyelid malformations, cleft lip with or without cleft palate (CLP), and dental anomalies. CLP is usually bilateral and eyelid malformations are typical (ectropion of the lower eyelids, euryblepharon, and lagophthalmia). Patients harbor variable expression of ectodermal dysplasia, with constant dental anomalies corresponding to conical teeth and tooth agenesis. Additional variable features have been reported, including congenital hypothyroidism due to thyroid gland hypoplasia or aplasia, imperforate anus, neural tube defect, and syndactyly. Patients have normal intellectual development. Significant interindividual and intrafamilial variability have been reported, as well as incomplete penetrance. Diffuse gastric cancer and lobular breast cancer have been reported in two families so far. To date, the risk of cancer in BCD syndrome is not precisely known, since cancers were not reported in the other reported families.
Etiology
BCD syndrome is due to either heterozygous CDH1 or CTNND1 variants. CDH1 encodes the E-cadherin, a transmembrane glycoprotein. CTNND1 encodes the Delta-Catenin, a protein linked to the cytoplasmic domain of E-cadherin. Both proteins are involved in a cell-cell adhesion complex, critical for establishing and maintaining polarized and differentiated epithelia during development. Recurrent missense CDH1 variants have been identified in BCD syndrome, probably impairing ion calcium binding. Variations in CTNND1 correspond predominantly to truncating variants, but missense variants have also been reported. BCD-related to CDH1 and CTNND1 variants are clinically indistinguishable, although the latter usually shows a milder phenotype. CDH1 variants also cause hereditary diffuse gastric cancer (HDGC), and diffuse gastric cancer and lobular breast cancer have been reported in two BCD families with CDH1 variants. Since cancers have not been reported in other reported families to date, the risk of cancer development is not precisely known. No HDGC-related cancer has been reported in patients with CTNND1 variants.
Diagnostic methods
The syndrome is suspected on the association of CLP, typical eyelid malformations and ectodermal dysplasia features. Molecular genetic testing approaches include targeted sequencing of the entire CDH1 and CTNND1 coding regions.
Differential diagnosis
BSD presents with a unique constellation of features and there are no relevant differential diagnoses.
Antenatal diagnosis
Prenatal testing is possible if the pathogenic variant has been identified in an affected family member. However if the pathogenic variant is identified in the fetus, the severity of the condition is not predictable.
Genetic counseling
BCD syndrome is usually sporadic, but large families have been described. The disorder is autosomal dominant and patients harboring BCD syndrome features and carrying a CDH1 variant or a CTNND1 variant have 50% risk to transmit the pathogenic variant to their offspring. Due to intrafamilial variability and incomplete penetrance, prediction of the severity is difficult.
Management and treatment
Management of BCD syndrome is supportive and symptomatic. CLP management is surgical, dental, and orthodontic. Early orthodontic follow-up should be proposed. Blepharoplasty is required for ankyloblepharon and for severe eyelid anomalies. Lagophthalmos can lead to corneal abrasion. Ophthalmologic evaluation is recommended to assess eye movement and possible tearing reduction. Congenital hypothyroidism is usually diagnosed through neonatal screening and treated with thyroid replacement therapy. Assessment of risk of cancer is challenging. Currently, there are no clear guidelines for surveillance or prophylactic total gastrectomy.
Prognosis
The prognosis and functional consequences are variable and dependent on the associated anomalies. In families carrying a CDH1 variant and with a positive familial history of CDH1-related cancers, or fitting criteria for hereditary diffuse gastric cancer (HDGC), prognosis can be worsened by the occurrence of cancer.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Jamal GHOUMID | ITHACA* - Pr Florence PETIT | ITHACA*


                                * European Reference Network