Developmental disorders due to CDH1 variants comprise Non-Syndromic Cleft Lip with or without cleft Palate (NSCLP), with or without history of cancer, and Blepharocheilodontic (BCD) syndrome. Variants of CDH1 have been initially identified as cause of early-onset, multigenerational hereditary diffuse gastric cancer (HDGC) and lobular breast cancer (LBC) (MIM#137215). In a small number of families affected with HDGC, cleft lip/palate (CLP) has been found to segregate with the CDH1 variant. Then, variants of CDH1 have been identified in patients with NSCLP without history of HDGC or LBC.
Recently, variants of CDH1 and CTNND1 have been found to cause BCD syndrome (MIM#119580 and MIM#617681). BCD syndrome is a rare disorder characterized by eyelid malformations, CLP and dental anomalies. CLP, usually bilateral, is the major feature. Eyelid malformations (ectropion of the lower eyelids, euryblepharon, and lagophthalmia) are typical. Patients have variable expression of ectodermal dysplasia, with constant dental anomalies (i.e., conical teeth and tooth agenesis). In addition, hypothyroidism due to thyroid gland hypoplasia or aplasia, imperforate anus, neural tube defect, and syndactyly have been reported in a few patients. BCD syndrome is usually sporadic, but large families have been described.
Identification of CDH1 and CTNND1 as causing genes, confirmed the autosomal-dominant inheritance of the condition. To date, about 26 patients from 18 families have been reported with a variant in CDH1, highlighting significant intrafamilial variability. Prevalence of the disease is not known and there is no genotype/phenotype correlation explaining the wide phenotypic spectrum of the CDH1-related disorders.