Variants of CDH1 cause a wide spectrum of developmental disorders, ranging from NSCLP with or without cancer, to BCD syndrome. CDH1-related NSCLP has been reported in at least 57 individuals from 19 families. Cases are mostly sporadic, but large families have been reported. Description of these families shows that the pathogenic variant segregates with NSCLP in up to 4 generations, and highlights incomplete penetrance of the condition. In 51 patients from 10 families, CDH1-related CLP have been found to be associated with diffuse hereditary diffuse gastric cancer or lobular breast cancer, but not in all mutation carriers. No genotype/phenotype correlation underlies this association.
The most-recently identified CDH1-related developmental disorder is BCD syndrome. Based on the description of 26 individuals, all patients have eyelid anomalies and ectodermal dysplasia, which are cardinal features. Eyelids anomalies comprise euryblepharon (20/22), lagophthalmos (20/22), ectropion (18/22), lacrimal duct abnormalities (3/14). Patients also show distichiasis (17/22) and ankyloblepharon (3/14). Features of ectodermal dysplasia consist in delayed dentition (8/10), hypodontia (20/22) and sparse hair (15/22). Cleft lip/palate (CLP), thought to be constant, is reported in 22/24 patients. One patient without CLP, presents with unilateral choanal atresia. Patients also exhibit typical dysmorphism consisting of hypertelorism (13/18), flat face, high forehead (13/16) and, less frequently, asymmetrical face (1/26). Congenital hypothyroidism (6/23), anal atresia (4/26) and neural tube defect (6/25) were frequently reported as well. Additional rare features could be observed as cutaneous syndactyly, vertex aplasia and allodynia. Significant interindividual and intrafamilial variability has been reported. Diagnosis could be made retrospectively in patients’ relatives, when the condition is confirmed by genetic testing.