Witkop syndrome is not always caused by MSX1 mutation

Objectives: Witkop syndrome is an autosomal dominant disorder in the family of ectodermal dysplasias that affects approximately 2:10,000. Its hallmark findings include tooth agenesis and nail dysplasia. In a previous study of a family with Witkop syndrome, a nonsense mutation was identified in the homeodomain of MSX1. The purpose of our study was to determine the MSX1 mutations that are responsible for Witkop syndrome in two newly identified families. Methods: Two families with the characteristic features of Witkop syndrome were identified for analysis. DNA samples were obtained and analyzed by PCR amplification using intron-based, exon-specific primers for both exons of MSX1, followed by sequencing of the coding area of MSX1. Results: In the first family, a patient who was missing 26 permanent teeth and exhibited toenail dysplasia, was found to be heterozygous for a common polymorphism (C101G) in MSX1. Our previous statistical analysis revealed that this polymorphism may contribute to tooth agenesis in a statistically significant manner although it does not by itself lead to hypodontia. From a second family we studied a mother with hypodontia and a son with 26 congenitally missing teeth. Both had thin nails with marked vertical grooving. However, no amino acid changing mutations in the coding region of MSX1 were found in either individual. Conclusions: Two of the three subjects analyzed have severe tooth agenesis patterns and all have nail dysplasia closely resembling those of previously reported Witkop cases, yet no MSX1 mutation was found. To our knowledge there has been only one Witkop family described with multiple affected members showing a nonsense mutation in MSX1. Our findings suggest that the Witkop phenotype may be caused by mutations in other genes.

Supported by the Baylor Oral Health Foundation (SPW); NIH U24-PEI6472 (RDS).