Witkop Syndrome

A number sign (#) is used with this entry because Witkop syndrome is caused by heterozygous mutation in the MSX1 gene (142983) on chromosome 4p16.

Description

Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings.

Witkop syndrome is a rare autosomal dominant ectodermal dysplasia involving the teeth and nails. Although a few reported cases have sparse or fine hair, almost all affected individuals have normal hair, sweat glands, and ability to tolerate heat. Affected individuals have a variable number and variable types of congenitally missing permanent and/or primary teeth, which frequently results in lip eversion due to loss of occlusion in the vertical dimension. Nails are generally thin, slow-growing, brittle, and spoon-shaped (koilonychia). Toenails are usually more severely affected than fingernails. The nail defects are alleviated with age and may not be easily detectable during adulthood (summary by Jumlongras et al., 2001).

Clinical Features

Changes are limited largely to teeth (some of which are missing) and nails (which are poorly formed early in life, especially toenails). The teeth are not as severely affected. Witkop (1965) stated that the condition is frequent among Dutch Mennonites in Canada. He presented a pedigree supporting autosomal dominant inheritance.

Giansanti et al. (1974) reported a single case. The main features were hypoplastic nails and hypodontia. Eyebrows and eyelashes were normal, but the scalp hair was fine. The patient showed bilateral polycystic ovaries. Redpath and Winter (1969) probably reported cases.

Hudson and Witkop (1975) presented clinical details on 23 cases in 6 families, with several instances of male-to-male transmission. Characteristic, centrally hollowed, dysplastic toenails were frequently apparent only in childhood. The condition is usually not detected until the permanent teeth fail to erupt. Mandibular incisors, second molars, and maxillary canines are most often absent. Somewhat pouting lower lip was described.

Wicomb et al. (2004) documented the manifestations of Witkop syndrome in an affected child and his father. The paternal grandfather was also affected.

Inheritance

Witkop syndrome is inherited as an autosomal dominant trait (Hudson and Witkop, 1975; Jumlongras et al., 2001).

Mapping

Jumlongras et al. (2001) found linkage between the tooth-and-nail syndrome, which they referred to as Witkop syndrome, and polymorphic markers in the region of the MSX1 locus (142983) in a 3-generation family.

Molecular Genetics

In a 3-generation family with Witkop syndrome, Jumlongras et al. (2001) identified a nonsense mutation in the MSX1 gene (142983.0003) that cosegregated with the phenotype.

Animal Model

Jumlongras et al. (2001) generated Msx1-deficient mice. Histologic analysis of Msx1-knockout mice, combined with a finding of Msx1 expression in mesenchyme of developing nail beds, revealed that not only was tooth development disrupted in these mice, but nail development was affected as well. Nail plates in Msx1-null mice were defective and were thinner than those of their wildtype littermates.