Hypotonia, Ataxia, Developmental Delay, And Tooth Enamel Defect Syndrome

A number sign (#) is used with this entry because of evidence that hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (HADDTS) is caused by heterozygous mutation in the CTBP1 gene (602618) on chromosome 4p16.

Clinical Features

Beck et al. (2016) reported 4 unrelated patients, ranging in age from 8 to 20 years, with a similar complex neurodevelopmental disorder. The patients had hypotonia and variably delayed motor development: 2 patients were nonambulatory at ages 12 and 20 years, whereas the others learned to walk in the first years of life but had an ataxic gait. All had early language delay, but 1 child (patient 3) had normal speech and no intellectual disability at age 9 years. The other 3 patients had moderate to severe intellectual disability and feeding difficulties necessitating feeding tube placement. Muscle biopsies showed nonspecific dystrophic or inflammatory changes. All patients had enamel defects of the teeth, including soft enamel with tooth discoloration. Dysmorphic features were not prominent, although 1 patient had a highly arched palate and retrognathia, and another had frontal bossing and deep-set eyes. Brain imaging showed mild cerebellar atrophy in 2 patients but was normal in the other 2.

Molecular Genetics

In 4 unrelated patients with HADDTS, Beck et al. (2016) identified a de novo heterozygous missense mutation in the CTBP1 gene (R331W; 602618.0001). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. One patient (patient 1) was maternally somatic mosaic for the mutation; his mother, who carried a low mutation load (5.3%), was phenotypically normal with no neurologic features. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a dominant-negative effect. The patients were part of a cohort of 5,471 trios containing probands with neurodevelopmental disorders who underwent whole-exome sequencing.