A novel mutation of NKX2-1 affecting 2 generations with hypothyroidism and choreoathetosis: part of the spectrum of brain-thyroid-lung syndrome

The NKX2-1 (TTF-1 or TITF-1) gene on chromosome 14q13 codes for the thyroid transcription factor 1 (TTF-1). It is expressed in the developing brain, lung, and thyroid. Defects have been associated with chorea, hypothyroidism, and lung disease, comprising the "brain-thyroid-lung syndrome." We describe here 3 cases of novel missense mutation (c.626G>C; p.Arg209Pro) in NKX2-1 in 2 generations of a nonconsanguinous family. Firstly 2 sons were affected by childhood-onset hypothyroidism and a movement disorder characterized by ataxia in the early years followed by the emergence of a superimposed chorea. The mutation was also found in the granddaughter, when she presented with the same clinical features. We hypothesize that the mutation arose as a result of gonadal mosaicism, as the mutation was not detected in leucocyte DNA from either grandparent. The features are consistent with a diagnosis of Brain-thyroid-lung syndrome, which previously could have been classified as benign hereditary chorea with hypothyroidism.