A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature.

Benign hereditary chorea (BHC) is a rare autosomal dominant condition characterized by early onset, non-progressive chorea, usually caused by mutations in the thyroid transcription factor-1 gene (TITF1). We describe a novel mutation arising de novo in a proband presenting in infancy with delayed walking and ataxia. She later developed chorea, then hypothyroidism and a large cystic pituitary mass. Her daughter presented in infancy with delayed walking and ataxia and went on to develop non-progressive chorea and a hormonally inactive cystic pituitary mass. Mutational analysis of the whole coding region of the TITF1 gene was undertaken and compared with a population study of 160 control subjects. This showed that both affected subjects have a heterozygous A > T substitution at nucleotide 727 of the TITF1 gene changing lysine to a stop codon at residue 211. Genetic analysis of parents and siblings of the proband confirmed that the mutation arose de novo in the proband. The mutated lysine is an evolutionarily highly conserved amino acid in the protein homoeodomain (HD) where most point mutations associated with BHC are located. The range of mutations in BHC is reviewed with particular emphasis on pituitary abnormalities. Cystic pituitary masses and abnormalities of the sella turcica are reported in just 6.4 % of published cases. This is a new nonsense mutation associated with ataxia, benign chorea and pituitary abnormalities which further extends the phenotype of this condition. Mutational screening of TITF1 is important in cases of sporadic or dominant juvenile-onset ataxia, with mild chorea where no other cause is found, particularly if pituitary abnormalities are seen on imaging.