Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid 
syndrome, characterized by congenital hypothyroidism (CH), infant respiratory 
distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of 
the present study were (i) detection of NKX2-1 mutations in patients with CH 
associated with pneumopathy and/or BHC, (ii) functional analysis of new 
mutations in vitro and (iii) description of the phenotypic spectrum of 
brain-lung-thyroid syndrome. We identified three new heterozygous missense 
mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one 
deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations 
revealed loss of transactivation capacity on the human thyroglobulin 
enhancer/promoter. Interestingly, we showed that deficient transcriptional 
activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, 
whereas the synergistic effect was abolished by L176V and Q210P. The clinical 
spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from 
the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid 
disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and 
compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of 
patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 
20% developed severe chronic interstitial lung disease, and 16% died. In 
conclusion, we describe five new NKX2.1 mutations with, for the first time, 
complete rescue by PAX8 of the deficient transactivating capacity in one case. 
Additionally, our review shows that the majority of affected patients display 
neurological and/or thyroidal problems and that, although less frequent, lung 
disease is responsible for a considerable mortality.