Hypoperfusion in caudate nuclei in patients with brain-lung-thyroid syndrome

Mutations in NKX2-1 cause neurological, pulmonary, and thyroid hormone impairment. Recently, the disease was named brain-lung-thyroid syndrome. Here, we report three patients with brain-lung-thyroid syndrome. All patients were unable to walk until 24 months of age, and still have a staggering gait, without mental retardation. They have also had choreoathetosis since early infancy. Genetic analysis of NKX2-1 revealed a novel missense mutation (p.Val205Phe) in two patients who were cousins and their maternal families, and a novel 2.6-Mb deletion including NKX2-1 on chromosome 14 in the other patient. Congenital hypothyroidism was not detected on neonatal screening in the patient with the missense mutation, and frequent respiratory infections were observed in the patient with the deletion in NKX2-1. Oral levodopa did not improve the gait disturbance or involuntary movement. The results of (99m)Tc-ECD single-photon emission computed tomography (ECD-SPECT) analyzed using the easy Z-score imaging system showed decreased cerebral blood flow in the bilateral basal ganglia, especially in the caudate nuclei, in all three patients, but no brain magnetic resonance imaging (MRI) abnormalities. These brain nuclear image findings indicate that NKX2-1 haploinsufficiency causes dysfunction of the basal ganglia, especially the caudate nuclei, resulting in choreoathetosis and gait disturbance in this disease.