Brain-lung-thyroid syndrome

Brain-lung-thyroid syndrome (BLTS), also known as NKX2-1-related disorder or benign hereditary chorea, is a rare genetic condition caused by mutations or deletions in the NKX2-1 gene (also called TITF1 or TTF-1) located on chromosome 14q13.3. This gene encodes a transcription factor critical for the normal development and function of the brain, lungs, and thyroid gland. The syndrome is characterized by a classic triad of neurological, pulmonary, and thyroid manifestations, though not all affected individuals display involvement of all three organ systems. Neurological features are the most common presentation and typically include benign hereditary chorea — involuntary, irregular movements that usually appear in infancy or early childhood. Additional neurological findings may include hypotonia, developmental delay, dysarthria, ataxia, and learning difficulties. Pulmonary involvement can range from neonatal respiratory distress syndrome and recurrent pulmonary infections to interstitial lung disease (ILD), including surfactant metabolism dysfunction. Thyroid abnormalities most commonly present as congenital hypothyroidism, which may be detected through newborn screening, though some patients have a normally located but dysfunctional thyroid gland or thyroid agenesis. The severity and combination of features vary widely, even within the same family. Some individuals may present with isolated chorea, while others experience life-threatening neonatal lung disease. Treatment is symptom-based and multidisciplinary. Congenital hypothyroidism is managed with levothyroxine replacement therapy. Chorea may respond to levodopa or benzodiazepines in some cases. Pulmonary complications may require respiratory support, surfactant therapy, or long-term management of interstitial lung disease. Genetic counseling is recommended for affected families given the autosomal dominant inheritance pattern. Early diagnosis through genetic testing allows for appropriate surveillance and management of all three organ systems.

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