Mutations in the gene encoding thyroid transcription factor (NKX2-1) result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress (RDS) known as the “Brain-Thyroid-Lung syndrome.” We identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease in order to characterize the spectrum of associated pulmonary phenotypes.
Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathology, electron microscopy and immunohistochemical analysis for surfactant associated proteins were assessed in a subset of 10 children for whom lung tissue was available.
We identified 16 individuals with heterozygous missense, nonsense and frameshift mutations and 5 individuals with heterozygous whole gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 (76%), interstitial lung disease in 4 (19%), and pulmonary fibrosis in 1 adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but 5 (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in 9 subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases and at least 5 cases had evidence of disrupted lung growth.
Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development, are likely mechanisms for the respiratory disease.