Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1

Abstract

Background: Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease.

Methods: Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available.

Results: We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth.

Conclusions: 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.

Figure 1.

A, Diagram of the region of chromosome 14q. B, Chromosome 14q region expanded to demonstrate 14q13.1-14q21.1, which includes NKX2-1 (small black vertical bar at 14q13.3). C, An expanded view of NKX2-1 localizing each of the mutations found in this report. Coordinates shown are according to the hg18 build of the human genome. The region “HD” in exon 3 represents the region encoding the DNA binding domain (homeodomain, c.565-759 corresponding to amino acids 189-253). Gray bars denote large deletions (subjects A, B, C, and D have approximately 1 Mb or larger deletions, and Subject E has a deletion that spans at least exons 1 and 2.) Δ = deletion; fs = frameshift; i = insertion; O = missense; X = nonsense.

Figure 2.

Venn diagram demonstrating the constellation of neurologic, thyroid, or pulmonary disease present in each of the subjects at any time during their course (denoted by letters corresponding to Table 1). Five individuals from three families had pulmonary symptoms only, but thyroid function was not examined in L2* and L3*. Subject R+ died at 6 mo, before neurologic symptoms were detected. Because pulmonary symptoms prompted the initial evaluation in all these cases, we did not identify any individuals with only neurologic or thyroid abnormalities.

Figure 3.

Histopathologic variability between patients. A, A growth abnormality with alveolar enlargement and simplification present in lungs from subject N (hematoxylin-eosin stain). B, A growth abnormality with alveolar enlargement and simplification present in lungs from subject I (hematoxylin-eosin stain). C, In contrast, minimal changes without alveolar enlargement are present in lung from subject H, shown at same magnification (hematoxylin-eosin stain). D, Electron micrograph from subject E shows hyperplastic pneumocytes with normal lamellar bodies (long arrow), cytoplasmic heterogeneous dense structures some containing lamellar body like membranes and small vacuoles (short arrow), and composite lamellar body and dense structures (dashed arrow).