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Original Research: Diffuse Lung Disease |

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1Pulmonary Phenotypes and NKX2-1 Mutations

Aaron Hamvas, MD; Robin R. Deterding, MD; Susan E. Wert, PhD; Frances V. White, MD; Megan K. Dishop, MD; Danielle N. Alfano, MD; Ann C. Halbower, MD; Benjamin Planer, MD; Mark J. Stephan, MD; Derek A. Uchida, MD; Lee D. Williames, MD; Jill A. Rosenfeld, MS; Robert Roger Lebel, MD; Lisa R. Young, MD; F. Sessions Cole, MD; Lawrence M. Nogee, MD
Author and Funding Information

From the Edward Mallinckrodt Department of Pediatrics (Drs Hamvas, Alfano, and Cole), and Lauren Ackerman Department of Pathology and Immunology (Dr White), Washington University, St. Louis, MO; Department of Pediatrics (Drs Deterding and Halbower), and Department of Pathology and Laboratory Medicine (Dr Dishop), University of Colorado School of Medicine, Aurora, CO; The Perinatal Institute (Dr Wert), Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Department of Pediatrics (Dr Planer), Hackensack University Medical Center, Hackensack, NJ; Department of Pediatrics (Dr Stephan), University of Washington, Seattle, WA; Department of Pediatrics (Dr Uchida), University of Utah School of Medicine, Salt Lake City, UT; Department of Pediatrics (Dr Williames), Madigan Healthcare System, Tacoma, WA; Signature Genomic Laboratories (Ms Rosenfeld), PerkinElmer, Inc, Spokane, WA; Section of Medical Genetics (Dr Lebel), Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY; Departments of Pediatrics and Medicine (Dr Young), Vanderbilt University, Nashville, TN; and the Department of Pediatrics (Dr Nogee), Johns Hopkins University, Baltimore, MD.

Correspondence to: Aaron Hamvas, MD, Division of Newborn Medicine, Washington University School of Medicine, Campus Box 8116, 660 S Euclid Ave, St. Louis, MO 63110; e-mail: hamvas@kids.wustl.edu


For editorial comment see page 728

Drs Hamvas and Deterding contributed equally to this work.

A preliminary report of some of these studies was presented at the American Thoracic Society International Conference in May 2010 and published in abstract form (Deterding RR, Uchida DA, Stephan M, et al. Thyroid transcription factor 1 gene abnormalities: an under recognized cause of Children’s Interstitial Lung Disease. Am J Respir Crit Care Med. 2010;181:A6725). Data from three subjects described in this manuscript were reported in 2001, before the mechanism for their lung disease was identified (Amin RS, Wert SE, Baughman RP, et al. Surfactant protein deficiency in familial interstitial lung disease. J Pediatr. 2001;139[1]:85-92).

Funding/Support: This study was supported by National Institutes of Health grants to Drs Hamvas and Cole [HL065174, HL082747] and Dr Nogee [HL54703].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(3):794-804. doi:10.1378/chest.12-2502
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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.

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