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Original Research: Genetic and Developmental Disorders |

A Mutation in TTF1/NKX2.1 Is Associated With Familial Neuroendocrine Cell Hyperplasia of InfancyNeuroendocrine Cell Hyperplasia of Infancy

Lisa R. Young, MD; Gail H. Deutsch, MD; Ronald E. Bokulic, DO; Alan S. Brody, MD; Lawrence M. Nogee, MD
Author and Funding Information

From the Division of Pulmonary Medicine, Department of Pediatrics (Dr Young) and Division of Allergy, Pulmonary and Critical Care, Department of Medicine (Dr Young), Vanderbilt University School of Medicine, Nashville, TN; Department of Pathology (Dr Deutsch), Seattle Children’s Hospital and University of Washington, Seattle, WA; Division of Pulmonary Medicine (Dr Bokulic) and Department of Radiology (Dr Brody), Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH; and Eudowood Neonatal Pulmonary Division, Department of Pediatrics (Dr Nogee), Johns Hopkins University, Baltimore, MD.

Correspondence to: Lawrence M. Nogee, MD, Eudowood Neonatal Pulmonary Division, Department of Pediatrics, Johns Hopkins University, CMSC 6-104A, 600 N Wolfe St, Baltimore, MD 21287; e-mail: lnogee@jhmi.edu


Funding/Support: This work was supported by grants through the National Institutes of Health [HL54703, Dr Nogee]; American Thoracic Society/chILD Foundation/chILD (Lung) Foundation-UK (Dr Young); and the Eudowood Foundation (Dr Nogee).

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


Chest. 2013;144(4):1199-1206. doi:10.1378/chest.13-0811
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Background:  Neuroendocrine cell hyperplasia of infancy (NEHI) is a childhood diffuse lung disease of unknown etiology. We investigated the mechanism for lung disease in a subject whose clinical, imaging, and lung biopsy specimen findings were consistent with NEHI; the subject’s extended family and eight other unrelated patients with NEHI were also investigated.

Methods:  The proband’s lung biopsy specimen (at age 7 months) and serial CT scans were diagnostic of NEHI. Her mother, an aunt, an uncle, and two first cousins had failure to thrive in infancy and chronic respiratory symptoms that improved with age. Genes associated with autosomal-dominant forms of childhood interstitial lung disease were sequenced.

Results:  A heterozygous NKX2.1 mutation was identified in the proband and the four other adult family members with histories of childhood lung disease. The mutation results in a nonconservative amino acid substitution in the homeodomain in a codon extensively conserved through evolution. None of these individuals have thyroid disease or movement disorders. NKX2.1 mutations were not identified by sequence analysis in eight other unrelated subjects with NEHI.

Conclusions:  The nature of the mutation and its segregation with disease support that it is disease-causing. Previously reported NKX2.1 mutations have been associated with “brain-thyroid-lung” syndrome and a spectrum of more severe pulmonary phenotypes. We conclude that genetic mechanisms may cause NEHI and that NKX2.1 mutations may result in, but are not the predominant cause of, this phenotype. We speculate that altered expression of NKX2.1 target genes other than those in the surfactant system may be responsible for the pulmonary pathophysiology of NEHI.

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