title: 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.
authors: Edward Mallinckrodt Department of Pediatrics, Washington University, St. Louis, MO. Electronic address: hamvas@kids.wustl.edu.
authors: Aaron
authors: A
authors: Hamvas
authors: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
authors: Robin R
authors: RR
authors: Deterding
authors: The Perinatal Institute, 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.
authors: Susan E
authors: SE
authors: Wert
authors: Lauren Ackerman Department of Pathology and Immunology, Washington University, St. Louis, MO.
authors: Frances V
authors: FV
authors: White
authors: Department of Pathology and Laboratory Medicine, University of Colorado School of Medicine, Aurora, CO.
authors: Megan K
authors: MK
authors: Dishop
authors: Edward Mallinckrodt Department of Pediatrics, Washington University, St. Louis, MO.
authors: Danielle N
authors: DN
authors: Alfano
authors: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
authors: Ann C
authors: AC
authors: Halbower
authors: Department of Pediatrics, Hackensack University Medical Center, Hackensack, NJ.
authors: Benjamin
authors: B
authors: Planer
authors: Department of Pediatrics, University of Washington, Seattle, WA.
authors: Mark J
authors: MJ
authors: Stephan
authors: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT.
authors: Derek A
authors: DA
authors: Uchida
authors: Department of Pediatrics, Madigan Healthcare System, Tacoma, WA.
authors: Lee D
authors: LD
authors: Williames
authors: Signature Genomic Laboratories, PerkinElmer, Inc, Spokane, WA.
authors: Jill A
authors: JA
authors: Rosenfeld
authors: Section of Medical Genetics, Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY.
authors: Robert Roger
authors: RR
authors: Lebel
authors: Departments of Pediatrics and Medicine, Vanderbilt University, Nashville, TN.
authors: Lisa R
authors: LR
authors: Young
authors: Edward Mallinckrodt Department of Pediatrics, Washington University, St. Louis, MO.
authors: F Sessions
authors: FS
authors: Cole
authors: Department of Pediatrics, Johns Hopkins University, Baltimore, MD.
authors: Lawrence M
authors: LM
authors: Nogee
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism / Q000648:ultrastructure; D008171:Lung Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012189:Retrospective Studies; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D004247:DNA