ArticleChest2013
Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.
Article in Chest, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00014859 (Epidemiology of Surfactant Protein-B Deficiency), which is not on this map. Cited by 82 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Epidemiology of Surfactant Protein-B Deficiency
Who cites it
82 citing papers in PubMed, 2 syntheses or guidelines pooled it, 188 citations in OpenAlex.
- Respiratory and other organ manifestations inFrontiers in medicine · 2025Pooled it
- Guideline
- Pulmonary Alveolar Proteinosis: Rethinking Surfactant Homeostasis Through Alveolar Macrophage Lipid-Handling Dysfunction.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- The Genetic Landscape of Fibrotic Interstitial Lung Diseases: Clinical Implications and Diagnostic Challenges in Familial Pulmonary Fibrosis.Journal of clinical medicine · 2026Review
- Evaluation and Management of Genetic Respiratory Disorders Presenting as Hypoxemic Respiratory Failure in the Newborn Infant.Clinics in perinatology · 2026Review
- Long isoforms of the COPD risk gene FAM13A orchestrate human lung epithelial development.American journal of respiratory cell and molecular biology · 2026Article
- Biallelic LAMP3 variants in 5 families with interstitial lung disease: Evidence of a disease-gene association.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- International Registry of NKX2-1-Related Disorders: Clinical, Genetic, and Imaging Perspectives.Movement disorders : official journal of the Movement Disorder Society · 2026Observational
- Article
- A comparative analysis of clinical phenotypes and outcomes in childhood interstitial lung disease due to surfactant dysfunction disorders: focusing on mutations in SFTPC, ABCA3, and NKX2-1 genes.Italian journal of pediatrics · 2025Article
- Genetic Disorders of Surfactant Metabolism.NeoReviews · 2025Review
- Interstitial lung disease in the newborn.Journal of perinatology : official journal of the California Perinatal Association · 2025Review
- Deciphering the pathogenicity of three NKX2-1 variants in ultra-severe forms of childhood interstitial lung disease.PloS one · 2025Article
- Exploring Differentially Methylated Genes among Preterm Birth and Full-Term Birth.Lifestyle genomics · 2025Article
- Innovations in Childhood Interstitial and Diffuse Lung Disease.Clinics in chest medicine · 2024Review
- Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.American journal of respiratory and critical care medicine · 2024Review
- CRISPR-Cas9 Genome Editing Allows Generation of the Mouse Lung in a Rat.American journal of respiratory and critical care medicine · 2024Article
- Pathogenesis-driven treatment of primary pulmonary alveolar proteinosis.European respiratory review : an official journal of the European Respiratory Society · 2024Review
- Haploinsufficiency ofIntractable & rare diseases research · 2024Article
- Functional characterization of two novel NKX2-1 frameshift variants that cause pulmonary surfactant dysfunction.Pediatric research · 2024Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 12 institutions in 1 country.
Funding
Abstract
backgroundMutations 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.
methodsRetrospective 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.
resultsWe 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.
conclusionsPatients 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.