Interstitial lung disease in children with Rubinstein-Taybi syndrome
Corresponding Author
Lauren Bradford MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Correspondence Lauren Bradford, MD, Wake Forest Baptist Health / Brenner Children's Pediatric Pulmonology, Medical Center Boulevard, Winston Salem NC 27157, USA.
Email: [email protected]
Search for more papers by this authorMindy K. Ross MD
Division of Pediatric Pulmonology, University of California-Los Angeles, Los Angeles, California, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorJagila Minso MD
Division of Pediatric Critical Care, Sanford Health, Fargo, North Dakota, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorMateja Cernelc-Kohan MD
Department of Pediatrics, UC-San Diego Pediatric Respiratory Medicine, La Jolla, California, USA
Division of Pediatric Respiratory Medicine, Rady Children's Hospital, San Diego, California, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorKatayoon Shayan MD
Division of Pediatric Respiratory Medicine, Rady Children's Hospital, San Diego, California, USA
Contribution: Data curation (equal), Formal analysis (equal), Writing - original draft (equal)
Search for more papers by this authorSimon S. Wong MD
Department of Pediatrics, UC-San Diego Pediatric Respiratory Medicine, La Jolla, California, USA
Contribution: Conceptualization (equal), Methodology (equal)
Search for more papers by this authorXiaoping Li MD
Department of Pediatrics, UC-San Diego Pediatric Respiratory Medicine, La Jolla, California, USA
Contribution: Conceptualization (equal), Methodology (equal)
Search for more papers by this authorLauraine Rivier PhD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Contribution: Methodology (equal), Project administration (equal), Writing - original draft (equal)
Search for more papers by this authorAnil G. Jegga DVM, MRes
Department of Pediatrics, Division of Biomedical Informatics, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA
Department of Pediatrics, Division of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Writing - original draft (equal)
Search for more papers by this authorGail H. Deutsch MD
Department of Pathology and Laboratory Medicine, Seattle Children's Hospital, Seattle, Washington, USA
Contribution: Data curation (equal), Methodology (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorTimothy J. Vece MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Contribution: Conceptualization (equal), Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorCeila E. Loughlin MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Search for more papers by this authorWilliam A. Gower MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Search for more papers by this authorCaitlin Hurley MD
Critical Care Medicine Division, Departments of Pediatric Medicine and Bone Marrow Transplant, St. Jude Children's Hospital, Memphis, Tennessee, USA
Department of Oncology, Division of Solid Tumor, St. Jude Children's Hospital, Memphis, Tennessee, USA
Contribution: Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorWayne Furman MD
Critical Care Medicine Division, Departments of Pediatric Medicine and Bone Marrow Transplant, St. Jude Children's Hospital, Memphis, Tennessee, USA
Department of Oncology, Division of Solid Tumor, St. Jude Children's Hospital, Memphis, Tennessee, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorDennis Stokes MD
Department of Pediatrics, Division of Pediatric Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorJames S. Hagood MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), Funding acquisition (equal), Methodology (equal), Resources (equal), Supervision (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Lauren Bradford MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Correspondence Lauren Bradford, MD, Wake Forest Baptist Health / Brenner Children's Pediatric Pulmonology, Medical Center Boulevard, Winston Salem NC 27157, USA.
Email: [email protected]
Search for more papers by this authorMindy K. Ross MD
Division of Pediatric Pulmonology, University of California-Los Angeles, Los Angeles, California, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorJagila Minso MD
Division of Pediatric Critical Care, Sanford Health, Fargo, North Dakota, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorMateja Cernelc-Kohan MD
Department of Pediatrics, UC-San Diego Pediatric Respiratory Medicine, La Jolla, California, USA
Division of Pediatric Respiratory Medicine, Rady Children's Hospital, San Diego, California, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorKatayoon Shayan MD
Division of Pediatric Respiratory Medicine, Rady Children's Hospital, San Diego, California, USA
Contribution: Data curation (equal), Formal analysis (equal), Writing - original draft (equal)
Search for more papers by this authorSimon S. Wong MD
Department of Pediatrics, UC-San Diego Pediatric Respiratory Medicine, La Jolla, California, USA
Contribution: Conceptualization (equal), Methodology (equal)
Search for more papers by this authorXiaoping Li MD
Department of Pediatrics, UC-San Diego Pediatric Respiratory Medicine, La Jolla, California, USA
Contribution: Conceptualization (equal), Methodology (equal)
Search for more papers by this authorLauraine Rivier PhD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Contribution: Methodology (equal), Project administration (equal), Writing - original draft (equal)
Search for more papers by this authorAnil G. Jegga DVM, MRes
Department of Pediatrics, Division of Biomedical Informatics, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio, USA
Department of Pediatrics, Division of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Writing - original draft (equal)
Search for more papers by this authorGail H. Deutsch MD
Department of Pathology and Laboratory Medicine, Seattle Children's Hospital, Seattle, Washington, USA
Contribution: Data curation (equal), Methodology (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorTimothy J. Vece MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Contribution: Conceptualization (equal), Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorCeila E. Loughlin MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Search for more papers by this authorWilliam A. Gower MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Search for more papers by this authorCaitlin Hurley MD
Critical Care Medicine Division, Departments of Pediatric Medicine and Bone Marrow Transplant, St. Jude Children's Hospital, Memphis, Tennessee, USA
Department of Oncology, Division of Solid Tumor, St. Jude Children's Hospital, Memphis, Tennessee, USA
Contribution: Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorWayne Furman MD
Critical Care Medicine Division, Departments of Pediatric Medicine and Bone Marrow Transplant, St. Jude Children's Hospital, Memphis, Tennessee, USA
Department of Oncology, Division of Solid Tumor, St. Jude Children's Hospital, Memphis, Tennessee, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorDennis Stokes MD
Department of Pediatrics, Division of Pediatric Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Contribution: Data curation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorJames S. Hagood MD
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), Funding acquisition (equal), Methodology (equal), Resources (equal), Supervision (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorAs this is a cooperative study, majority of research was performed at UC-San Diego Pediatric Respiratory Medicine.
Abstract
Introduction
Rubinstein-Taybi syndrome (RSTS) is a rare genetic syndrome caused primarily by a mutation in the CREBBP gene found on chromosome 16. Patients with RSTS are at greater risk for a variety of medical problems, including upper airway obstruction and aspiration. Childhood interstitial lung disease (ILD) thus far has not been definitively linked to RSTS. Here we present three patients with RSTS who developed ILD and discuss possible mechanisms by which a mutation in CREBBP may be involved in the development of ILD.
Methods
Routine hematoxylin and eosin staining was performed on lung biopsy tissue for histological analysis. Immunofluorescent staining was performed on lung biopsy tissue for markers of fibrosis, surfactant deficiency and histone acetylation. Cases 1 and 2 had standard clinical microarray analysis. Case 3 had whole exome sequencing. Bioinformatics analyses were performed to identify possible causative genes using ToppGene.
Results
Computed tomography images in all cases showed consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages. Immunofluorescent staining showed increase in surfactant protein C staining, patchy areas of increased anti-smooth muscle antibody staining, and increased staining for acetylated histone 2 and histone 3 lysine 9.
Discussion
Clinical characteristics, radiographic imaging, lung histopathology, and immunofluorescent staining results shared by all cases demonstrated findings consistent with ILD. Immunofluorescent staining suggests two possible mechanisms for the development of ILD: abnormal surfactant metabolism and/or persistent activation of myofibroblasts. These two pathways could be related to dysfunctional CREBBP protein.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Supporting Information
| Filename | Description |
|---|---|
| ppul25709-sup-0001-E-figure_1.tif12.7 MB | Immunofluorescence overlay images; 20x; Blue (DAPI): nuclei; Green (FITC): acetylated histone 2B (H2BAc). A) Control; B) Case 1; C) Case 2; D) Case 3. |
| ppul25709-sup-0002-E-figure_2.tif12.6 MB | Immunofluorescence overlay images; 20x; Blue (DAPI): nuclei; Green (FITC): acetylated histone 3 lysine 9 (H3K9Ac). A) Control; B) Case 1; C) Case 2; D) Case 3. |
| ppul25709-sup-0003-E-figure_3.tif2.3 MB | Genetic ranking in four categories of “training genes”. This Venn diagram illustrates the number of genes in the top 10 list for each category and combination of categories. CREBBP and PDPK1 are the only genes ranked in the top 10 in all four categories. EMT = epithelial-mesenchymal transition. Tissue remodel = tissue remodeling. Pulm fibrosis = pulmonary fibrosis. |
| ppul25709-sup-0004-E_Table_1.docx14.4 KB | Supporting information. |
| ppul25709-sup-0005-E-table_2.docx15 KB | Supporting information. |
| ppul25709-sup-0006-E-table_3.docx13.5 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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