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Interstitial lung disease in children with Rubinstein-Taybi syndrome
Lauren Bradford1, Mindy K Ross2, Jagila Minso3
1Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Insights
Rubinstein-Taybi syndrome (RSTS) patients may develop interstitial lung disease (ILD). Genetic mutations in CREBBP may cause ILD through abnormal surfactant metabolism or myofibroblast activation.
Area of Science:
- Genetics
- Pulmonology
- Pathology
Background:
- Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder.
- Patients with RSTS have increased risks for medical issues, but interstitial lung disease (ILD) has not been definitively linked.
- This study investigates a potential link between RSTS and ILD.
Purpose of the Study:
- To present three cases of RSTS patients who developed ILD.
- To explore potential mechanisms by which CREBBP gene mutations may contribute to ILD development.
Main Methods:
- Histological and immunofluorescent staining of lung biopsy tissue.
- Clinical microarray analysis and whole exome sequencing.
- Bioinformatics analysis using ToppGene to identify causative genes.
Main Results:
- Radiographic imaging showed consolidated densities and ground glass opacities.
- Histopathology revealed protein accumulation, fibrosis, and increased alveolar macrophages.
- Immunofluorescence indicated increased surfactant protein C, myofibroblast activation, and altered histone acetylation.
Conclusions:
- The findings suggest RSTS may be associated with ILD.
- Dysfunctional CREBBP protein may lead to ILD via abnormal surfactant metabolism or myofibroblast activation.
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.
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