Interstitial lung disease in children with Rubinstein-Taybi syndrome

Pediatr Pulmonol. 2022 Jan;57(1):264-272. doi: 10.1002/ppul.25709. Epub 2021 Oct 28.


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.

Keywords: interstitial lung disease; medical genetics; pediatric; pulmonology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CREB-Binding Protein / genetics
  • Child
  • Exome Sequencing
  • Humans
  • Lung Diseases, Interstitial* / etiology
  • Lung Diseases, Interstitial* / genetics
  • Mutation
  • Rubinstein-Taybi Syndrome* / complications
  • Rubinstein-Taybi Syndrome* / diagnosis
  • Rubinstein-Taybi Syndrome* / genetics


  • CREB-Binding Protein