Interstitial lung disease in children with Rubinstein‐Taybi syndrome

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.

Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement

“…The diagnosis is made through the radiological characteristics of CT and can be confirmed by biopsy. 64 Management is as in the general population and is problematic.…”

“…Bronchiectasis has been described only in individuals with severe immunological malfunctioning. 63 Interstitial lung disease that becomes evident either in childhood, 64 or adulthood, 65 is uncommon but potentially severe. The diagnosis is made through the radiological characteristics of CT and can be confirmed by biopsy.…”

Pediatric Pulmonology 2022 year in review: Rare and diffuse lung disease

“…Affected patients typically have characteristic facial features, broad thumbs and toes, short stature, and intellectual disability. Bradford et al 1 report three patients with RTS, all with computed tomography images that include consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages.…”

Use of pirfenidone in pediatric patients with interstitial lung disease and pulmonary fibrosis

“…Patient 4 was a 2-year-old girl with Rubinstein-Taybi syndrome and related ILD as well as chronic tracheostomy and ventilator dependence and history of pulmonary hemorrhage, treated with hydroxychloroquine, azithromycin, and systemic corticosteroids with a lung biopsy that showed pulmonary alveolar proteinosis and fibrosis consistent with recently described Rubinstein-Taybi ILD. 2 At the time of pirfenidone initiation, she had worsening lung disease as evidenced by worsening hypoxemia.…”