TTF-1 Associated Surfactant Deficiency: Role of Ultrastructural Evaluation
John Hicks, Gary Mierau, Eric Wartchow, Claire Langston. Baylor College of Medicine & Texas Children's Hospital, Houston, TX; Children's Hospital Colorado, Aurora, CO
Background: Defects in NKX2-1 gene (14q13-21) encodes thyroid transcription factor-1 (TTF-1) and results in Brain-Thyroid-Lung Syndrome (MIM 610978), characterized by benign hereditary chorea, hypotonia, ataxia, congenital hypothyroidism and respiratory disease. TTF-1 is a critical factor in type II pneumocyte differentiation. In addition, surfactant protein synthesis is dependent on TTF-1. Deficiency of TTF-1 leads to a congenital surfactant deficiency syndrome that may be mistaken for Surfactant A, B, C or ABCA3 deficiency.
Design: Pathology archives of 2 pediatric hospitals identified 6 neonates, infants and young children (3F:3M, age range 6 mos to 3 yrs) with severe respiratory disease that lead to lung biopsy and/or subsequent lung transplantation. Clinical features were variable with some presenting in infancy with respiratory distress syndrome and others presented in early childhood with gradual onset of respiratory insufficiency, hypoxemia, failure to thrive and interstitial lung disease. Lung biopsies were performed and evaluated by routine histologic and electron microscopic (EM) techniques.
Results: Lung biopsies and explants showed features of chronic pneumonitis of infancy, lipoid pneumonia and cholesterol pneumonia. There was alveolar wall widening with prominent alveolar epithelial hyperplasia and increased interstitial cells with mild chronic inflammation and mild interstitial fibrosis. There was hyperplasia and interlobular extension of smooth muscle cells. PAS positive globules, macrophages, eosinophils and cholesterol clefts were seen in alveolar spaces. Abnormal growth development was present, characterized by decreased alveolar density, and poorly subdivided and enlarged airspaces. EM showed relatively normal lamellar bodies with infrequent disorganized lamellar bodies with concentric phospholipid membranes and eccentric dense cores. The features were those typically associated with surfactant deficiency, with exclusion of Surfactant B and ABCA3 Deficiency from consideration.
Conclusions: Discovery of features of surfactant deficiency that may be associated with TTF-1 deficiency on lung biopsy is often the first indicaton that a child may have Brain-Thyroid-Lung Syndrome secondary to NKX2-1 gene mutation. Ultrastructural examination in these cases is important in eliminating Surfactant B and ABCA3 Deficiencies from consideration based upon ultrastructural features of lamellar bodies. EM findings may guide appropriate genetic testing for the specific mutation responsible for the child's underlying respiratory disease.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 300, Wednesday Morning