Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome

Csaba Galambos, Hara Levy, Carolyn L. Cannon, Sara O. Vargas, Lynne M. Reid, Robert Cleveland, Robert Lindeman, Daphne E. DeMello, Susan E. Wert, Jeffrey A. Whitsett, Antonio R. Perez-Atayde, Harry Kozakewich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Thyroid transcription factor-1 (TTF-1) deficiency syndrome is characterized by neurologic, thyroidal, and pulmonary dysfunction. Children usually have mild-to-severe respiratory symptoms and occasionally die of respiratory failure. Herein, we describe an infant with a constitutional 14q12-21.3 haploid deletion encompassing the TTF-1 gene locus who had cerebral dysgenesis, thyroidal dysfunction, and respiratory insufficiency.The clinical course was notable for mild hyaline membrane disease, continuous ventilatory support, and symmetrically distributed pulmonary cysts by imaging. He developed pneumonia and respiratory failure and died at 8 months. Pathologically, the lungs had grossly visible emphysematous changes with "cysts" up to 2 mm in diameter. The airway generations and radial alveolar count were diminished. In addition to acute bacterial pneumonia, there was focally alveolar septal fibrosis, pneumocyte hypertrophy, and clusters of airspace macrophages. Ultrastructurally, type II pneumocytes had numerous lamellar bodies, and alveolar spaces contained fragments of type II pneumocytes and extruded lamellar bodies. Although immunoreactivity for surfactant protein SP-A and ABCA3 was diminished, that for SP-B and proSP-C was robust, although irregularly distributed, corresponding to the distribution of type II pneumocytes. Immunoreactivity for TTF-1 protein was readily detected. In summation, we document abnormal airway and alveolar morphogenesis and altered expression of surfactant-associated proteins, which may explain the respiratory difficulties encountered in TTF-1 haploinsufficiency. These findings are consistent with experimental evidence documenting the important role of TTF-1 in pulmonary morphogenesis and surfactant metabolism.

Original languageEnglish (US)
Pages (from-to)549-554
Number of pages6
JournalAmerican journal of respiratory and critical care medicine
Issue number4
StatePublished - Aug 15 2010


  • Alveolar growth abnormality
  • Bronchopulmonary dysplasia
  • Cerebral dysgenesis
  • Surfactant protein
  • Thyroid transcription factor-1

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine


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