title: Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome.
abstract: 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.
authors.affiliation: Department of Pathology, Children's Hospital Boston, Massachusetts 02115, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Galambos
authors.forename: Hara
authors.initials: H
authors.lastname: Levy
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cannon
authors.forename: Sara O
authors.initials: SO
authors.lastname: Vargas
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Reid
authors.forename: Robert
authors.initials: R
authors.lastname: Cleveland
authors.forename: Robert
authors.initials: R
authors.lastname: Lindeman
authors.forename: Daphne E
authors.initials: DE
authors.lastname: deMello
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: Harry
authors.initials: H
authors.lastname: Kozakewich
mesh_terms: D000015:Abnormalities, Multiple; D001927:Brain Diseases / Q000150:complications / Q000151:congenital; D017809:Fatal Outcome; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008168:Lung / Q000473:pathology* / Q000648:ultrastructure; D008171:Lung Diseases / Q000150:complications / Q000151:congenital / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D009687:Nuclear Proteins / Q000172:deficiency*; D011014:Pneumonia / Q000150:complications; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency; D012131:Respiratory Insufficiency / Q000150:complications* / Q000151:congenital; D013577:Syndrome; D013959:Thyroid Diseases / Q000150:complications; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000172:deficiency*
chemical_list: C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D037662:Pulmonary Surfactant-Associated Protein A; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors