Absence of Lamellar Bodies with Accumulation of Dense Bodies Characterizes a Novel Form of Congenital Surfactant Defect

Tryka, A. Francine; Wert, Susan E.; Mazursky, Jon E.; Arrington, Robert W.; Nogee, Lawrence M.

doi:10.1007/s100249910048

Cited by 55 publications

(29 citation statements)

References 30 publications

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“…The improvement of symptoms with surfactant administration in this infant and in another child with TTF-1 deficiency (7) is clinical evidence supporting a surfactant abnormality component. In contrast to genetic disorders of surfactant function (i.e., SP-B and ABCA3 deficiencies), wherein lamellar bodies are reduced, absent, or abnormally formed (30)(31)(32)(33), or alveolar proteinosis, wherein there is accumulation of phospholipid membranes and abnormal tubular myelin (34), the ultrastructure of the lamellar bodies in this infant appeared normal and were abundant in alveolar lumens. Tubular myelin was not seen, but is generally not observed in lung specimens routinely examined by electron microscopy (Reference [35] and personal observations, A.R.P-A.).…”

Section: Discussionmentioning

confidence: 62%

Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome

Galambos

Levy

Cannon

et al. 2010

Am J Respir Crit Care Med

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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.Keywords: alveolar growth abnormality; cerebral dysgenesis; thyroid transcription factor-1; bronchopulmonary dysplasia; surfactant protein Thyroid transcription factor-1 (TTF-1, also known as TITF-1, NKX2-1, or TEBP), a member of the NKx2 homeodomain transcription factor family, is essential for the morphogenesis of thyroid, lungs, and brain (3).TTF-1 knockout mice fail to develop these organs and die at birth, whereas the heterozygous mice reach term (4).TTF-1 haploinsufficiency in humans is responsible for a rare syndrome (TTF-1 deficiency syndrome) characterized by neurological, thyroidal, and pulmonary dysfunction (5-9). In a recent series that also reviewed the clinical and pathologic findings of 46 patients with TTF-1 deficiency, pulmonary disease occurred in 54%, with ''infant respiratory distress syndrome'' being the most common (7). The pulmonary pathology has been described briefly in one patient, whereas only one other case report illustrates the pathologic findings (10, 11).We identified an infant with cerebral dysgenesis, thyroidal dysfunction, respiratory insufficiency, and a karyotype showing a 14q13-21.3 deletion encompassing the TTF-1 gene locus. The infant died at 8 months with pneumonia and respiratory insufficiency. We describe his pulmonary pathology, incl...

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Section: Discussionmentioning

confidence: 62%

Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome

Galambos

Levy

Cannon

et al. 2010

Am J Respir Crit Care Med

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“…There was variable, but extensive interstitial fibrosis and pneumocyte hyperplasia, along with alveolar macrophages, but without alveolar proteinosis. Normal appearing lamellar bodies and tubular myelin were seen by electron microscopy (3,14,15,20). Among the 15 ABCA3 haplotypes computationally inferred from the E292V and control cohorts (n ϭ 23), we identified two common haplotypes among the 35 alleles that did not carry E292V: haplotype 1 with 13 (37%) and haplotype 2 with 9 (26%) ( Table 5).…”

Section: Resultsmentioning

confidence: 98%

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

et al. 2008

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ABSTRACT:The prevalence of the common mutations in the surfactant protein-B (121ins2), surfactant protein-C (I73T), and ATP-binding cassette member A3 (E292V) genes in populationbased or case-control cohorts of newborn respiratory distress syndrome (RDS) is unknown. We determined the frequencies of these mutations in ethnically diverse population and disease-based cohorts using restriction enzyme analysis (121ins2 and E292V) and a 5Ј nuclease assay (I73T) in DNA samples from population-based cohorts in Missouri, Norway, South Korea, and South Africa, and from a case-control cohort of newborns with and without RDS (n ϭ 420). We resequenced the ATP-binding cassette member A3 gene (ABCA3) in E292V carriers and computationally inferred ABCA3 haplotypes. The population-based frequencies of 121ins2, E292V, and I73T were rare (Ͻ0.4%). E292V was present in 3.8% of newborns with RDS, a 10-fold greater prevalence than in the Missouri cohort (p Ͻ 0.001). We did not identify other loss of function mutations in ABCA3 among patients with E292V that would account for their RDS. E292V occurred on a unique haplotype that was derived from a recombination of two common ABCA3 haplotypes. E292V was over-represented in newborns with RDS suggesting that E292V or its unique haplotype impart increased genetic risk for RDS. (Pediatr Res 63: 645-649, 2008)

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“…Variably sized homogeneous and heterogeneous dense bodies were present, including a few with a "fried egg" appearance similar to that seen with ABCA3 defi ciency (subjects I and J). 3,22 …”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

Hamvas

Deterding

Wert

et al. 2013

Chest

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Thyroid transcription factor 1 (TTF-1), encoded by the gene NKX2-1 (Entrez gene identifi cation number 7080 ), is expressed in the thyroid gland, brain, and lung. In the lung, it is an early marker of lung differentiation and is important for structural development M utations in genes encoding surfactant protein-B ( SFTPB ), member A3 of the ATP-binding cassette family of transporters ( ABCA3 ), and surfactant protein-C ( SFTPC ) cause neonatal respiratory distress syndrome (RDS) or childhood interstitial and diffuse lung disease (ChILD). 1 Considerable overlap in the clinical and histologic features of the lung disease associated with these mutations exists, which are collectively referred to as surfactant dysfunction disorders. Children with fi ndings of surfactant dysfunction but without identifi able mutations in the SFTPB , SFTPC, or ABCA3 genes have been reported. 2,3 Background: Mutations in the gene encoding thyroid transcription factor, NKX2-1 , result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identifi ed individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. Methods: Retrospective and prospective approaches identifi ed infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available.

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Absence of Lamellar Bodies with Accumulation of Dense Bodies Characterizes a Novel Form of Congenital Surfactant Defect

Cited by 55 publications

References 30 publications

Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome

Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

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