Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene

Maquet, Emilie; Costagliola, Sabine; Parma, Jasmine; Christophe-Hobertus, Christiane; Oligny, Luc L.; Fournet, Jean‐Christophe; Robitaille, Yves; Vuissoz, Jean-Marc; Payot, Antoine; Laberge, Sophie; Vassart, Gilbert; Vliet, Guy Van; Deladoëy, Johnny

doi:10.1210/jc.2008-1402

Cited by 76 publications

(45 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A few normal-sized follicles with cuboidal epithelium and intense nuclear NKX2-1 staining were interspersed between slightly enlarged to extremely dilated, multilobulated follicles with a flattened epithelium and thyrocytes exhibiting non-NKX2-1 nuclear staining. In the only other paper describing thyroid histology in a patient with an NKX2-1 mutation, no abnormalities were found [Maquet et al, 2009]. In contrast, the histological alterations found in our patient were very similar to those described in adult mice of the thyroid follicular cell-specific conditional KO mouse line Nkx2-1(fl/fl);TPO-Cre [Kusakabe et al, 2006], which suggested that NKX2-1 was required to maintain the normal architecture and function of the differentiated thyroid gland.…”

Section: Discussionsupporting

confidence: 76%

“…Few detailed descriptions are available in the literature. The case of an infant with lethal respiratory failure and an I207F NKX2-1 mutation was reported recently [Maquet et al, 2009]. In our two patients, severe neonatal respiratory distress evolving to ILD was the most prominent manifestation of the triad, similar to the picture observed in surfactant protein disorders.…”

Section: Discussionsupporting

confidence: 74%

See 1 more Smart Citation

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

et al. 2010

View full text Add to dashboard Cite

NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast, NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WT NKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 74%

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

et al. 2010

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome

Galambos

Levy

Cannon

et al. 2010

Am J Respir Crit Care Med

View full text Add to dashboard Cite

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...

show abstract

“…У экспериментальных мышей с нулевой мутацией NKX2-1 были зарегистрированы легочные дефекты, включающие аномальную альвеоляризацию, локальное утолщение альвеолярных перегородок, гипертрофию альвеолоцитов II типа, снижение синтеза сурфактанта [24][25][26]. По некоторым данным, у пациентов с мутацией NKX2-1 и легочной манифестацией заболевания высока вероятность летального исхода (16-24%) [12,23].…”

Section: клиническая характеристика и диагностикаunclassified

Brain–lung–thyroid Syndrome

Zhestkova¹,

Ovsyannikov²

2014

PPh

View full text Add to dashboard Cite

Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene

Abstract: This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis.

Cited by 76 publications

References 31 publications

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome

Brain–lung–thyroid Syndrome

Contact Info

Product

Resources

About