Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis

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

“…8,9,11 Several previous studies demonstrated diminished expression or levels of surfactant-associated proteins, and the fi nding of an NKX2-1 mutation in the subjects from family L potentially explains the reduced SP-C expression previously observed in those subjects. 2,8,9,11 In contrast, the p.R195W mutation seen in subject I was also found in a previously reported patient (designated p.R165W in that report), and was associated with increased transactivation of SFTPC in A549 cells, suggesting a dominant negative effect. 9 Variability in immunohistochemical phenotyping suggests that the corresponding mutation may have differential effects on gene expression; however, this variability may also refl ect differences in timing of tissue acquisition, interventions, or history of infection.…”

“…4 Haploinsuffi ciency for NKX2-1 due to either complete gene deletions or loss-of-function mutations results in brain-thyroid-lung syndrome (MIM 610978), with affected individuals having variable degrees of pulmonary disease, thyroid dysfunction, and neurologic abnormalities. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Neonatal RDS and chronic lung disease in older individuals have been reported in association with NKX2-1 mutations, but the pulmonary phenotype remains incompletely characterized, particularly in older children. Given the role of NKX2-1 in the surfactant system, we hypothesized that individuals with mutations in NKX2-1 may present not only with neonatal RDS, but also with ChILD and evidence of surfactant dysfunction.…”

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

“…The evidence described here is from more than 10 case reports (111,114,115,(161)(162)(163) and case series (110,113,164). The major limitations of the evidence are the study design and that the prevalence of the mutation in patients with this triad of findings has never been estimated; therefore, the yield of testing is uncertain.…”

Surfactant proteins in pediatric interstitial lung disease

“…In particular, no studies have compared the full range of these diseases, to yield better estimates of variability and to examine the relative importance of biochemical determinations of their BALF levels. It has been shown that the levels of SP-C in patients with known mutations in SFTPB (17,18), SFTPC (19,20), ABCA3 (21), and TTF1 (22) are low. Thus, we hypothesized that SP-C might serve as a helpful screening tool for such and additional surfactant dysfunction disorders.…”