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Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis
  1. Barbara Kleinlein1,
  2. Matthias Griese2,
  3. Gerhard Liebisch3,
  4. Heiko Krude4,
  5. Peter Lohse5,
  6. Charalampos Aslanidis3,
  7. Gerd Schmitz3,
  8. Jochen Peters1,
  9. Andreas Holzinger2
  1. 1Kinderklinik Dritter Orden, Munich, Germany
  2. 2Dr von Hauner Children's Hospital, Ludwig-Maximilian University, Munich, Germany
  3. 3Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
  4. 4Institute of Experimental Pediatric Endocrinology, Charité – Universitätsmedizin Berlin, Berlin, Germany
  5. 5Department of Clinical Chemistry – Großhadern, Ludwig-Maximilian University, Munich, Germany
  1. Correspondence to Professor Andreas Holzinger, Dr von Hauner Children's Hospital, Ludwig-Maximilian University Munich, Lindwurmstrasse 4, Munich, 80337, Germany; andreas.holzinger{at}


Defects of the NKX2-1 gene, encoding thyroid transcription factor-1, cause brain-thyroid-lung syndrome (MIM 610978), characterised by benign hereditary chorea, congenital hypothyroidism and respiratory disease. The case of a term infant with mild primary congenital hypothyroidism and neonatal persistent respiratory failure with fatal outcome at 10 months of age despite continuous ventilatory support is described. Congenital defects of genes known to disturb surfactant protein and lipid homeostasis (SFTPB, SFTPC, ABCA3) were excluded. Hypothyroidism prompted sequencing of NKX2-1, which revealed a heterozygous 29 bp deletion (c.278_306del29) disrupting the affected allele. Analysis of bronchoalveolar lavage fluid demonstrated an abnormally low amount of surfactant protein C (SP-C) in relation to SP-B, and low levels of surfactant phospholipids, indicating disturbance of SP and lipid homeostasis as a consequence of NKX2-1 haploinsufficiency. NKX2-1 haploinsufficiency may lead to lethal respiratory failure of the newborn due to disruption of pulmonary surfactant homeostasis. NKX2-1 gene analysis should be considered when investigating irreversible respiratory insufficiency of the newborn.

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  • Funding This work was supported by a grant from the Bundesministerium für Bildung und Forschung (

  • Competing interests None.

  • Patient consent Parental consent obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.