Skip to main content
Log in

Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

A 23-year-old man was diagnosed with pulmonary alveolar proteinosis at the age of 11 months, and primary hypothyroidism gradually developed during infancy. He had delayed developmental milestones and severe hypotonia that evolved into non-progressive chorea during childhood. He died from large cell lung carcinoma at the age of 23 years. A de novo heterozygous insertion mutation 859–860insC in the TITF-1 gene was demonstrated. Conclusion: TITF-1 gene mutations should be considered in paediatric and adult patients with unexplained (combinations of) chorea, mental retardation, primary hypothyroidism, and chronic lung disease. Introduction of a name for the disorder, e.g. Brain-Thyroid-Lung syndrome, would probably facilitate further recognition. Whether the TITF-1 gene mutation in this patient predisposed to the development of lung cancer remains speculative.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

PAP :

pulmonary alveolar proteinosis

TITF-1 :

thyroid transcription factor 1

References

  1. Breedveld GJ, van Dongen JW, Danesino C, Guala A, Percy AK, Dure LS, Harper P, Lazarou LP, van der Linde H, Joosse M, Gruters A, MacDonald ME, de Vries BB, Arts WF, Oostra BA, Krude H, Heutink P (2002) Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 11: 971–979

    Article  CAS  Google Scholar 

  2. DeMello DE, Lin Z (2001) Pulmonary alveolar proteinosis: a review. Pediatr Pathol Mol Med 20: 413–432

    Article  CAS  Google Scholar 

  3. Devriendt K, Vanhole C, Matthijs G, de Zegher F (1998) Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 338: 1317–1318

    Article  CAS  Google Scholar 

  4. Doyle DA, Gonzalez I, Thomas B, Scavina M (2004) Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr 145: 190–193

    Article  CAS  Google Scholar 

  5. Kang Y, Hebron H, Ozbun L, Mariano J, Minoo P, Jakowlew SB (2004) Nkx2.1 transcription factor in lung cells and a transforming growth factor-beta1 heterozygous mouse model of lung carcinogenesis. Mol Carcinog 40: 212–231

    Article  Google Scholar 

  6. Kleiner-Fisman G, Rogaeva E, Halliday W, Houle S, Kawarai T, Sato C, Medeiros H, St George-Hyslop PH, Lang AE (2003) Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol 54: 244–247

    Article  CAS  Google Scholar 

  7. Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, De Felice M, von Deimling A, van Landeghem F, Di Lauro R, Gruters A (2002) Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 109: 475–480

    Article  CAS  Google Scholar 

  8. Lazzaro D, Price M, De Felice M, Di Lauro R (1991) The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 113: 1093–1104

    CAS  PubMed  Google Scholar 

  9. Minoo P (2000) Transcriptional regulation of lung development: emergence of specificity. Respir Res 1: 109–115

    Article  CAS  Google Scholar 

  10. Pohlenz J, Dumitrescu A, Zundel D, Martine U, Schonberger W, Koo E, Weiss RE, Cohen RN, Kimura S, Refetoff S (2002) Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest 109: 469–473

    Article  CAS  Google Scholar 

  11. Seymour JF, Presneill JJ (2002) Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 166: 15–35

    Article  Google Scholar 

  12. Trapnell BC, Whitsett JA, Nakata K (2003) Pulmonary alveolar proteinosis. N Engl J Med 349: 2527–2539

    Article  CAS  Google Scholar 

  13. Watada H, Mirmira RG, Kalamaras J, German MS (2000) Intramolecular control of transcriptional activity by the NK2-specific domain in NK-2 homeodomain proteins. Proc Natl Acad Sci U S A 97: 9443–9448

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michel A. A. P. Willemsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Willemsen, M.A.A.P., Breedveld, G.J., Wouda, S. et al. Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr 164, 28–30 (2005). https://doi.org/10.1007/s00431-004-1559-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-004-1559-x

Keywords

Navigation