BRAIN–LUNG–THYROID SYNDROME
https://doi.org/10.15690/pf.v11i6.1216
Abstract
Brain-lung-thyroid syndrome is a rare genetic disease characterized by pathology of the syndrome affected organs. This syndrome is based on mutations of the NKX2-1 gene, which encodes the thyroid transcription factor. Clinical manifestation of brain-lung-thyroid syndrome is characterized by a variable phenotype. The article presents the first Russian clinical observation of a patient with a genetically confirmed disease. Combination of such symptoms as motor development delay, ataxia, muscular hypotonia, recurrent lower airway infections, hypothyroidism helped to assume and then confirm brain-lung-thyroid syndrome by means of genetic analysis. The article also presents world literature findings (1998-2014) on clinical observations of this disease in respect of genetics, pathogenesis, pathomorphology, clinical pattern and therapy.
About the Authors
M. A. Belyashova
Peoples’ Friendship University of Russia, Moscow, Russian Federation
Russian Federation
Russian Federation
D. Yu. Ovsyannikov
Peoples’ Friendship University of Russia, Moscow, Russian Federation
Russian Federation
Russian Federation
References
1. Guazzi S., Price M., De Felice M., Mattei M.G., Di Lauro R. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J. 1990; 9: 3631–9.
2. Pan Q., Li C., Xiao J., Kimura S., Rubenstein J., Puelles L., Minoo P. In vivo characterization of the Nkx2.1 promoter/enhancer elements in transgenic mice. Gene. 2004; 331: 73–82.
3. Kimura S., Hara Y., Pineau T., Fernandez-Salguero P., Fox C.H., Ward J.M., Gonzalez F.J. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996; 10: 60–9.
4. Pohlenz J., Dumitrescu A., Zundel D., Martiné U., Schönberger W., Koo E., Weiss R.E., Cohen R.N., Kimura S., Refetoff S. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest. 2002; 109: 469–73.
5. Minoo P. Transcriptional regulation of lung development: emergence of specificity. Respir Res. 2000; 1: 109–115.
6. Lazzaro D., Price M., De Felice M., Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the fetal brain. Development. 1991; 113: 1093–1104.
7. Krude H., Schutz B., Biebermann H., von Moers A., Schnabel D., Neitzel H., Tönnies H., Weise D., Lafferty A., Schwarz S., De Felice M., von Deimling A., van Landeghem F., Di Lauro R., Grüters A. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest. 2002; 109: 475–80.
8. Willemsen M.A., Breedveld G.J., Wouda S., Otten B.J., Yntema J.L., Lammens M., de Vries B.B. 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. 2005; 164: 28–30.
9. Doyle D.A., Gonzalez I., Thomas B., Scavina M. Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr. 2004; 145: 190–3.
10. Gras D., Jonard L., Roze E., Chantot-Bastaraud S., Koht J., Motte J., Rodriguez D., Louha M., Caubel I., Kemlin I., Lion-François L., Goizet C., Guillot L., Moutard M.L., Epaud R., Héron B., Charles P., Tallot M., Camuzat A., Durr A., Polak M., Devos D., Sanlaville D., Vuillaume I., Billette de Villemeur T., Vidailhet M., Doummar D. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry. 2012; 83: 956–62.
11. Inzelberg R., Weinberger M., Gak E. Benign hereditary chorea: an update. Parkinsonism Relat Disord. 2011; 17: 301–307.
12. Carre A., Szinnai G., Castanet M., Sura-Trueba S., Tron E., Broutin-L'Hermite I., Barat P., Goizet C., Lacombe D., Moutard M.L., Raybaud C., Raynaud-Ravni C., Romana S., Ythier H., Léger J., Polak M. Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet. 2009; 18: 2266–2276.
13. Devriendt K., Vanhole C., Matthijs G., de Zegher F. Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med. 1998; 338: 1317–1318.
14. LaFranchi S. Disorders of the thyroid gland. In: R. Behrman, R. Kliegman, editors. Nelson textbook of pediatrics. 16th ed. Philadelphia (PA): WB Saunders. 2000. Р. 1696–714.
15. Kusakabe T., Kawaguchi A., Hoshi N., Kawaguchi R., Hoshi S., Kimura S. Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid. Mol Endocrinol. 2006; 20: 1796–809.
16. Perna M.G., Civitareale D., De Fillipis V., Sacco M., Cisternino C., Tassi V. Absence of mutations in the gene encoding thyroid transcription factor-1 (TTF-1) in patients with thyroid dysgenesis. Thyroid. 1997; 7: 377–81.
17. Hishinuma A., Kuribayashi T., Kanno Y., Onigata K., Nagashima K., Ieiri T. Sequence analysis of thyroid transcription factor-1 gene reveals absence of mutations in patients with thyroid dysgenesis but presence of polymorphisms in the 59 flanking region and intron. Endocrinol J. 1998; 45: 563–7.
18. Lapi P., Macchia P.E., Chiovato L., Biffali E., Moschini L., Larizza D., Baserga M., Pinchera A., Fenzi G., Di Lauro R. Mutations in the gene encoding thyroid transcription factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis. Thyroid. 1997; 7: 383–7.
19. Iwatani N., Mabe H., Devriendt K. et al. Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J Pediatr. 2000; 137: 272–276.
20. Devos D., Vuillaume I., de Becdelievre A., Kodama M., Miike T. New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord. 2006; 21: 2237–2240.
21. Kurland G., Deterding R.R., Hagood J.S., Young L.R., Brody A.S., Castile R.G., Dell S., Fan L.L., Hamvas A., Hilman B.C., Langston C., Nogee L.M., Redding G.J. American Thoracic Society Committee on Childhood Interstitial Lung Disease (chILD) and the chILD Research Network. An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Сhildhood Interstitial Lung Disease in Infancy. Am J Respir Crit Care Med. 2013; 188 (Iss. 3): 376–394.
22. Ovsyannikov D.Yu., Boitsova E.V., Belyashova M.A., Asherova I.K. Interstitsial'nye zabolevaniya legkikh u mladentsev: monografiya [Interstitial Lung Disease in Infants: Monograph]. Moscow, RUDN, 2014. 182 p.
23. Hamvas A., Deterding R.R., Wert S.E., White F.V., Dishop M.K., Alfano D.N., Halbower A.C., Planer B., Stephan M.J., Uchida D.A., Williames L.D., Rosenfeld J.A., Lebel R.R., Young L.R., Cole F.S., Nogee L.M. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013; 144: 794–804.
24. Yuan B., Li C., Kimura S., Engelhardt R.T., Smith B.R., Minoo P. Inhibition of distal lung morphogenesis in Nkx2.1 (-/-) embryos. Dev Dyn. 2000; 217: 180–90.
25. Costa R.H., Kalinichenko V.V., Lim L. Transcription factors in mouse lung development and function. Am J Physiol Lung Cell Mol Physiol. 2001; 280: 823–38.
26. Maquet E., Costagliola S., Parma J., Christophe-Hobertus C., Oligny L.L., Fournet J.C., Robitaille Y., Vuissoz J.M., Payot A., Laberge S., Vassart G., Van Vliet G., Deladoëy J. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. J Clin Endocrinol Metab. 2009; 94: 197–203.
27. Kamnasaran D., O’Brien P.C., Schuffenhauer S., Quarrell O., Lupski J.R., Grammatico P. Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes. Am J Med Genet. 2001; 102: 173–182.
28. Barnett C.P., Mencel J.J., Gecz J., Waters W., Kirwin S.M., Vinette K.M., Uppill M., Nicholl J. Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2-1. Am J Med Genet A. 2012; 158A (12): 3168–73.
29. Galambos C., Levy H., Cannon C.L., Vargas S.O., Reid L.M., Cleveland R., Lindeman R., de Mello D.E., Wert S.E., Whitsett J.A., Perez-Atayde A.R., Kozakewich H. Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome. Am J Resp Crit Care Med. 2010; 182: 549–54.
30. Breedveld G.J., van Dongen J.W., Danesino C., Guala A., Percy A.K., Dure L.S., Harper P., Lazarou L.P., van der Linde H., Joosse M., Grüters A., MacDonald M.E., de Vries B.B., Arts W.F., Oostra B.A., Krude H., Heutink P. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet. 2002; 11: 971–979.
31. Ferrara J.M., Adam O.R., Kirwin S.M., Houghton D.J., Shepherd C., Vinette K.M., Litvan I. Brain-lung-thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation. J Child Neurol. 2012; 27 (1): 68–73.
32. Teissier R., Guillot L., Carre A., Morandini M., Stuckens C., Ythier H., Munnich A., Szinnai G., de Blic J., Clement A., Leger J., Castanet M., Epaud R., Polak M. Multiplex Ligation-Dependent Probe Amplification Improves the Detection Rate of NKX2.1 Mutations in Patients Affected by Brain-Lung-Thyroid Syndrome. Horm Res Paediatr. 2012; 77: 146–151.
33. Shetty V.B., Kiraly-Borri C., Lamont P., Bikker H., Choong C.S.Y. NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. J Pediatr Endocr Met. 2014; 27 (3–4): 373–378.
34. Peall K.J., Lumsden D., Kneen R., Madhu R., Peake D., Gibbon F., Lewis H., Hedderly T., Meyer E., Robb S.A., Lynch B., King M.D., Lin J.P., Morris H.R., Jungbluth H., Kurian M.A. Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum. Dev Med Child Neurol. 2014; 56 (7): 642–8.
35. Williamson S., Kirkpatrick M., Greene S., Goudie D. A Novel Mutation of NKX2-1 Affecting 2 Generations With Hypothyroidism and Choreoathetosis: Part of the Spectrum of Brain-Thyroid-Lung Syndrome. J Child Neurol. 2014 May; 29 (5): 666–9.
36. Deutsch G.H., Young L.R., Deterding R.R., Fan L.L., Dellhttp://www.atsjournals.org/doi/abs/10.1164/rccm.200703-393OC - AFF5 S.D., Bean J.A., Brodyhttp://www.atsjournals.org/doi/abs/10.1164/rccm.200703-393OC - AFF7 A.S., Nogeehttp://www.atsjournals.org/doi/abs/10.1164/rccm.200703-393OC - AFF8 L.M., Trapnellhttp://www.atsjournals.org/doi/abs/10.1164/rccm.200703-393OC - AFF9 B.C., Langston C. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007; 176 (11): 1120–8.
37. Wert S.E., Whitsett J.A., Nogee L.M. Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol. 2009; 12 (4): 253–274.
38. Asmus F., Horber V., Pohlenz J., Schwabe D., Zimprich A., Munz M., Schöning M., Gasser T. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology. 2005; 64: 1952–1954.
39. Friederich R.L. Benign hereditary chorea improved on stimulant therapy. Pediatr Neurol. 1996; 14: 326–327.
40. Fernandez M., Raskind W., Matsushita M., Wolff J., Lipe H., Bird T. Hereditary benign chorea: clinical and genetic features of a distinct disease. Neurology. 2001; 57: 106–110.
41. Butt S.J., Sousa V.H., Fuccillo M.V., Hjerling-Leffler J., Miyoshi G., Kimura S., Fishell G. The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron. 2008; 59: 722–732.
Review
For citations:
Belyashova M.A., Ovsyannikov D.Yu. BRAIN–LUNG–THYROID SYNDROME. Pediatric pharmacology. 2014;11(6):56-61. (In Russ.) https://doi.org/10.15690/pf.v11i6.1216
Views:
2676
Email this article 