Case of congenital hypothyroidism related to NKX2-1
https://doi.org/10.14341/probl201662321-24
Abstract
NKX2-1 is a transcription factor. Gene NKX2-1 is expressed in tissues of the thyroid gland, brain and lungs. Mutations of NKX2-1 can lead to neurological disorders, hypothyroidism, and respiratory distress syndrome. The combinations of these symptoms are known as brain-lung-thyroid syndrome. Benign hereditary chorea is the characteristic feature of this disease and the most common manifestation of it. Chorea progresses into the second decade after which it remains stable or may even spontaneously remit. Pulmonary dysfunction is the second most common manifestation of NKX2-1-related disorders. They include respiratory distress syndrome of the newborns, interstitial lung disease between ages four months and seven years and pulmonary fibrosis in older individuals. Thyroid dysfunction can present as congenital hypothyroidism or subclinical hypothyroidism in adolescents. The combination of triad of the syndrome is present in only 50% of patients. This study includes a description of patient with brain-lung-thyroid syndrome. We described the novel mutation c.628_772del in the gene NKX2-1.
Keywords
Supporting agencies: Fund for Support and Development of Philanthropy
About the Authors
Nina A. Makretskaya
Endocrinology Research Centre
Russian Federation
MD, postgraduate student
Russian Federation
MD, postgraduate student
Natalya Y. Kalinchenko
Endocrinology Research Centre
Russian Federation
MD, PhD, Researcher
Russian Federation
MD, PhD, Researcher
Evgeny V. Vasiliev
Endocrinology Research Centre
Russian Federation
PhD, Researcher
Russian Federation
PhD, Researcher
Vasiliy M. Petrov
Endocrinology Research Centre
Russian Federation
PhD, Researcher
Russian Federation
PhD, Researcher
Anatoly N. Tiulpakov
Endocrinology Research Centre
Russian Federation
MD, PhD
Russian Federation
MD, PhD
References
1. Carre A, Szinnai G, Castanet M, et al. Five new TITF1/NKX2.1 mutations in brain—lung—thyroid syndrome: rescue by Pax8 synergism in one case. Hum Mol Genet. 2009;18(12):2266-2276. doi: 10.1093/hmg/ddp162
2. Thorwarth A, Schnittert-Hubener S, Schrumpf P, et al. Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum. J Med Genet. 2014;51(6):375-387. doi: 10.1136/jmedgenet-2013-102248
3. Di Palma T, Nitsch R, Mascia A, et al. The paired domain-containing factor Pax8 and the homeodomain-containing factor TITF-1 directly interact and synergistically activate transcription. J Biol Chem. 2003;278(5):3395-3402. doi: 10.1074/jbc.M205977200
4. Miccadei S, De Leo R, Zammarchi E, et al. The synergistic activity of thyroid transcription factor 1 and Pax8 relies on the promoter/enhancer interplay. Mol Endocrinol. 2002;16(4):837-846. doi: 10.1210/mend.16.4.0808
5. De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev. 2004;25(5):722-746. doi: 10.1210/Er.2003-0028
6. Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144(3):794-804. doi: 10.1378/chest.12-2502
7. Carre A, Szinnai G, Castanet M, et al. Five new TITF1/NKX2.1 mutations in brain—lung—thyroid syndrome: rescue by Pax8 synergism in one case. Hum Mol Genet. 2009;18(12):2266-2276. doi: 10.1093/hmg/ddp162
8. Gras D, Jonard L, Roze E, et al. 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(10):956-962. doi: 10.1136/Jnnp-2012-302505
9. Беляшова М.А., Овсянникова Д.Ю. Синдром мозг—легкие—щитовидная железа. // Педиатрическая фармакология. — 2014. — Т. 11. — №6. — С. 56–61. [Belyashova MА, Ovsyannikov DY. Brain—lung—thyroid syndrome. Pediatric Pharmacology. 2014:11(6):56-61. (In Russ.)].
10. 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(18):1317-1318. doi: 10.1056/nejm199804303381817
11. Willemsen MA, Breedveld GJ, 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. 2005;164(1):28-30. doi: 10.1007/s00431-004-1559-x
12. Harper PS. Benign hereditary chorea. Clinical and genetic aspects. Clin Genet. 1978;13(1):85-95.
13. Patel NJ, Jankovic J. NKX2-1-related disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, Eds. Gene Reviews [Internet]. Seattle (Wa): University Of Washington, Seattle;1993—2015;2014 Feb 20.
14. Schady W, Meara RJ. Hereditary progressive chorea without dementia. J Neurol Neurosurg Psychiatry. 1988;51(2):295-297. doi: 10.1136/jnnp.51.2.295
15. Schrag A, Quinn NP, Bhatia KP, Marsden CD. Benign hereditary chorea—entity or syndrome? Mov Disord. 2000;15(2):280-288.
16. Shimohata T, Hara K, Sanpei K, et al. Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 Q23.3. Brain. 2007;130(Pt 9):2302-2309. doi: 10.1093/brain/awm036
17. Glik A, Vuillaume I, Devos D, Inzelberg R. Psychosis, short stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation. Mov Disord. 2008;23(12):1744-1747. doi: 10.1002/mds.22215
18. Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited: a journey to understanding. Mov Disord. 2007;22(16):2297-2305; Quiz 2452. doi: 10.1002/mds.21644
19. Gras D, Jonard L, Roze E, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long-term follow-up in a large series with new mutations n the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry. 2012;83(10):956-962. doi: 10.1136/jnnp-2012-302505
20. Maquet E, Costagliola S, Parma J, et al. 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(1):197-203. doi: 10.1210/jc.2008-1402
21. Gillett ES, Deutsch GH, Bamshad MJ, et al. Novel NKX2.1 mutation associated with hypothyroidism and lethal respiratory failure in a full-term neonate. J Perinatol. 2013;33(2):157-160. doi: 10.1038/jp.2012.50
22. Fernandez M, Raskind W, Matsushit AM, et al. Hereditary benign chorea: clinical and genetic features of a distinct disease. Neurology. 2001;57(1):106-110.
23. Ferrara AM, De Michele G, Salvatore E, et al. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid. 2008;18(9):1005-1009. doi: 10.1089/thy.2008.0085
24. Salvatore E, Di Maio L, Filla A, et al. Benign hereditary chorea: clinical and neuroimaging features in an Italian family. Mov Disord. 2010;25(10):1491-1496. doi: 10.1002/mds.23065
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For citations:
Makretskaya N.A., Kalinchenko N.Y., Vasiliev E.V., Petrov V.M., Tiulpakov A.N. Case of congenital hypothyroidism related to NKX2-1. Problems of Endocrinology. 2016;62(3):21-24. https://doi.org/10.14341/probl201662321-24
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