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de Filippis T, Marelli F, Vigone MC, et al. Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome. Eur Thyroid J. 2014;3(4):227-33doi: 10.1159/000366274.
de Filippis, T., Marelli, F., Vigone, M. C., Di Frenna, M., Weber, G., & Persani, L. (2014). Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome. European thyroid journal, 3(4), 227-33. https://doi.org/10.1159/000366274
de Filippis, Tiziana, et al. "Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome." European thyroid journal vol. 3,4 (2014): 227-33. doi: https://doi.org/10.1159/000366274
de Filippis T, Marelli F, Vigone MC, Di Frenna M, Weber G, Persani L. Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome. Eur Thyroid J. 2014 Dec;3(4):227-33. doi: 10.1159/000366274. Epub 2014 Oct 15. PMID: 25759798; PMCID: PMC4311306.
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Eur Thyroid J. 2014 Dec;3(4):227-33. doi: 10.1159/000366274. Epub 2014 Oct 15.

Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome.

European thyroid journal

Tiziana de Filippis, Federica Marelli, Maria Cristina Vigone, Marianna Di Frenna, Giovanna Weber, Luca Persani

Affiliations

  1. Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  2. Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
  3. Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

PMID: 25759798 PMCID: PMC4311306 DOI: 10.1159/000366274

Abstract

OBJECTIVES: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of postnatal onset.

METHODS: The candidates were selected by a case-finding approach in 130 CH and 53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex ligation-dependent probe amplification. The variants were studied in vitro, by expression analyses and luciferase bioassay.

RESULTS: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were identified. Two children were affected with respiratory distress and CH, but wild-type NKX2-1 gene. The remaining two presented choreic movements and no pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with lingual ectopy and the other one IMH with gland in situ. They were carriers of new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and c.153_166del14). The c.177delG leads to a prematurely truncated protein (p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to the generation of an elongated aberrant protein (p.A52RfsX351) able to translocate into the nucleus, but completely inactive on a responsive promoter.

CONCLUSIONS: Two novel heterozygous frameshift mutations of NKX2-1 were identified in 2 cases selected on the basis of a BLT-like phenotype among 183 hypothyroid infants. The atypical hypothyroid phenotypes of these 2 children (CH with lingual ectopy or IMH of postnatal onset) further expand the clinical spectrum that can be associated with NKX2-1 mutations.

Keywords: Brain-lung-thyroid syndrome; Choreoathetosis; Congenital hypothyroidism; NKX2-1; Thyroid dysgenesis; Thyroid ectopy

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