title: Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome.
abstract: OBJECTIVE
  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.
authors.affiliation: Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: de Filippis
authors.affiliation: Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marelli
authors.affiliation: Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Vigone
authors.affiliation: Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Frenna
authors.affiliation: Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Weber
authors.affiliation: 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.
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
keywords: Brain-lung-thyroid syndrome; Choreoathetosis; Congenital hypothyroidism; NKX2-1; Thyroid dysgenesis; Thyroid ectopy