title: Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene.
abstract: NK2 homeobox-1 (NKX2.1) gene encoding the thyroid transcription factor-1 (TTF-1) plays a critical role in lung, thyroid, and central nervous system morphogenesis and function; mutations cause a rare form of progressive respiratory failure associated with alterations of surfactant synthesis, composition, and homeostasis. Molecular mechanisms are heterogeneous and poorly explored. A 28 days old male, soon after birth, presented respiratory failure requiring oxygen treatment at FiO2 27%, prolonged for 2 weeks. Routine neonatal screenings detected a high thyroid stimulating hormone concentration. On day 27 congenital hypothyroidism was confirmed and substitutive treatment was begun. Since the persistence of respiratory symptoms sweat test, CFTR mutation, lymphocyte subpopulations, and sputum cultures were tested, resulting negative. Brain and cardiac defects were also ruled out. Bronchoscopy and BAL analysis were normal. Computed tomography showed bilateral multiple ground glass attenuation, consolidative areas and diffuse bronchial wall thickening. Based on the severity of symptoms, the exclusion of other causes of respiratory disease and the CT findings of interstitial lung disease, we investigated genes affecting the surfactant homeostasis. Sequencing analysis of the three exons of the TTF1 revealed a heterozygous mutation c.334G > T that results in the replacement of glycine in position 112 with a stop codon, generating a nonsense protein that lacks the correct transactivation domain in the C-terminal region. Genetic analysis of the family showed that the father, who was asymptomatic, carried the mutation. Screening for TTF-1 deletions or mutations should always be considered in children with congenital hypothyroidism and an unexplained neonatal respiratory distress or neurodevelopmental deficits.
authors.affiliation: Pneumology Unit, Department of Paediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Salerno
authors.forename: Donatella
authors.initials: D
authors.lastname: Peca
authors.forename: Laura
authors.initials: L
authors.lastname: Menchini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Schiavino
authors.forename: Francesca
authors.initials: F
authors.lastname: Petreschi
authors.forename: Francesca
authors.initials: F
authors.lastname: Occasi
authors.forename: Paola
authors.initials: P
authors.lastname: Cogo
authors.forename: Olivier
authors.initials: O
authors.lastname: Danhaive
authors.forename: Renato
authors.initials: R
authors.lastname: Cutrera
mesh_terms: D003409:Congenital Hypothyroidism / Q000150:complications / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008171:Lung Diseases / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012127:Respiratory Distress Syndrome, Newborn / Q000209:etiology / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000074482:Thyroid Nuclear Factor 1; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors
keywords: hypothyroidism; lung diseases; pulmonary surfactant; thyroid transcriptor factor 1