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.

Diseases of Pulmonary Surfactant Homeostasis

“…Haploinsufficient mutations in NKX2-1 are associated with pulmonary disease in infants and with variable inhibitory effects on the expression of target genes (e.g., the surfactant proteins) (13, 92, 93). The clinical presentation of NKX2-1 -related pulmonary disease is also variable, ranging from neonatal RDS with and without pulmonary hypertension to ILD in older children and pulmonary fibrosis in adults (13, 14, 92–96). Recurrent respiratory infections are frequently encountered (14).…”

Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum

“…Since then, 20 case reports and 7 series of patients with a total of 161 patients and 77 mutations have been reported (see online supplementary table 1), 6–33 but altogether they have failed to reveal a correlation between type, size and position of mutations and a specific phenotype. The only exceptions were reports on oligodontia in individuals harbouring chromosomal deletions simultaneously encompassing NKX2-1 and PAX9 , reflecting the role of PAX9 in odontogenesis.…”

Extrathyroidal congenital defects in children with congenital hypothyroidism – observations from a single paediatric centre in Central Europe with a review of literature

“…It is responsible for the differentiation of type 2 cells of the epithelium of pulmonary alveoli, expression of the genes for the surfactant protein (SP-A, SP-B, SP-C), and the gene ABCA3 (ABC transporter A3) involved in the transport of surfactant phospholipids and its appropriate composition. Additionally, it is important in the normal morphogenesis and functioning of the nervous system [4,5,[14][15][16][17]. Abnormalities in the region of the NKX2-1 gene may be the cause of the syndrome called "brain-lung-thyroid syndrome".…”