title: Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.
abstract: The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1, we investigated the human NKX2-1 gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C2519A, C1302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the NKX2-1 gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with NKX2-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.
authors.affiliation: Department of Pediatric Endocrinology, Otto Heubner Center for Pediatrics, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Barbara
authors.initials: B
authors.lastname: Schütz
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnabel
authors.forename: Heidi
authors.initials: H
authors.lastname: Neitzel
authors.forename: Holger
authors.initials: H
authors.lastname: Tönnies
authors.forename: Dagmar
authors.initials: D
authors.lastname: Weise
authors.forename: Antony
authors.initials: A
authors.lastname: Lafferty
authors.forename: Siegfried
authors.initials: S
authors.lastname: Schwarz
authors.forename: Mario
authors.initials: M
authors.lastname: DeFelice
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Frank
authors.initials: F
authors.lastname: van Landeghem
authors.forename: Roberto
authors.initials: R
authors.lastname: DiLauro
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001479:Basal Ganglia / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D002675:Child, Preschool; D002819:Chorea / Q000209:etiology* / Q000235:genetics*; D003409:Congenital Hypothyroidism; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006801:Humans; D007037:Hypothyroidism / Q000209:etiology* / Q000235:genetics*; D007223:Infant; D008171:Lung Diseases / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics*; D013577:Syndrome; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
chemical_list: C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D004247:DNA