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Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency
Heiko Krude, … , Roberto DiLauro, Annette Grüters
Heiko Krude, … , Roberto DiLauro, Annette Grüters
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):475-480. https://doi.org/10.1172/JCI14341.
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Article Genetics

Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency

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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

Heiko Krude, Barbara Schütz, Heike Biebermann, Arpad von Moers, Dirk Schnabel, Heidi Neitzel, Holger Tönnies, Dagmar Weise, Antony Lafferty, Siegfried Schwarz, Mario DeFelice, Andreas von Deimling, Frank van Landeghem, Roberto DiLauro, Annette Grüters

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Figure 3

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Morphological brain alterations of patients with NKX2-1 mutations. (a) I...
Morphological brain alterations of patients with NKX2-1 mutations. (a) Inversion recovery view of MRI sequence of supratentorial structures in a normal age-matched proband. White matter maturation is complete; basal ganglia appear hypointense in comparison. Medial and lateral parts of the pallidum are clearly distinguishable. c, caudate; p, putamen; lp, lateral part; mp, medial part. (b) MRI of patient 2 demonstrates abnormal basal ganglia. At a comparable level of MRI section a hypoplastic pallidum with a lack of differentiation into medial and lateral part can be seen (arrow). Structure and signal intensity of putamen and caudate nucleus are normal. Brain maturation is unaltered, and there is no malformation of cerebral cortical structure. (c) MRI of the pituitary-diencephalic region of patient 1 (T1-image) showing a cystic mass in the posterior part of the sella turcica (arrow). (d) MRI of this region of patient 2 (T2-image) showing an identical mass at the same position (arrow). Isodense appearance in respect to ventricular structures clearly demonstrates its cystic character.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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