Original ArticleAutosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1☆
Section snippets
Case reports
We present a 3-generation family with 4 affected members, all having a previously unreported mutation of the NKX2-1 gene. Clinical characteristics and laboratory findings of the two children are summarized in the Table, and the family pedigree is shown in Figure 1. Both children were born at term and had neonatal respiratory distress requiring prolonged mechanical ventilation. Compensated hypothyroidism was discovered when an elevated thyroid-stimulating hormone (TSH) level and a normal T4
Amplification and Sequencing of DNA
After institutional review board approval was received, informed consent was obtained from the children's mother and from the other adult members of the family to perform DNA sequencing analysis of the NKX2-1 gene on individuals I-1, II-1, II-2, II-3, III-1, III-2, and III-3 (Fig 1). The NKX2-1 genes of both affected children (III2 and III3), one unaffected sibling (III1), the mother (II1), the mother's half-siblings (II2 and II3), and the maternal grandmother (I1) were amplified by polymerase
Results
The same mutation at the 3′ splice consensus of intron 2 was present in both affected children (III2 and III3), their mother (II1), and their maternal grandmother (I1), as is indicated on the gene map of Figure 2. Both the normal AG and the mutant GG sequences were found in all affected subjects. This finding was confirmed by sequencing in the opposite direction.
The mutated gene product would prevent splicing together of exons 2 and 3. A ribosome that proceeds into intron 2 would encounter an
Discussion
Mutations of NKX2-1 should be suspected in instances of compensated, congenital hypothyroidism, especially when associated with neonatal respiratory distress in a term newborn, persistent neurodevelopmental defects, or both. In separate studies, 85 patients with congenital hypothyroidism were randomly chosen from neonatal screening programs to be screened for the presence of mutated NKX2-1 (previously referred to as TTF-1).4., 5., 6. The NKX2-1 mutations were absent in all patients studied. The
Acknowledgements
We thank Drs Steven Dowshen and Angelo M. DiGeorge for editorial assistance, and Dr Grafton Reeves for his valuable suggestions.
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Supported in part by Research and Development Account of the Division of Endocrinology at the Alfred I. duPont Hospital for Children.