期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 94, 期 1, 页码 197-203出版社
ENDOCRINE SOC
DOI: 10.1210/jc.2008-1402
关键词
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资金
- 2007 Hoffmann-La Roche/Canadian Pediatric Endocrinology Fellowship
- Canadian Child Health Clinician Scientist Program
- Belgian Fonds de la Recherche Scientifique Medicale
- Fonds ERASME and Action de Recherche Concertee de la Communaute Francaise de Belgique
- Fonds pour la Formation a la Recherche dans l'Industrie et dans l'Agriculture
- Belgian Fonds National de la Recherche Scientifique
Context: Thyroid transcription factor 1 (TITF1/NKX2.1) is expressed in the thyroid, lung, ventral forebrain, and pituitary. In the lung, TITF1/NKX2.1 activates the expression of genes critical for lung development and function. Titf/Nkx2.1(-/-) mice have pituitary and thyroid aplasia but also impairment of pulmonary branching. Humans with heterozygous TITF1/NKX2.1 mutations present with various combinations of primary hypothyroidism, respiratory distress, and neurological disorders. Objective: The objective of the study was to report clinical and molecular studies of the first patient with lethal neonatal respiratory distress from a novel heterozygous TITF1/NKX2.1 mutation. Participant: This girl, the first child of healthy nonconsanguineous French-Canadian parents, was born at 41 wk. Birth weight was 3460 g and Apgar scores were normal. Soon after birth, she developed acute respiratory failure with pulmonary hypertension. At neonatal screening on the second day of life, TSH was 31 mU/liter (N < 15) and total T-4 245 nmol/liter (N = 120-350). Despite mechanical ventilation, thyroxine, surfactant, and pulmonary vasodilators, the patient died on the 40th day. Results: Histopathology revealed pulmonary tissue with low alveolar counts. The thyroid was normal. Sequencing of the patient's lymphocyte DNA revealed a novel heterozygous TITF1/NKX2.1 mutation (1207F). This mutation was not found in either parent. In vitro, the mutant TITF-1 had reduced DNA binding and transactivation capacity. Conclusion: This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis. (J Clin Endocrinol Metab 94: 197-203, 2009)
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