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Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene

IRIBHM and Genetics Service (E.M., S.C., J.P., C.C.-H., G.V.), Erasme Hospital, Free University of Brussels ULB, B-1070 Brussels, Belgium; Departments of Pediatrics (A.P., S.L., G.V.V., J.D.) and Pathology (L.L.O., J.-C.F., Y.R.), Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Canada H3T 1C5; and Kinderklinik (J.-M.V.), Spitalzentrum Oberwallis, CH-3930 Visp, Switzerland

Address all correspondence and requests for reprints to: Johnny Deladoëy, M.D., Ph.D., Centre Hospitalier Universitaire Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Canada QC, H3T 1C5. E-mail: johnny.deladoey{at}umontreal.ca.

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 T₄ 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 (I207F). 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.

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