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

• Published in: The journal of clinical endocrinology and metabolism Vol. 94; no. 1; pp. 197 - 203
• Main Authors: Maquet, Emilie, Costagliola, Sabine, Parma, Jasmine, Christophe-Hobertus, Christiane, Oligny, Luc L., Fournet, Jean-Christophe, Robitaille, Yves, Vuissoz, Jean-Marc, Payot, Antoine, Laberge, Sophie, Vassart, Gilbert, Van Vliet, Guy, Deladoëy, Johnny
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-01-2009
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Cercopithecus aethiops; COS Cells; DNA - metabolism; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Heterozygote; Humans; Hypothyroidism - genetics; Immunohistochemistry; Infant, Newborn; Medical sciences; Molecular Sequence Data; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Respiratory Insufficiency - genetics; Sequence Analysis, DNA; Thyroid Nuclear Factor 1; Thyroid. Thyroid axis (diseases); Transcription Factors - chemistry; Transcription Factors - genetics; Transcriptional Activation; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Human; Obesity; Nutrition; Respiratory disease; Mortality; Thyroid diseases; Nutrition disorder; Metabolic diseases; Hypothyroidism; Epidemiology; De novo; Heterozygosity; Gene; Respiratory failure; Primary; Female; Genetics; Mutation; Child; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2008-1402

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.
A heterozygous mutation for thyroid transcription factor 1 (TITF1/NKX2.1) accounts for elevated thyrotropin levels associated with unexplained lethal respiratory failure in a term neonate.