Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene

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 (2009). Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. Journal of clinical endocrinology and metabolism, 94(1), pp. 197-203. Chevy Chase, Md.: Endocrine Society 10.1210/jc.2008-1402

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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 3,460 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 (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.

Item Type:

Journal Article (Further Contribution)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Vuissoz, Jean-Marc

ISSN:

0021-972X

Publisher:

Endocrine Society

Language:

English

Submitter:

Anette van Dorland

Date Deposited:

04 Oct 2013 15:12

Last Modified:

12 Oct 2023 15:40

Publisher DOI:

10.1210/jc.2008-1402

PubMed ID:

18957494

Web of Science ID:

000262260200031

BORIS DOI:

10.48350/31893

URI:

https://boris.unibe.ch/id/eprint/31893 (FactScience: 196666)

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