Background: A premature arrest of fetal lung development can be responsible for different diffuse developmental lung diseases including the most early and severe form, acinar dysplasia (AcDys). Apart from rare mutations in TBX4, the molecular causes of acinar dysplasia are poorly known (deMello et Reid 2000). We herein report the case of AcDys related to a NK2 homeobox 1 (NKX2.1) likely pathogenic variation.

Methods: Molecular analyses were performed in a full-term neonate who developed a refractory respiratory failure with pulmonary hypertension (PHT) requiring veno-arterial extra-corporeal membrane oxygenation (ECMO) support. Her thoracic CT-scan showed dense diffuse ground glass opacities and dilated bronchioles. Based on the lung disease and the discovery of a peripheral hypothyoidism, NKX2.1 and the genes usually involved in congenital PHT were first targeted. In parallel, a lung biopsy was performed.

Results: The next generation sequencing panel of PHT genes remained negative whereas Sanger sequencing of NKX2.1 (NM_001079668) led to identify a likely pathogenic missense heterozygous variation, c.731A>G p.(Tyr244Cys). The histologic aspect of the lung was similar to what is observed during the pseudo-glandular phase of the fetal lung consistently with an AcDys.

Discussion and conclusion: We report for the first time a patient with AcDys related to a NKX2.1 variation. NKX2.1 is a transcription factor involved in fetal development and associated so far to interstitial lung diseases included ?brain lung thyroid syndrome?(Thust et al. 2022). This extension of NKX2.1 variations phenotypic spectrum to AcDys might pave the way for a better understanding of AcDys pathophysiology.