Diminished TMEM 100 Expression in a Newborn With Acinar Dysplasia and a Novel TBX4 Variant: A Case Report

Abstract

Acinar dysplasia (AcDys) of the lung is a rare lethal developmental disorder in neonates characterized by severe respiratory failure and pulmonary arterial hypertension refractory to treatment. Recently, abnormalities of TBX4-FGF10-FGFR2-TMEM100 signaling regulating lung development have been reported in patients with AcDys due to heterozygous single-nucleotide variants or copy-number variant deletions involving TBX4, FGF10, or FGFR2. Here, we describe a female neonate who died at 4 hours of life due to severe respiratory distress related to AcDys diagnosed by postmortem histopathologic evaluation. Genomic analyses revealed a novel deleterious heterozygous missense variant c.728A>C (p.Asn243Thr) in TBX4 that arose de novo on paternal chromosome 17. We also identified 6 candidate hypomorphic rare variants in the TBX4 enhancer in trans to TBX4 coding variant. Gene expression analyses of proband's lung tissue showed a significant reduction of TMEM100 expression with near absence of TMEM100 within the endothelium of arteries and capillaries by immunohistochemistry. These results support the pathogenicity of the detected TBX4 variant and provide further evidence that disrupted signaling between TBX4 and TMEM100 may contribute to severe lung phenotypes in humans, including AcDys.

Keywords: T-box transcription factor; lethal lung developmental disorder; neonate; pathogenic single nucleotide variant; pulmonary arterial hypertension.

Figure 1.

Gross image of the evisceration at autopsy showing markedly small lungs.

Figure 2.

(A) Representative H&E-stained histology of the pulmonary pathology at 2X demonstrating arrested lung development resembling the pseudo-glandular stage. (B) Representative H&E-stained histology of the pulmonary pathology at 20X demonstrating lack of alveolar development.

Figure 3.

Markedly diminished immunohistochemical expression for TMEM100 in the vascular endothelium of the patient lung compared to TMEM100 expression within arteries (a) and capillaries (arrows) in normal fetal and term neonatal lung. Insert shows retained expression of CD31 within patient vessels.

Figure 4.

Decrease of TMEM100 transcript level in the proband with a missense c.728A>C (p.Asn243Thr) variant in TBX4 and diagnosis of AcDys.