Language
English
Publication Date
1-1-2024
Journal
Pediatric and Developmental Pathology
DOI
10.1177/10935266231213464
PMID
38044468
PMCID
PMC11087193
PubMedCentral® Posted Date
5-1-2025
PubMedCentral® Full Text Version
Post-print
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 (SNVs) or copy-number variant (CNV) 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 six 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
Female, Humans, Infant, Newborn, Acinar Cells, Fatal Outcome, Lung, Membrane Proteins, Mutation, Missense, T-Box Domain Proteins, Lethal lung developmental disorder, pulmonary arterial hypertension, T-box transcription factor, pathogenic single nucleotide variant, neonate, Lethal lung developmental disorder, pulmonary arterial hypertension, T-box transcription factor, pathogenic single nucleotide variant, neonate
Published Open-Access
yes
Recommended Citation
Szafranski, Przemyslaw; Patrizi, Silvia; Gambin, Tomasz; et al., "Diminished TMEM100 Expression in a Newborn With Acinar Dysplasia and a Novel TBX4 Variant: A Case Report" (2024). Faculty, Staff and Students Publications. 6405.
https://digitalcommons.library.tmc.edu/baylor_docs/6405