Long-Term Effect of TBX4 Germline Mutation on Pulmonary Clinico-Histopathologic Phenotype

Tbx4 protein, expressed in mesenchyme of the developing lung, contributes to airway branching and distal lung growth. An association between pediatric onset of pulmonary arterial hypertension (PAH) and genetic variations coding for the T-box transcription factor 4 gene (TBX4) has been increasingly recognized. Tbx4-related PAH onset has a bimodal age distribution, including severe to lethal PAH in newborns and later onset PAH. We present an autopsy study of a 24-year-old male with a heterozygous TBX4 variant, who developed pulmonary arterial hypertension at age 12 years. This unique case highlights the complex pulmonary histopathology leading to lethal cardiopulmonary failure in the setting of TBX4 mutation.