Pulmonary Arterial Hypertension Onset in an Adult Woman With a TBX4 Likely Pathogenic Variant Following Imatinib...

The TBX4 gene has a critical importance in the development of the lower limbs and lungs. Pathogenic variants in this gene are associated with a variable spectrum of skeletal anomalies of the lower limb and pneumological manifestations, with dominant or recessive inheritance. Heterozygous variants are associated with the "ischio-coxo-podo-patellar syndrome with or without pulmonary arterial hypertension (PAH)". This is an autosomal dominant syndrome characterized by aplasia or hypoplasia of the patellae, anomalies of the pelvis and feet and PAH. The typical onset of PAH in these patients is perinatally or during childhood. We here describe a patient with adult-onset presentation of TBX4-related PAH. The patient is a 64-year-old woman diagnosed with a gastrointestinal stromal tumor (GIST), for which she undertook treatment with Imatinib. After 2 years of treatment, she developed signs of pulmonary hypertension with a pre-capillary phenotype and received the diagnosis of drug-induced PAH. Despite interruption of Imatinib treatment, the patient did not show any improvement, prompting genetic evaluation and the identification of a loss-of-function variant in the TBX4 gene: c.810_819delinsCATCATGAGGT, p.(Ser271Ilefs*116). Further clinical and radiological investigations detected a mild skeletal dysplasia, confirming the diagnosis of ischio-coxo-podo-patellar syndrome. We speculate that Imatinib treatment caused the onset of PAH in a patient with genetic predisposition but no previous pneumological manifestations. This would be in line with the hypothesis of additional factors being involved in the determination of TBX4-associated phenotypes.