Beyond Heritable PAH: Pulmonary Hypertension in Genetic Syndromes

Pulmonary hypertension (PH) may complicate a broad range of genetic syndromes beyond the established spectrum of heritable pulmonary arterial hypertension. Although these conditions are individually rare, together they represent an emerging field at the crossroads of developmental biology, vascular medicine, and precision genomics. In many cases, PH may be the presenting feature or may remain unrecognized because it occurs within complex multisystem disorders involving congenital heart disease, developmental lung abnormalities, parenchymal lung disease, vascular malformations, or extra-pulmonary manifestations. Recent advances in human genetics have expanded the spectrum of genes and syndromes associated with PH, including disorders involving altered lung and vascular development, dysregulated hypoxia signaling, smooth muscle dysfunction, chromosomal abnormalities, and syndromic vasculopathies. In this review, we summarize the main genetic syndromes associated with PH and discuss their underlying mechanisms, clinical phenotypes, diagnostic clues, and therapeutic implications. We paid particular attention to conditions that illustrate the marked heterogeneity of syndromic PH such as FLNA -related disorders, neurofibromatosis type 1, Noonan syndrome, Down syndrome, Alagille syndrome, Cantú syndrome, Chuvash polycythaemia, cobalamin C deficiency, multisystemic smooth muscle dysfunction syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, and Moya Moya syndrome.