Tehran University of Medical Sciences Case Reports in Clinical Practice 2538-2683 10 6 2026 06 03 265 269 Mohammad Pourmirzaiee Pediatric Ward, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. AND Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran. 2026 02 20 2026 04 26 Respiratory complications are the leading cause of mortality in Down syndrome, yet “Down syndrome-associated lung disease” (DSLD) remains frequently underrecognized. DSLD represents a distinct phenotype characterized by the convergence of alveolar simplification, vascular dysgenesis, and immune dysregulation. I present a 2.5-year-old boy from those who visit the clinic with trisomy 21 and congenital hypothyroidism who presented with failure to thrive, progressive tachypnea, and signs of right heart failure. Physical examination revealed diffuse fine crackles and a loud P2. Echocardiography confirmed severe, suprasystemic pulmonary arterial hypertension (PAH) disproportionate to his minor cardiac septal defects. Highresolution computed tomography (HRCT) demonstrated the hallmark findings of DSLD: diffuse subpleural cysts and interlobular septal thickening. Polysomnography confirmed concurrent moderate obstructive sleep apnea. This case illustrates the aggressive nature of DSLD, where structural alveolar hypoplasia (subpleural cysts) correlates with intrinsic vascular fragility and severe PAH. The patient’s stabilization required a multimodal strategy targeting three pathogenic axes: hemodynamic offloading (sildenafil), airway obstruction (CPAP/surgery), and parenchymal inflammation (corticosteroids). Clinicians must recognize subpleural cysts as a “red flag” for this complex pan-pulmonary disorder to initiate early, targeted intervention. https://crcp.tums.ac.ir/index.php/crcp/article/view/1173 https://crcp.tums.ac.ir/index.php/crcp/article/download/1173/760