Diffuse Vascular Calcification Presenting as Refractory Pulmonary Hypertension in a Neonate: A Diagnostic Unravelling

Background: Persistent pulmonary hypertension of the newborn (PPHN) is a recognized cause of neonatal hypoxemic respiratory failure, most commonly associated with parenchymal lung disease or maladaptation of pulmonary circulation. Rarely, severe and refractory pulmonary hypertension may signal an underlying systemic vasculopathy. Generalized arterial calcification of infancy (GACI) is a rare genetic disorder characterized by diffuse arterial wall calcification and intimal proliferation, frequently resulting from ENPP1 mutations. Early manifestations may mimic common neonatal cardiopulmonary conditions, leading to diagnostic delay.

Case Presentation: We report a late preterm neonate (34+5 weeks) presenting at birth with severe respiratory failure and persistent hypoxemia requiring mechanical ventilation. Initial evaluation suggested respiratory distress syndrome with severe pulmonary hypertension. Despite optimized ventilatory support, surfactant therapy, pulmonary vasodilators, and inotropic support, pulmonary hypertension remained refractory. The emergence of systemic hypertension, depressed biventricular function, and differential oxygen saturations prompted further evaluation. Serial imaging revealed progressive arterial wall echogenicity on echocardiography and abdominal ultrasonography. Plain chest radiography demonstrated linear, tubular radio-opaque densities tracking along major vascular pathways, mimicking intravascular lines. Contrast-enhanced CT angiography confirmed extensive circumferential calcification involving the thoracic and abdominal aorta, pulmonary arteries, and major systemic branches with preserved luminal patency. Genetic testing identified a pathogenic ENPP1 mutation, establishing the diagnosis of generalized arterial calcification of infancy. The patient was managed with intensive cardiopulmonary support, antihypertensive therapy, and bisphosphonate treatment.

Conclusion: This case highlights generalized arterial calcification of infancy as an important differential diagnosis in neonates with refractory pulmonary hypertension, particularly when accompanied by early systemic hypertension and atypical vascular imaging findings. Careful review of plain radiographs and progressive arterial wall echogenicity on ultrasound may provide early diagnostic clues. Prompt recognition and genetic confirmation are essential for targeted management, prognostication, and family counseling in this rare but potentially fatal neonatal vasculopathy.