Patient 1 is a 6-month-old boy who was born term with a birth weight of 3.3 kg via urgent C-section due to maternal bleeding. Prenatal course was otherwise unremarkable. Due to severe hypoxemic respiratory failure at birth, he was treated with intubation, high frequency ventilation, supplemental oxygen (FiO2 = 1.00), iNO, and surfactant administration. Echocardiogram showed right to left ductal shunt consistent with severe PH. Intravenous epoprostenol, sildenafil and milrinone were started in addition to iNO. He underwent cardiac catheterization at 1.5 months of age. Hemodynamic evaluation showed an indexed pulmonary vascular resistance (PVRi) of 15.5 WU*m2 (iNO, oxygen and sildenafil) which decreased to 10.2 WU*m2 with acute uptitration of epoprostenol. Chest CT scan was significant for enlarged pulmonary arteries, patent ductus arteriosus and nonspecific findings suggestive of interstitial lung disease including interlobular septal thickening and ground-glass opacity without pulmonary nodules. He subsequently underwent lung biopsy which demonstrated alveolar simplification with interstitial widening, muscularization of small and medium sized pulmonary arteries and interstitial cells suggestive of pulmonary interstitial glycogenosis but no evidence of alveolar capillary dysplasia. Whole exome sequencing showed a pathogenic 17q23 microdeletion, which encompasses the PH associated TBX4 gene. He was then transferred to our institution at ~2 months of age for further care. His PAH therapy was titrated to combination therapy with sildenafil, bosentan, intravenous treprostinil, and iNO. His treatment also included an intravenous steroid burst followed by daily inhaled steroids with a modest clinical response but persistent severe pulmonary hypertension by echocardiogram. Over the subsequent 2 months, he continued to manifest hemodynamic instability and post-ductal hypoxemia suggestive of suprasystemic PH. At 4 months of age sildenafil was discontinued due to the lack of a clear clinical response as well as parental concerns regarding the use of this drug. He also developed significant transaminitis prompting cessation of bosentan at 5.5 months of age. He subsequently underwent a second cardiac catheterization at 6 months of age to evaluate his response to ongoing therapy, which showed improvement from his previous catheterization but still severe disease, with a mean pulmonary arterial pressure (mPAP) of 38 mmHg [systemic mean arterial pressure (sMAP) of 49 mmHg], and PVRi of 5.91 WU*m2 (iNO + oxygen + treprostinil). His Qp:Qs improved with increasing doses of iNO and treprostinil (Figure 1A). Due to hypotension after the catheterization, his treprostinil dose was maintained at 50 ng/kg/min and iNO increased to 60 ppm delivered via noninvasive ventilation. He failed multiple attempts to wean his iNO dose below 60 ppm, as evidenced by right to left ductal shunting on echocardiogram and significant pre- and post-ductal saturation gradients during attempted weans. Because of inability to even slowly wean from this high dose of iNO, the decision was made to start riociguat as additional targeted PAH therapy. Riociguat was initiated at 0.05 mg once daily (0.006 mg/kg/dose), and slowly increased to 0.5 mg/dose thrice daily. He had hypotension without signs of inadequate perfusion after the third dose of riociguat but responded well to saline bolus. Apart from this event, the titration was well tolerated and his hypoxemic events became less frequent. Riociguat was gradually increased to 2 mg/dose TID with iNO weaned and eventually discontinued 7 weeks after riociguat initiation (Figure 1B). He had no other reported side effects from riociguat during the titration period. During riociguat uptitration, he was able to wean from noninvasive positive pressure ventilation to nasal cannula. Repeat echocardiogram off iNO showed improved ventricular septal flattening and a greater degree of left to right shunting across the PDA, suggesting improved pulmonary vascular resistance. He was discharged home on subcutaneous treprostinil 37 ng/kg/min, riociguat 2 mg TID, and supplemental oxygen. Repeat echocardiogram 2 months later showed continuous low velocity left to right flow in his patent ductus arteriosus, moderate septal flattening and preserved biventricular systolic function. With improved growth and activity level, and no parental report of intolerance to medications after 4 months on this combination therapy, riociguat was increased to 2.5 mg TID at 13 months of age (body weight 9.4 kg). At latest outpatient follow up, he was 21 months old, World Health Organization functional class II with persistent sub-systemic pulmonary hypertension by echocardiogram, and preserved growth.