Abstract 8895: Clinical Outcomes of Mutation Carriers in Pulmonary Arterial Hypertension in Children

Background: In heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH), mutations have previously been described in genes for the bone morphogenetic protein receptor type 2 ( BMPR2 ) and the activin receptor-like kinase 1 ( ALK1 ). It is, however, not known, especially in childhood, how these mutations relate to the clinical characteristics. Methods: Sixty four childhood patients whose onset of IPAH/HPAH was under 16 years old were selected. Mutations were monitored by direct sequencing and multiplex ligation-dependent probe amplification in BMPR2, ALK1, endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, SMAD7, SMAD8 , BMPR1A and BMPR1B genes. One SMAD8 mutation carrier and 2 BMPR1B mutation carriers were excluded from the present analysis because of minority of cases. Functional characteristics, hemodynamic parameters, and clinical outcomes were compared among BMPR2 mutation group, ALK1 mutation group, and noncarrier group. Results: Among these 61 childhood IPAH/HPAH patients, 18 had BMPR2 mutation and 7 had ALK1 mutation. At the time of diagnosis, age, WHO functional class, mean pulmonary artery pressure, pulmonary resistance, serum brain natriuretic peptide level, and 6-minute walking distance were similar among 3 groups. Medications including bosentan and sildenafil were also similar among 3 groups. Among 61 patients, 5-year and 10-year survival were 77% and 74%, respectively. Despite targeted therapy, 5-year survival in the BMPR2 mutation group (55%) was lowest among these 3 groups. The 5-year survival in the ALK1 mutation group (64%) tended to be lower than that in the noncarrier group (91%). Intravenous epoprostenol therapy strongly ameliorated the WHO functional class in all groups. Especially in the ALK1 mutation group, pulmonary vasodilator therapies were not effective except for intravenous epoprostenol. Conclusions: Prognosis of IPAH/HPAH in children with BMPR2 and ALK1 mutation is poor. Aggressive treatment including intravenous epoprostenol may be warranted in those children.