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Pulmonary arterial hypertension (PAH) is a disease characterized by pathological remodeling of the pulmonary vasculature causing elevated pulmonary artery pressures and ultimately, right ventricular failure from chronic pressure overload. Heterozygous pathogenic GDF2 (encoding bone morphogenetic protein 9 (BMP9)) variants account for some (>1%) adult PAH cases. Only three pediatric PAH cases, harboring homozygous or compound heterozygous variants, are reported to date. Ultra-rare pathogenic GDF2 variants are reported in hereditary hemorrhagic telangiectasia and overlapping disorders characterized by telangiectasias and arteriovenous malformations (AVMs). Here, we present two siblings with PAH homozygous for a GDF2 mutation that impairs BMP9 proprotein processing and reduces growth factor domain availability. We confirm an absence of measurable plasma BMP9 whereas BMP10 levels are detectable and serum-dependent endothelial BMP activity is evident. This contrasts with the absence of activity which we reported in two children with homozygous pathogenic GDF2 nonsense variants, one with PAH and one with pulmonary AVMs, both with telangiectasias, suggesting loss of BMP10 and endothelial BMP activity in the latter may precipitate telangiectasia development. An absence of phenotype in related heterozygous GDF2 variant carriers suggests incomplete penetrance in PAH and AVM-related diseases, indicating that additional somatic and/or genetic modifiers may be necessary for disease precipitation.

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It may be feasible for some patients using simplified meal-planning approaches and short-acting insulin regimens to use an insulin pump instead of 2 daily injections of 70/30 insulin. Although this approach may not be possible for everyone, the methods discussed in this article open the door for some individuals whose main stumbling blocks are calculating insulin dosing and grams of CHO. In our practice, we have seen repeatedly that simplified approaches for counting CHO intake and calculating insulin dose can work successfully even with intensive insulin management. It is our challenge as diabetes health professionals to continually search for creative ways to help our patients simplify their daily diabetes management tasks. In many cases, the patient is more likely to commit to healthful changes when the meal plan is simpler and more visual. It is not possible, however, to make patients proficient in CHO counting and insulin dosing in one visit. Referral to a registered dietitian who specializes in diabetes allows a tailored plan to be developed with each individual based on health parameters, treatment goals, lifestyle, and cognitive skills.