pulmonary arterial hypertension ( pah ) is a rare incapacitating disease with progressive functional limitation and deterioration to right heart failure and death . in addition to various disorders that can cause pah , a genetic predisposition to this disease was identified with the discovery of mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( bmpr2 ) , a member of the transforming growth factor- ( tgf- ) receptor , in both the familial and the sporadic cases of pah [ 13 ] . heritable pah ( hpah ) segregates as an autosomal - dominant disorder with variable age of onset , reduced penetrance , approximately a 2:1 female : male ratio , and genetic anticipation in some pedigrees [ 46 ] . approximately 6% of the individuals diagnosed with pah have a family history of this disorder . bmpr2 mutations are heterogeneous , with missense , nonsense , frameshift , splice site , and both small and large gene deletions and duplications found throughout the gene [ 7 , 8 ] . disease - causing mutations have been identified in approximately 70% of hpah and 526% of idiopathic pah ( ipah ) patients [ 811 ] . we present a novel bmpr2 mutation - associated case of pah first diagnosed at 83  years of age . to the best of our knowledge an 83-year - old world war ii veteran presented for evaluation of fatigue and breathlessness with exertion at new york heart association iii functional class with findings of elevated right - sided pressures on echocardiogram . he gave a history of progressive dyspnea with physical activity for 4  years and pedal edema for 6  months which was symmetrical and worse during the evenings . his past medical history included mild hypertension , nocturnal hypoxemia requiring oxygen therapy , gout , and degenerative arthritis of his right knee from shrapnel injury during world war ii . he had an episode of syncope approximately 1  year prior to evaluation that was attributed to dehydration and heat exhaustion . echocardiogram done at that time had shown preserved left ventricular ejection fraction at 70% , enlarged right - sided chambers , and estimated right ventricular systolic pressures of 80  mmhg . he had no history of thromboembolic disease , chronic lung disease , or prior transfusions . he recalled his mother ( nonsmoker ) was diagnosed with pulmonary hypertension ( ph ) and emphysema and had died at age 65 . his brother and a maternal first cousin had died with a diagnosis of ph at age 49 and 71 , respectively . the patient remembered that ph was identified on echocardiograms in his affected relatives but did not recollect details of other diagnostic workup . one of his brothers died of cirrhosis while his youngest brother was alive and had a history of coronary artery disease . his blood pressure was 92/61  mmhg , heart rate was 105/min , respiratory rate was 1820/min , oxygen saturation was 92% on room air , and body mass index was 26.6  kg / m . abnormal findings on examination included accentuated pulmonic component of second heart sound , 3/6 pansystolic murmur at the left lower sternal border , and bilateral pitting pedal edema . abnormal laboratory parameters included a brain natriuretic peptide of 335  pg / ml , serum creatinine of 1.4  mg / dl , and hemoglobin of 18  g / dl . chest x - ray showed cardiomegaly , prominent pulmonary vasculature , and normal lung fields . electrocardiogram showed right axis deviation , right ventricular hypertrophy , and inverted t waves in v1-v4 . echocardiogram was repeated and showed marked dilatation of right atrium and ventricle , impaired systolic right ventricular function , moderate to severe tricuspid regurgitation , and estimated peak pulmonary artery pressures of 100  mmhg with left ventricular ejection fraction of 55% without segmental wall motion abnormalities or pericardial effusion . a 6-min walk test was severely impaired with a total distance of 67.06  m or 30.9% of the predicted lower limit of normal calculated to be 216.8  m for his age and body mass index using the enright and sherrill formula . collagen vascular workup and hepatitis screen were negative , and hiv testing was not done as he denied risk factors . right heart catheterization confirmed pulmonary arterial hypertension with pulmonary artery pressures of 102/44  mmhg ( mean  =  63  mmhg ) , mean pulmonary artery occlusive pressure of 9  mmhg , mean right atrial pressure of 19  mmhg , mixed venous saturation of 61.5% , thermodilution cardiac output of 2.72  l / min , and cardiac index and pulmonary vascular resistance calculated at 1.48  l / min / m and 1588  dyn  s / cm , respectively . acute vasodilator study with inhaled nitric oxide did not show vasoreactivity . with a family history of relatives carrying a diagnosis of ph , genetic testing using previously described techniques , bmpr2 dna and rna mutation screening was performed upon peripheral lymphocytes and identified mutation c.241inst in exon 2 of the bmpr2 gene ( fig .  1 ) . this disease - causing mutation in codon 81 replaced lysine with a stop codon.fig . 1sequencing results demonstrating mutation c.241inst in dna and mrna sequencing results demonstrating mutation c.241inst in dna and mrna amlodipine was stopped and he was started on digoxin , warfarin , and bosentan , which was titrated to a target dose of 125  mg two times a day . at the time of his last office visit and after a year of bosentan therapy , he reported better tolerance for physical activity with improvement in functional class to nyha ii . his 6-min walk distance had improved to 146.3  m ( 67.5% of predicted lower limit of normal ) and was mainly limited by knee pain . follow - up right heart catheterization showed a right atrial mean pressure of 3  mmhg , pulmonary artery pressure of 95/20  mmhg ( mean  =  45  mmhg ) , pulmonary capillary wedge pressure of 6  mmhg , cardiac output of 2.9  l / min , and calculated cardiac index and pulmonary vascular resistance of 1.6  l / min / m and 1075  dyn  s / cm , respectively . we describe the case of an 83-year - old man presenting with pulmonary arterial hypertension due to a previously unreported bmpr2 mutation c.241inst . this dna single base insertion at codon 81 results in a frameshift with a stop codon at this site causing premature truncation of the bmpr2 protein . this mutation creates messenger ribonucleic acid ( mrna ) that would be identified and subjected to nonsense - mediated decay ( nmd ) . interestingly , a low level of aberrant mrna was detected in the lymphocytes from this patient ( fig .  1 ) . recently , sztrymf et al .   reported that pah carriers of bmpr2 mutations presented 10  years earlier than ipah patients ( 36.5    14.5 vs. 46.0    16.1 ) . carriers of bmpr2-truncating mutations ( nmd positive ) have a later age of diagnosis and death than carriers of a bmpr2 missense mutation ( nmd negative ) . this recent study of nmd - associated bmpr2 mutations provides additional evidence of the protective function of nmd in heterozygote carriers of dominant disorders . since only 1020% of individuals with a bmpr2 mutation develop pah , it is suggested that both environmental factors and modifier genes explain the reduced penetrance of hpah [ 1721 ] . single nucleotide polymorphisms in the tgf1 gene and variations in genes associated with proliferation , gtp signaling , stress response , and estrogen metabolism have been proposed to modulate the age of diagnosis and penetrance in these families [ 18 , 19 ] . recently , expression of wild - type allele bmpr2 transcripts has been reported as being important in determining penetrance of hpah . thus , the late age of onset in our patient can be likely explained by a nmd - positive bmpr2 mutation and the presence of modifier genes and/or unknown environmental factors which conveyed protection from pah at an earlier age . it is interesting that the mutant bmpr2 mrna was detected at a low level in the lymphocytes of the patient and apparently escaped complete nmd in this tissue . the status of the mutant bmpr2 mrna in the lung of the patient is unknown . however , if the mutant bmpr2 mrna also escaped complete degradation by nmd in the lung tissue of our patient , it is then presumed that the severely truncated mutant protein was unable to interfere effectively with the function of the wild - type bmpr2 protein in a dominant - negative manner . thus , one would predict that this patient probably developed pah through haploinsufficiency of the bmpr2 protein . clinical testing for bmpr2 mutations is appropriate care for the management of patients with a family history of pah regardless of the age at presentation as detection of family - specific mutations can be used to counsel family members at risk for developing pah . identification and analysis of different mutations will help understand the disease at a genetic level and explore treatment options that can be offered to patients and their families with hpah . prior to proceeding with presymptomatic genetic testing , counseling to discuss the complexity of this disease and the reduced risk for developing the disease in the presence of the mutation is required .