Case Study
Non-BMPR2 mutation heritable pulmonary arterial hypertension in Southeast Asia
Asian Cardiovascular & Thoracic Annals 2015, Vol. 23(4) 481–483 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314541133 aan.sagepub.com
Burabha Pussadhamma1, Songsak Kiatchoosakun1, Suda Vannaprasaht2 and Chiara Barozzi3
Abstract A 29-year-old Thai man presented with progressive dyspnea and evidence of pulmonary hypertension. Computed tomography was negative for pulmonary embolism. Cardiac catheterization confirmed the diagnosis of pulmonary arterial hypertension (mean pulmonary artery pressure 54 mm Hg, left ventricular end-diastolic pressure 4 mm Hg, and pulmonary vascular resistance 25 Wood units) without an intracardiac shunt. Two family members had been previously diagnosed with pulmonary hypertension. There was no evidence of left heart disease or respiratory disorders. Based on the definite diagnosis of pulmonary hypertension in 3 family members, heritable pulmonary arterial hypertension was confirmed. Genetic testing indicated no BMPR2 mutation.
Keywords Asia, southeastern, genetic predisposition to disease, hypertension, pulmonary
Introduction Heritable pulmonary arterial hypertension (HPAH) is rare. It was first described in 1954 by Dresdale and colleagues.1 HPAH is suspected or documented in approximately 6% to 10% of patients with pulmonary arterial hypertension (PAH).2 The main hereditary predisposition to HPAH is represented by BMPR2 mutation (75%), while mutation of other genes (ACVRL1, BMPR1B, CAV1, ENG, SMAD9) are considerably less common (1%).3 Hence, in approximately 25% of families with familial PAH, the responsible mutation has not yet been discovered. To the best of our knowledge, this is the first reported case of non-BMPR2 mutation HPAH in Southeast Asia.
Case report A 29-year-old Thai man presented with dyspnea for 8 months, in New York Heart Association functional class III with orthopnea. Initial examination revealed neck vein engorgement, right ventricular heaving, and prominent P2 sound. Neither a cardiac murmur nor leg swelling was noted. His oxygen saturation was 88% on
room air, but his lungs were clear. A chest radiograph showed mild cardiomegaly and pulmonary artery dilatation. Electrocardiography revealed right ventricular hypertrophy and right ventricular pressure overload. Two-dimensional transthoracic echocardiography showed dilatation of the right atrium, right ventricle, and pulmonary artery, with moderate tricuspid regurgitation and a right ventricular systolic pressure of 68 mm Hg. Computed tomography of the chest demonstrated no evidence of pulmonary embolism. Cardiac catheterization indicated a diagnosis of PAH, with mean pulmonary artery pressure of 54 mm Hg, 1 Division of Cardiology, Queen Sirikit Heart Center of the Northeast, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 2 Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 3 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
Corresponding author: Burabha Pussadhamma, Division of Cardiology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 40002. Email: [email protected]
Downloaded from aan.sagepub.com at Stockholm University Library on November 17, 2015
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Figure 1. Three-generation family pedigree. The father and the 3rd sibling were definitely diagnosed with pulmonary arterial hypertension before death. The 4th sibling developed peripartum sudden death; pulmonary arterial hypertension was suspected. The other family members, apart from the affected patient, currently have no pulmonary hypertension.
normal left ventricular end-diastolic pressure (4 mm Hg), increased pulmonary vascular resistance (25 Wood units), and decreased cardiac output (2 L min 1) and cardiac index (1.05 L min 1 m 2), without evidence of an intracardiac shunt. Further investigations for associated conditions, left heart disease, and respiratory disorders were all negative. A review of the patient’s family history disclosed a catheterizationderived diagnosis of PAH in his father and younger sister. The former developed sudden death at the age of 61 years and the later suffered a peripartum death on giving birth to her first child at the age of 27 years. There was also a peripartum sudden death at the age of 24 years in another sister (Figure 1). Genetic testing indicated absence of a BMPR2 mutation. According to the diagnostic criteria (2 or more family members with PAH or no family history but found to have genetic mutations associated with PAH),3 the patient was diagnosed as having HPAH.
Discussion HPAH can be clinically classified into 2 categories: with or without a family history of PAH.4 Among the group with HPAH and a known family history, approximately 20% have undetectable mutations in currently known PAH-causing genes.5 Due to the absence of BMPR2 mutation in our patient’s family and the fact that tests for other mutations are not possible, the PAH-causing mutation in this family might be a new or less common mutation. The pattern of presentation at a younger age than in the previous generation is strongly demonstrated in this family: the father, who is suspected to be the first affected individual, developed PAH at the age of 61 years, whereas at least 2 of his offspring developed PAH during their third decade. A pattern of younger age and more severe clinical and hemodynamic characteristics at diagnosis among BMPR2 mutation carriers had been previously reported.6 A progressively younger age at PAH diagnosis among ACVRL1 mutation carriers was also found.7 The observations in this family of
younger age at onset and a severe hemodynamic phenotype can be found in HPAH other than BMPR2 mutation; this characteristic might be a universal suggestion of HPAH diagnosis. Nevertheless, clinical and hemodynamic information on other mutations is still lacking, hence gathering data from both groups of HPAH (mutation known and unknown) is warranted to confirm this clinical and hemodynamic presentation pattern. Although the consensus guideline recommends offering genetic testing to patients with a history that suggests HPAH,8 the therapeutic strategy for HPAH is exactly the same as for idiopathic PAH, and the appropriate management of unaffected family members is still unknown. Clinical and transthoracic echocardiography screening of the 2 unaffected siblings did not revealed any evidence of PAH, which may suggest that they are unaffected by any mutation, or they might have a mutation other than BMPR2 gene but have a still silent disease and might be permanently unaffected. Because there is no predictive parameter to guide the disease occurrence, annual transthoracic echocardiography is warranted for the other siblings. The optimal age for PAH screening in the patient’s daughter is not know, but due to the strong penetration and dismal prognosis among the affected members, longitudinal follow-up of the unaffected siblings and members of later generations is certainly necessary. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement None declared.
References 1. Dresdale DT, Michtom RJ and Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 1954; 30: 195–207.
Downloaded from aan.sagepub.com at Stockholm University Library on November 17, 2015
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2. McLaughlin VV and McGoon MD. Pulmonary arterial hypertension. Circulation 2006; 114: 1417–1431. 3. Loyd JE, Phillips JA. Heritable pulmonary arterial hypertension. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews. Seattle: University of Washington, 2002:1993–2014. 4. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D13–D21. 5. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D34–D41. 6. Sztrymf B, Coulet F, Girerd B, et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008; 177: 1377–1383.
7. Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181: 851–861. 8. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119: 2250–2294.
Downloaded from aan.sagepub.com at Stockholm University Library on November 17, 2015
Non-BMPR2 mutation heritable pulmonary arterial hypertension in Southeast Asia
Asian Cardiovascular & Thoracic Annals 2015, Vol. 23(4) 481–483 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314541133 aan.sagepub.com
Burabha Pussadhamma1, Songsak Kiatchoosakun1, Suda Vannaprasaht2 and Chiara Barozzi3
Abstract A 29-year-old Thai man presented with progressive dyspnea and evidence of pulmonary hypertension. Computed tomography was negative for pulmonary embolism. Cardiac catheterization confirmed the diagnosis of pulmonary arterial hypertension (mean pulmonary artery pressure 54 mm Hg, left ventricular end-diastolic pressure 4 mm Hg, and pulmonary vascular resistance 25 Wood units) without an intracardiac shunt. Two family members had been previously diagnosed with pulmonary hypertension. There was no evidence of left heart disease or respiratory disorders. Based on the definite diagnosis of pulmonary hypertension in 3 family members, heritable pulmonary arterial hypertension was confirmed. Genetic testing indicated no BMPR2 mutation.
Keywords Asia, southeastern, genetic predisposition to disease, hypertension, pulmonary
Introduction Heritable pulmonary arterial hypertension (HPAH) is rare. It was first described in 1954 by Dresdale and colleagues.1 HPAH is suspected or documented in approximately 6% to 10% of patients with pulmonary arterial hypertension (PAH).2 The main hereditary predisposition to HPAH is represented by BMPR2 mutation (75%), while mutation of other genes (ACVRL1, BMPR1B, CAV1, ENG, SMAD9) are considerably less common (1%).3 Hence, in approximately 25% of families with familial PAH, the responsible mutation has not yet been discovered. To the best of our knowledge, this is the first reported case of non-BMPR2 mutation HPAH in Southeast Asia.
Case report A 29-year-old Thai man presented with dyspnea for 8 months, in New York Heart Association functional class III with orthopnea. Initial examination revealed neck vein engorgement, right ventricular heaving, and prominent P2 sound. Neither a cardiac murmur nor leg swelling was noted. His oxygen saturation was 88% on
room air, but his lungs were clear. A chest radiograph showed mild cardiomegaly and pulmonary artery dilatation. Electrocardiography revealed right ventricular hypertrophy and right ventricular pressure overload. Two-dimensional transthoracic echocardiography showed dilatation of the right atrium, right ventricle, and pulmonary artery, with moderate tricuspid regurgitation and a right ventricular systolic pressure of 68 mm Hg. Computed tomography of the chest demonstrated no evidence of pulmonary embolism. Cardiac catheterization indicated a diagnosis of PAH, with mean pulmonary artery pressure of 54 mm Hg, 1 Division of Cardiology, Queen Sirikit Heart Center of the Northeast, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 2 Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 3 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
Corresponding author: Burabha Pussadhamma, Division of Cardiology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 40002. Email: [email protected]
Downloaded from aan.sagepub.com at Stockholm University Library on November 17, 2015
482
Asian Cardiovascular & Thoracic Annals 23(4)
Figure 1. Three-generation family pedigree. The father and the 3rd sibling were definitely diagnosed with pulmonary arterial hypertension before death. The 4th sibling developed peripartum sudden death; pulmonary arterial hypertension was suspected. The other family members, apart from the affected patient, currently have no pulmonary hypertension.
normal left ventricular end-diastolic pressure (4 mm Hg), increased pulmonary vascular resistance (25 Wood units), and decreased cardiac output (2 L min 1) and cardiac index (1.05 L min 1 m 2), without evidence of an intracardiac shunt. Further investigations for associated conditions, left heart disease, and respiratory disorders were all negative. A review of the patient’s family history disclosed a catheterizationderived diagnosis of PAH in his father and younger sister. The former developed sudden death at the age of 61 years and the later suffered a peripartum death on giving birth to her first child at the age of 27 years. There was also a peripartum sudden death at the age of 24 years in another sister (Figure 1). Genetic testing indicated absence of a BMPR2 mutation. According to the diagnostic criteria (2 or more family members with PAH or no family history but found to have genetic mutations associated with PAH),3 the patient was diagnosed as having HPAH.
Discussion HPAH can be clinically classified into 2 categories: with or without a family history of PAH.4 Among the group with HPAH and a known family history, approximately 20% have undetectable mutations in currently known PAH-causing genes.5 Due to the absence of BMPR2 mutation in our patient’s family and the fact that tests for other mutations are not possible, the PAH-causing mutation in this family might be a new or less common mutation. The pattern of presentation at a younger age than in the previous generation is strongly demonstrated in this family: the father, who is suspected to be the first affected individual, developed PAH at the age of 61 years, whereas at least 2 of his offspring developed PAH during their third decade. A pattern of younger age and more severe clinical and hemodynamic characteristics at diagnosis among BMPR2 mutation carriers had been previously reported.6 A progressively younger age at PAH diagnosis among ACVRL1 mutation carriers was also found.7 The observations in this family of
younger age at onset and a severe hemodynamic phenotype can be found in HPAH other than BMPR2 mutation; this characteristic might be a universal suggestion of HPAH diagnosis. Nevertheless, clinical and hemodynamic information on other mutations is still lacking, hence gathering data from both groups of HPAH (mutation known and unknown) is warranted to confirm this clinical and hemodynamic presentation pattern. Although the consensus guideline recommends offering genetic testing to patients with a history that suggests HPAH,8 the therapeutic strategy for HPAH is exactly the same as for idiopathic PAH, and the appropriate management of unaffected family members is still unknown. Clinical and transthoracic echocardiography screening of the 2 unaffected siblings did not revealed any evidence of PAH, which may suggest that they are unaffected by any mutation, or they might have a mutation other than BMPR2 gene but have a still silent disease and might be permanently unaffected. Because there is no predictive parameter to guide the disease occurrence, annual transthoracic echocardiography is warranted for the other siblings. The optimal age for PAH screening in the patient’s daughter is not know, but due to the strong penetration and dismal prognosis among the affected members, longitudinal follow-up of the unaffected siblings and members of later generations is certainly necessary. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement None declared.
References 1. Dresdale DT, Michtom RJ and Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 1954; 30: 195–207.
Downloaded from aan.sagepub.com at Stockholm University Library on November 17, 2015
Pussadhamma et al.
483
2. McLaughlin VV and McGoon MD. Pulmonary arterial hypertension. Circulation 2006; 114: 1417–1431. 3. Loyd JE, Phillips JA. Heritable pulmonary arterial hypertension. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews. Seattle: University of Washington, 2002:1993–2014. 4. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D13–D21. 5. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62(25 Suppl): D34–D41. 6. Sztrymf B, Coulet F, Girerd B, et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008; 177: 1377–1383.
7. Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181: 851–861. 8. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119: 2250–2294.
Downloaded from aan.sagepub.com at Stockholm University Library on November 17, 2015
